99 results on '"Timothy E. Corcoran"'
Search Results
2. Nasal epithelial cell culture fluorescence recovery after photobleaching predicts cystic fibrosis therapeutic response
- Author
-
Timothy E. Corcoran, Carol A. Bertrand, Michael M. Myerburg, Daniel J. Weiner, Sheila A. Frizzell, Anna Li, Brittani Agostini, Robert S. Parker, Monica E. Shapiro, Ashok Muthukrishnan, Nicholas D. Hages, Brian P. Mulhern, and Joseph M. Pilewski
- Subjects
Medicine - Abstract
Background Human nasal epithelial (HNE) cells can be sampled noninvasively and cultured to provide a model of the airway epithelium that reflects cystic fibrosis (CF) pathophysiology. We hypothesised that in vitro measures of HNE cell physiology would correlate directly with in vivo measures of lung physiology and therapeutic response, providing a framework for using HNE cells for therapeutic development and precision medicine. Methods We sampled nasal cells from participants with CF (CF group, n=26), healthy controls (HC group, n=14) and single CF transmembrane conductance regulator (CFTR) mutation carrier parents of the CF group (CR group, n=16). Participants underwent lung physiology and sweat chloride testing, and nuclear imaging-based measurement of mucociliary clearance (MCC) and small-molecule absorption (ABS). CF participants completed a second imaging day that included hypertonic saline (HS) inhalation to assess therapeutic response in terms of MCC. HNE measurements included Ussing chamber electrophysiology, small-molecule and liquid absorption rates, and particle diffusion rates through the HNE airway surface liquid (ASL) measured using fluorescence recovery after photobleaching (FRAP). Results Long FRAP diffusion times were associated with increased MCC response to HS in CF. This implies a strong relationship between inherent factors affecting ASL mucin concentration and therapeutic response to a hydrating therapy. MCC decreased with age in the CR group, which had a larger range of ages than the other two groups. Likely this indicates a general age-related effect that may be accentuated in this group. Measures of lung ABS correlated with sweat chloride in both the HC and CF groups, indicating that CFTR function drives this measure of paracellular small-molecule probe absorption. Conclusions Our results demonstrate the utility of HNE cultures for assessing therapeutic response for hydrating therapies. In vitro measurements of FRAP were particularly useful for predicting response and for characterising important properties of ASL mucus that were ultimately reflected in lung physiology.
- Published
- 2022
- Full Text
- View/download PDF
3. CFD Study of Dry Pulmonary Surfactant Aerosols Deposition in Upper 17 Generations of Human Respiratory Tract
- Author
-
Tevfik Gemci, Valery Ponyavin, Richard Collins, Timothy E. Corcoran, Suvash C. Saha, and Mohammad S. Islam
- Subjects
dry pulmonary surfactant aerosol ,particle deposition in airways ,polydisperse particles ,respiratory drug delivery ,human tracheobronchial airway model ,CFD ,Meteorology. Climatology ,QC851-999 - Abstract
The efficient generation of high concentrations of fine-particle, pure surfactant aerosols provides the possibility of new, rapid, and effective treatment modalities for Acute Respiratory Distress Syndrome (ARDS). SUPRAER-CATM is a patented technology by Kaer BiotherapeuticsTM, which is a new class of efficient aerosol drug generation and delivery system using Compressor Air (CA). SUPRAER-CA is capable of aerosolizing relatively viscous solutions or suspensions of proteins and surfactants and of delivering them as pure fine particle dry aerosols. In this Computational Fluid Dynamics (CFD) study, we select a number of sites within the upper 17 generations of the human respiratory tract for calculation of the deposition of dry pulmonary surfactant aerosol particles. We predict the percentage of inhaled dry pulmonary surfactant aerosol arriving from the respiratory bronchioles to the terminal alveolar sacs. The dry pulmonary surfactant aerosols, with a Mass Median Aerodynamic Diameter (MMAD) of 2.6 µm and standard deviation of 1.9 µm, are injected into the respiratory tract at a dry surfactant aerosol flow rate of 163 mg/min to be used in the CFD study at an air inhalation flow rate of 44 L/min. This CFD study in the upper 17th generation of a male adult lung has shown computationally that the penetration fraction (PF) is approximately 25% for the inhaled surfactant aerosols. In conclusion, an ARDS patient might receive approximately one gram of inspired dry surfactant aerosol during an administration period of one hour as a possible means of further inflating partly collapsed alveoli.
- Published
- 2022
- Full Text
- View/download PDF
4. Mucociliary Clearance Scans Show Infants Undergoing Congenital Cardiac Surgery Have Poor Airway Clearance Function
- Author
-
Phillip S. Adams, Timothy E. Corcoran, Jiuann-Huey Lin, Daniel J. Weiner, Joan Sanchez-de-Toledo, and Cecilia W. Lo
- Subjects
nuclear medicine ,congenital heart disease ,airway clearance ,Technetium 99 ,critical care ,pulmonary ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background: Infants undergoing congenital cardiac surgery with cardiopulmonary bypass are at high risk for respiratory complications. As impaired airway mucociliary clearance (MCC) can potentially contribute to pulmonary morbidity, our study objective was to measure airway clearance in infants undergoing congenital cardiac surgery and examine correlation with clinical covariables that may impair airway clearance function.Materials and Methods: Airway clearance in infants was measured over 30 min using inhaled nebulized Technetium 99m sulfur colloid administered either via a nasal cannula or the endotracheal tube in intubated infants. This was conducted bedside with a portable gamma camera. No difficulty was encountered in positioning the gamma camera over the patient, and neither the camera nor the MCC scan interfered with routine medical care or caused any adverse events. Patient and perioperative variables were examined relative to the MCC measurements.Results: We prospectively enrolled 57 infants undergoing congenital cardiac surgery and conducted a single MCC scan per patient. MCC data from 42 patients were analyzable, including five pre-operative, 15 (40.5%) in the immediate post-operative period (days 1–2), and 22 (59.5%) were later post-operative (≥3 days). Pre-operative MCC was inversely proportional to days requiring post-operative mechanical ventilation (p = 0.006) and non-invasive positive pressure ventilation (p = 0.017). MCC was higher at later post-operative days (p = 0.002) with immediate post-operative MCC being lower (3%; 0–13%) than either pre-operative (21%; 4–25%) (p = 0.091) or later post-operative MCC (18%; 0–29%) (p = 0.054). Among the infants with low post-operative MCC, significantly more were pre-mature [5/19 (26%) vs. 0/18 (0%); p = 0.046], were intubated [14/19 (75%) vs. only 7/18 (39%); p = 0.033] and were receiving higher FiO2 (40%, 27–47% vs. 26%, 21–37%; p = 0.015).Conclusions: This is the first study to show that infants undergoing congenital cardiac surgery have impaired MCC. MCC appeared lowest in the immediate post-operative period. Worse MCC was associated with pre-maturity, mechanical ventilation, or receiving higher FiO2. These findings suggest MCC scans should be further explored for informing clinical decision making to improve post-surgical respiratory outcomes. The possible therapeutic benefit of airway clearance maneuvers for infants with poor MCC function should also be investigated.
- Published
- 2021
- Full Text
- View/download PDF
5. Effect of a Surfactant Additive on Drug Transport and Distribution Uniformity After Aerosol Delivery to Ex Vivo Lungs
- Author
-
Robert D. Tilton, Lawrence Weber, Mauricio Rojas, Stephen Garoff, Darragh J. Johnston, Amy Z. Stetten, John Sembrat, Brian Mulhern, Timothy E. Corcoran, Madeline Sauleda, and Nicholas D. Hages
- Subjects
Pulmonary and Respiratory Medicine ,Drug ,media_common.quotation_subject ,Inhaled drug ,Pharmaceutical Science ,Dose distribution ,Excipients ,Surface-Active Agents ,Aerosol delivery ,Pulmonary surfactant ,Administration, Inhalation ,Humans ,Pharmacology (medical) ,Lung ,Research Articles ,media_common ,Drug transport ,Aerosols ,Chemistry ,Nebulizers and Vaporizers ,food and beverages ,Pulmonary Surfactants ,respiratory system ,Technetium Tc 99m Pentetate ,Distribution uniformity ,Ex vivo ,Biomedical engineering - Abstract
BACKGROUND: Inhaled drug delivery can be limited by heterogeneous dose distribution. An additive that would disperse drug over the internal surfaces of the lung after aerosol deposition could improve dosing uniformity and increase the treated area. Our previous studies demonstrated that surfactant additives can produce surface tension-driven (Marangoni) flows that effectively dispersed aerosol-delivered drugs over mucus surfaces. Here we sought to determine whether the addition of a surfactant would increase transport of an aerosol between lung regions and also improve dosing uniformity in human lungs. METHODS: We compared the deposition and postdeposition dispersion of surfactant (10 mg/mL dipalmitoylphosphatidylcholine; DPPC) and saline-based liquid aerosols, admixed with Technetium 99m (Tc99m) diethylenetriaminepentaacetic acid, using gamma scintigraphy. Deposition images were obtained ex vivo in eight pairs of ventilated human lungs. The trachea was intubated and the mainstem bronchi were alternately clamped so that saline was delivered to one lung and then DPPC to the other (sides alternated). The lungs were continually imaged for 15 minutes during delivery. We assessed transport of the deposited aerosol by quantifying the percentage of Tc99m in each of four lung quadrants over time. We quantified dose uniformity within each lung quadrant by measuring the coefficient of variation (CV = standard deviation of the pixel associated radioactive counts/mean of the counts within each quadrant). RESULTS: There was no change in the percentage of Tc99m in each quadrant over time, indicating no improvement in transport with the addition of the surfactant. The addition of surfactant was associated with a statistically significant decrease in CV in the lower inner lung quadrant at each of the three time points, indicating an improvement in dosing uniformity. CONCLUSION: These preliminary results indicate the possible utility of adding surfactant to aerosols to improve drug distribution uniformity to lower inner lung regions.
- Published
- 2022
6. Preclinical Studies of the Nebulized Delivery of Liposomal Amphotericin B
- Author
-
Sagar Kothari, Steven G. Kefalos, Nicholas D. Hages, Timothy E. Corcoran, and Shahid Husain
- Subjects
Pulmonary and Respiratory Medicine ,Aerosols ,Amphotericin B ,Nebulizers and Vaporizers ,Administration, Inhalation ,Pharmaceutical Science ,Humans ,Pharmacology (medical) - Published
- 2022
7. Pilot study of nuclear scintigraphy to assess cough clearance in DMD
- Author
-
Daniel J. Weiner, Hoda Abdel‐Hamid, and Timothy E. Corcoran
- Subjects
Muscular Dystrophy, Duchenne ,Pulmonary and Respiratory Medicine ,Cough ,Vital Capacity ,Pediatrics, Perinatology and Child Health ,Humans ,Peak Expiratory Flow Rate ,Pilot Projects ,Radionuclide Imaging - Published
- 2022
8. Carrier Gases and Their Effects on Aerosol Drug Delivery
- Author
-
Timothy E. Corcoran
- Subjects
Pulmonary and Respiratory Medicine ,medicine.drug_class ,Pharmaceutical Science ,Carbon dioxide removal ,Helium ,030226 pharmacology & pharmacy ,Heliox ,03 medical and health sciences ,0302 clinical medicine ,Bronchodilator ,Administration, Inhalation ,medicine ,Pharmacology (medical) ,Process engineering ,Aerosols ,business.industry ,respiratory system ,Breathing gas ,Bronchodilator Agents ,Aerosol ,Oxygen ,030228 respiratory system ,Breathing ,Environmental science ,Delivery system ,business ,Aerosol drug delivery - Abstract
Carrier gases provide the medium for delivery of inhaled aerosol therapies. The physical properties of these gases substantially affect both fluid and aerosol mechanics in the lung. Gas density affects both the pressure/flow relationship in the airways and the extent of turbulence within the flow. These physical properties also affect the operation of some components of respiratory and aerosol drug delivery equipment. The lower resistance associated with breathing low density gases has prompted many studies of therapeutic applications. This includes the respiration of helium-oxygen gas mixtures to improve oxygenation and carbon dioxide removal, and the use of these gases to improve the delivery of inhaled medications. Results of these studies have been mixed but meta-analyses indicate a benefit of helium-oxygen respiration for croup and bronchiolitis and for bronchodilator delivery in obstructive disease. Some of the variability demonstrated in these studies is likely associated with specific technical aspects of how the gases are delivered. The utility of alternate carrier gases for aerosol delivery would be facilitated by simultaneous assessment of both aerosol deposition and clinical effect during studies. Previous successful applications may offer a basis for improved delivery system designs that fully realize the effects that might be available with these gases.
- Published
- 2021
9. Aerosol and Droplet Risk of Common Otolaryngology Clinic Procedures
- Author
-
Lindsey K. Goyal, Eric W. Wang, Harish Dharmarajan, Edward S. Sim, Noel Jabbour, Monika E. Freiser, Rachel L. Whelan, Devi Sai Sri Kavya Boorgu, David H. Chi, Michael S. Weinstock, and Timothy E. Corcoran
- Subjects
medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Suction ,Risk Assessment ,Otolaryngology ,03 medical and health sciences ,0302 clinical medicine ,Outcome Assessment, Health Care ,Cadaver ,Disease Transmission, Infectious ,medicine ,Humans ,Medical physics ,030223 otorhinolaryngology ,Personal Protective Equipment ,Aerosols ,SARS-CoV-2 ,business.industry ,COVID-19 ,Endoscopy ,General Medicine ,Aerosol ,Otorhinolaryngology ,Research Design ,030220 oncology & carcinogenesis ,Risk Adjustment ,business - Abstract
Objectives: Define aerosol and droplet risks associated with routine otolaryngology clinic procedures during the COVID-19 era. Methods: Clinical procedures were simulated in cadaveric heads whose oral and nasal cavities were coated with fluorescent tracer (vitamin B2) and breathing was manually simulated through retrograde intubation. A cascade impactor placed adjacent to the nares collected generated particles with aerodynamic diameters ≤14.1 µm. The 3D printed models and syringes were used to simulate middle and external ear suctioning as well as open suctioning, respectively. Provider’s personal protective equipment (PPE) and procedural field contamination were also recorded for all trials using vitamin B2 fluorescent tracer. Results: The positive controls of nebulized vitamin B2 produced aerosol particles ≤3.30 µm and endonasal drilling of a 3D model generated particles ≤14.1 µm. As compared with positive controls, aerosols and small droplets with aerodynamic diameter ≤14.1 µm were not detected during rigid nasal endoscopy, flexible fiberoptic laryngoscopy, and rigid nasal suction of cadavers with simulated breathing. There was minimal to no field contamination in all 3 scenarios. Middle and external ear suctioning and open container suctioning did not result in any detectable droplet contamination. The clinic suction unit contained all fluorescent material without surrounding environmental contamination. Conclusion: While patients’ coughing and sneezing may create a baseline risk for providers, this study demonstrates that nasal endoscopy, flexible laryngoscopy, and suctioning inherently do not pose an additional risk in terms of aerosol and small droplet generation. An overarching generalization cannot be made about endoscopy or suctioning being an aerosol generating procedure. Level of Evidence: 3
- Published
- 2021
10. Effect of lumacaftor-ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis: Results from the PROSPECT MCC sub-study
- Author
-
John P. Clancy, Agathe Ceppe, Jihong Wu, Timothy E. Corcoran, Pradeep Bhambhvani, Peter J. Mogayzel, Beth L. Laube, Scott D. Sagel, Felix Ratjen, Joseph M. Pilewski, Steven M. Rowe, William D. Bennett, and Scott H. Donaldson
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Cystic Fibrosis ,Mucociliary clearance ,Sweat chloride ,Aminopyridines ,Cystic Fibrosis Transmembrane Conductance Regulator ,Lung Clearance Index ,Quinolones ,Aminophenols ,Cystic fibrosis ,Gastroenterology ,Article ,Ivacaftor ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Benzodioxoles ,Longitudinal Studies ,Prospective Studies ,Child ,Chloride Channel Agonists ,Lung ,business.industry ,Lumacaftor ,respiratory system ,Middle Aged ,medicine.disease ,respiratory tract diseases ,Drug Combinations ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,chemistry ,Mucociliary Clearance ,Pediatrics, Perinatology and Child Health ,Female ,business ,medicine.drug - Abstract
CFTR function is required for normal mucociliary clearance (MCC) and cough-assisted clearance (CC). Lumacaftor-ivacaftor is approved for use in people with cystic fibrosis (CF) carrying two copies of F508del-CFTR. In this observational study performed at four study sites, we characterized the effect of lumacaftor-ivacaftor on mucociliary and cough clearance and related this to other clinical and research endpoints after one month of treatment. Twenty-five adolescents and adults were enrolled. No effect on whole lung MCC was observed, but CC was significantly increased. Sweat chloride improved by 18 mEq/L in this group, indicating a modest restoration of CFTR activity, but no demonstrable change in FEV1 or lung clearance index was observed. We speculate that the modest effect of lumacaftor-ivacaftor on CFTR function was insufficient to yield an improvement in MCC.
- Published
- 2021
11. A physiologically-motivated compartment-based model of the effect of inhaled hypertonic saline on mucociliary clearance and liquid transport in cystic fibrosis.
- Author
-
Matthew R Markovetz, Timothy E Corcoran, Landon W Locke, Michael M Myerburg, Joseph M Pilewski, and Robert S Parker
- Subjects
Medicine ,Science - Abstract
Cystic Fibrosis (CF) lung disease is characterized by liquid hyperabsorption, airway surface dehydration, and impaired mucociliary clearance (MCC). Herein, we present a compartment-based mathematical model of the airway that extends the resolution of functional imaging data.Using functional imaging data to inform our model, we developed a system of mechanism-motivated ordinary differential equations to describe the mucociliary clearance and absorption of aerosolized radiolabeled particle and small molecules probes from human subjects with and without CF. We also utilized a novel imaging metric in vitro to gauge the fraction of airway epithelial cells that have functional ciliary activity.This model, and its incorporated kinetic rate parameters, captures the MCC and liquid dynamics of the hyperabsorptive state in CF airways and the mitigation of that state by hypertonic saline treatment.We postulate, based on the model structure and its ability to capture clinical patient data, that patients with CF have regions of airway with diminished MCC function that can be recruited with hypertonic saline treatment. In so doing, this model structure not only makes a case for durable osmotic agents used in lung-region specific treatments, but also may provide a possible clinical endpoint, the fraction of functional ciliated airway.
- Published
- 2014
- Full Text
- View/download PDF
12. Mucociliary Clearance Scans Show Infants Undergoing Congenital Cardiac Surgery Have Poor Airway Clearance Function
- Author
-
Joan Sanchez-de-Toledo, Daniel J. Weiner, Timothy E. Corcoran, Phillip S. Adams, Jiuann-Huey Lin, and Cecilia W. Lo
- Subjects
medicine.medical_specialty ,Mucociliary clearance ,pulmonary ,medicine.medical_treatment ,Cardiovascular Medicine ,030204 cardiovascular system & hematology ,airway clearance ,medicine.disease_cause ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,030225 pediatrics ,Cardiopulmonary bypass ,Medicine ,Diseases of the circulatory (Cardiovascular) system ,nuclear medicine ,Adverse effect ,Original Research ,Mechanical ventilation ,business.industry ,Technetium 99 ,food and beverages ,Perioperative ,congenital heart disease ,Cardiac surgery ,critical care ,Anesthesia ,RC666-701 ,Cardiology and Cardiovascular Medicine ,business ,Airway ,Nasal cannula - Abstract
Background: Infants undergoing congenital cardiac surgery with cardiopulmonary bypass are at high risk for respiratory complications. As impaired airway mucociliary clearance (MCC) can potentially contribute to pulmonary morbidity, our study objective was to measure airway clearance in infants undergoing congenital cardiac surgery and examine correlation with clinical covariables that may impair airway clearance function.Materials and Methods: Airway clearance in infants was measured over 30 min using inhaled nebulized Technetium 99m sulfur colloid administered either via a nasal cannula or the endotracheal tube in intubated infants. This was conducted bedside with a portable gamma camera. No difficulty was encountered in positioning the gamma camera over the patient, and neither the camera nor the MCC scan interfered with routine medical care or caused any adverse events. Patient and perioperative variables were examined relative to the MCC measurements.Results: We prospectively enrolled 57 infants undergoing congenital cardiac surgery and conducted a single MCC scan per patient. MCC data from 42 patients were analyzable, including five pre-operative, 15 (40.5%) in the immediate post-operative period (days 1–2), and 22 (59.5%) were later post-operative (≥3 days). Pre-operative MCC was inversely proportional to days requiring post-operative mechanical ventilation (p = 0.006) and non-invasive positive pressure ventilation (p = 0.017). MCC was higher at later post-operative days (p = 0.002) with immediate post-operative MCC being lower (3%; 0–13%) than either pre-operative (21%; 4–25%) (p = 0.091) or later post-operative MCC (18%; 0–29%) (p = 0.054). Among the infants with low post-operative MCC, significantly more were pre-mature [5/19 (26%) vs. 0/18 (0%); p = 0.046], were intubated [14/19 (75%) vs. only 7/18 (39%); p = 0.033] and were receiving higher FiO2 (40%, 27–47% vs. 26%, 21–37%; p = 0.015).Conclusions: This is the first study to show that infants undergoing congenital cardiac surgery have impaired MCC. MCC appeared lowest in the immediate post-operative period. Worse MCC was associated with pre-maturity, mechanical ventilation, or receiving higher FiO2. These findings suggest MCC scans should be further explored for informing clinical decision making to improve post-surgical respiratory outcomes. The possible therapeutic benefit of airway clearance maneuvers for infants with poor MCC function should also be investigated.
- Published
- 2021
13. Droplet and Aerosol Generation With Mastoidectomy During the COVID-19 Pandemic: Assessment of Baseline Risk and Mitigation Measures With a High-performance Cascade Impactor
- Author
-
Edward S. Sim, Devi Sai Sri Kavya Boorgu, David H. Chi, Harish Dharmarajan, Noel Jabbour, Monika E. Freiser, and Timothy E. Corcoran
- Subjects
Suction ,Coronavirus disease 2019 (COVID-19) ,medicine.medical_treatment ,Mastoidectomy ,Baseline risk ,complex mixtures ,Droplet ,03 medical and health sciences ,0302 clinical medicine ,Basic Science ,Cadaver ,Medicine ,Humans ,030223 otorhinolaryngology ,Aerosol ,Cascade impactor ,Aerosols ,Drill ,Petroleum engineering ,business.industry ,SARS-CoV-2 ,Drilling ,COVID-19 ,respiratory system ,Sensory Systems ,Coronavirus ,Otorhinolaryngology ,Neurology (clinical) ,Safety ,business ,030217 neurology & neurosurgery - Abstract
HYPOTHESIS: Aerosols are generated during mastoidectomy and mitigation strategies may effectively reduce aerosol spread. BACKGROUND: An objective understanding of aerosol generation and the effectiveness of mitigation strategies can inform interventions to reduce aerosol risk from mastoidectomy and other open surgeries involving drilling. METHODS: Cadaveric and fluorescent three-dimensional printed temporal bone models were drilled under variable conditions and mitigation methods. Aerosol production was measured with a cascade impactor set to detect particle sizes under 14.1âµm. Field contamination was determined with examination under UV light. RESULTS: Drilling of cadaveric bones and three-dimensional models resulted in strongly positive aerosol production, measuring positive in all eight impactor stages for the cadaver trials. This occurred regardless of using coarse or cutting burs, irrigation, a handheld suction, or an additional parked suction. The only mitigation factor that led to a completely negative aerosol result in all eight stages was placing an additional microscope drape to surround the field. Bone dust was scattered in all directions from the drill, including on the microscope, the surgeon, and visually suspended in the air for all but the drape trial. CONCLUSIONS: Aerosols are generated with drilling the mastoid. Using an additional microscope drape to cover the surgical field was an effective mitigation strategy to prevent fine aerosol dispersion while drilling.
- Published
- 2021
14. Mucociliary Clearance Differs in Mild Asthma by Levels of Type 2 Inflammation
- Author
-
Timothy E. Corcoran, Sherri L. Hill, Lawrence Weber, Elisa M. Heidrich, Ashok Muthukrishnan, Landon W. Locke, Mike M. Myerburg, Alexander Huber, and Sally E. Wenzel
- Subjects
Pulmonary and Respiratory Medicine ,Adult ,Male ,medicine.medical_specialty ,Mucociliary clearance ,Nitric Oxide Synthase Type II ,Inflammation ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Severity of Illness Index ,Bronchial Provocation Tests ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Bronchoscopy ,medicine ,Humans ,030212 general & internal medicine ,Correlation of Data ,Asthma ,business.industry ,Chemokine CCL26 ,Gene Expression Profiling ,food and beverages ,medicine.disease ,Mucus ,Respiratory Function Tests ,ALOX15 ,Cross-Sectional Studies ,Respiratory Tract Absorption ,030228 respiratory system ,Mucociliary Clearance ,Cohort ,Exhaled nitric oxide ,Female ,CCL26 ,medicine.symptom ,Radiopharmaceuticals ,Cardiology and Cardiovascular Medicine ,business ,Cell Adhesion Molecules ,Asthma: Original Research - Abstract
BACKGROUND: Although mucus plugging is a well-reported feature of asthma, whether asthma and type 2 inflammation affect mucociliary clearance (MCC) is unknown. RESEARCH QUESTION: Does type 2 inflammation influence mucus clearance rates in patients with mild asthma who are not receiving corticosteroids? STUDY DESIGN AND METHODS: The clearance rates of inhaled radiolabeled particles were compared between patients with mild asthma with low (n = 17) and high (n = 18) levels of T2 inflammation. Fraction exhaled nitric oxide (Feno) was used to prospectively segregate subjects into T2 Lo (Feno < 25 ppb) and T2 Hi (Feno > 35 ppb) cohorts. Bronchial brush samples were collected with fiber-optic bronchoscopy, and quantitative polymerase chain reaction was performed to measure expression of genes associated with T2 asthma. MCC rate comparisons were also made with a historical group of healthy control subjects (HCs, n = 12). RESULTS: The T2 Lo cohort demonstrated increased MCC when compared with both T2 Hi and historic HCs. MCC within the T2 Hi group varied significantly, with some subjects having low or zero clearance. MCC decreased with increasing expression of several markers of T2 airway inflammation (CCL26, NOS2, and POSTN) and with Feno. MUC5AC and FOXJ1 expression was similar between the T2Lo and T2Hi cohorts. INTERPRETATION: Increasing T2 inflammation was associated with decreasing MCC. High rates of MCC in T2 Lo subjects may indicate a compensatory mechanism present in mild disease but lost with high levels of inflammation. Future studies are required to better understand mechanisms and whether impairments in MCC in more severe asthma drive worse clinical outcomes.
- Published
- 2020
15. Novel Use of Vitamin B2 as a Fluorescent Tracer in Aerosol and Droplet Contamination Models in Otolaryngology
- Author
-
Timothy E. Corcoran, Harish Dharmarajan, Edward S. Sim, Devi Sai Sri Kavya Boorgu, David H. Chi, Michael S. Weinstock, Rachel L. Whelan, Eric W. Wang, Monika E. Freiser, Noel Jabbour, and Lindsey K. Goyal
- Subjects
Models, Anatomic ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,aerosol ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Riboflavin ,impactor ,complex mixtures ,Models, Biological ,03 medical and health sciences ,Otolaryngology ,0302 clinical medicine ,contamination ,Nasopharynx ,Cadaver ,Disease Transmission, Infectious ,Fluorescent tracer ,Medicine ,Humans ,030212 general & internal medicine ,Particle Size ,030223 otorhinolaryngology ,Fluorescent Dyes ,Aerosols ,Chromatography ,business.industry ,SARS-CoV-2 ,Nebulizers and Vaporizers ,COVID-19 ,Endoscopy ,General Medicine ,Contamination ,respiratory system ,Aerosol ,Otorhinolaryngologic Surgical Procedures ,Otorhinolaryngology ,Fluorescein ,Original Article ,business ,aerodynamics ,Vitamin b2 - Abstract
Objective: During the COVID-19 era, a reliable method for tracing aerosols and droplets generated during otolaryngology procedures is needed to accurately assess contamination risk and to develop mitigation measures. Prior studies have not investigated the reliability of different fluorescent tracers for the purpose of studying aerosols and small droplets. Objectives include (1) comparing vitamin B2, fluorescein, and a commercial fluorescent green dye in terms of particle dispersion pattern, suspension into aerosols and small droplets, and fluorescence in aerosolized form and (2) determining the utility of vitamin B2 as a fluorescent tracer coating the aerodigestive tract mucosa in otolaryngology contamination models. Methods: Vitamin B2, fluorescein, and a commercial fluorescent dye were aerosolized using a nebulizer and passed through the nasal cavity from the trachea in a retrograde-intubated cadaveric head. In another scenario, vitamin B2 was irrigated to coat the nasal cavity and nasopharyngeal mucosa of a cadaveric head for assessment of aerosol and droplet generation from endonasal drilling. A cascade impactor was used to collect aerosols and small droplets ≤14.1 µm based on average aerodynamic diameter, and the collection chambers were visualized under UV light. Results: When vitamin B2 was nebulized, aerosols ≤5.4 µm were generated and the collected particles were fluorescent. When fluorescein and the commercial water tracer dye were nebulized, aerosols ≤8.61 µm and ≤2.08 µm respectively were generated, but the collected aerosols did not appear visibly fluorescent. Endonasal drilling in the nasopharynx coated with vitamin B2 irrigation yielded aerosols ≤3.30 µm that were fluorescent under UV light. Conclusion: Vitamin B2’s reliability as a fluorescent tracer when suspended in aerosols and small droplets ≤14.1 µm and known mucosal safety profile make it an ideal compound compared to fluorescein and commercial water-based fluorescent dyes for use as a safe fluorescent tracer in healthcare contamination models especially with human subjects.
- Published
- 2020
16. Reducing Aerosol-Related Risk of Transmission in the Era of COVID-19: An Interim Guidance Endorsed by the International Society of Aerosols in Medicine
- Author
-
Philip J. Kuehl, Chantal Darquenne, Andrew R. Martin, Bernhard Muellinger, Stephan Ehrmann, Patricia Dailey, Paul J McKiernan, Rajiv Dhand, Barbara Rothen-Rutishauser, James B Fink, Ronan MacLoughlin, Sabine Häussermann, Timothy E. Corcoran, Gerald C. Smaldone, Jie Li, Service de Médecine Intensive Réanimation [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Infectious Disease Transmission, Patient-to-Professional ,medicine.medical_treatment ,Pharmaceutical Science ,030226 pharmacology & pharmacy ,Airborne transmission ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Risk Assessment ,aerosol generating procedures ,03 medical and health sciences ,0302 clinical medicine ,Bronchoscopy ,Risk Factors ,Acute care ,Occupational Exposure ,medical aerosol ,Pandemic ,medicine ,Intubation ,Humans ,Pharmacology (medical) ,Cardiopulmonary resuscitation ,Intensive care medicine ,Personal protective equipment ,ComputingMilieux_MISCELLANEOUS ,Occupational Health ,bioaerosol dispersion ,Aerosols ,Inhalation Exposure ,Invited Review ,medicine.diagnostic_test ,Transmission (medicine) ,business.industry ,COVID-19 ,3. Good health ,filters ,030228 respiratory system ,business - Abstract
National and international guidelines recommend droplet/airborne transmission and contact precautions for those caring for coronavirus disease 2019 (COVID-19) patients in ambulatory and acute care settings. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, an acute respiratory infectious agent, is primarily transmitted between people through respiratory droplets and contact routes. A recognized key to transmission of COVID-19, and droplet infections generally, is the dispersion of bioaerosols from the patient. Increased risk of transmission has been associated with aerosol generating procedures that include endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, turning the patient to the prone position, disconnecting the patient from the ventilator, noninvasive positive-pressure ventilation, tracheostomy, and cardiopulmonary resuscitation. The knowledge that COVID-19 subjects can be asymptomatic and still shed virus, producing infectious droplets during breathing, suggests that health care workers (HCWs) should assume every patient is potentially infectious during this pandemic. Taking actions to reduce risk of transmission to HCWs is, therefore, a vital consideration for safe delivery of all medical aerosols. Guidelines for use of personal protective equipment (glove, gowns, masks, shield, and/or powered air purifying respiratory) during high-risk procedures are essential and should be considered for use with lower risk procedures such as administration of uncontaminated medical aerosols. Bioaerosols generated by infected patients are a major source of transmission for SARS CoV-2, and other infectious agents. In contrast, therapeutic aerosols do not add to the risk of disease transmission unless contaminated by patients or HCWs.
- Published
- 2020
17. Linking Cell and Organ Level Physiology and Therapeutic Response in Cystic Fibrosis Using Functional Imaging Methods
- Author
-
Robert S. Parker, Mike M. Myerburg, F. Serrano-Castillo, S. Frizzell, K. Moghbeli, Darragh J. Johnston, Carol A. Bertrand, Monica E. Shapiro, Joseph M. Pilewski, N. Shi, N. Hages, and Timothy E. Corcoran
- Subjects
Functional imaging ,Pathology ,medicine.medical_specialty ,medicine.anatomical_structure ,business.industry ,Cell ,medicine ,medicine.disease ,business ,Cystic fibrosis - Published
- 2020
18. Mucociliary Clearance (MCC) in Mild-Asthma Without Inhaled Corticosteroid Treatment Is Inversely Proportional to Exhaled Nitric Oxide
- Author
-
Mike M. Myerburg, Alexander Huber, Timothy E. Corcoran, Sally E. Wenzel, J.B. Trudeau, Landon W. Locke, and S.L. Hill
- Subjects
medicine.medical_specialty ,business.industry ,Mucociliary clearance ,Internal medicine ,Exhaled nitric oxide ,Mild asthma ,medicine ,Corticosteroid treatment ,business ,Gastroenterology - Published
- 2020
19. Aerosolizing Lipid Dispersions Enables Antibiotic Transport Across Mimics of the Lung Airway Surface Even in the Presence of Pre-existing Lipid Monolayers
- Author
-
Steven V. Iasella, Amy Z. Stetten, Robert D. Tilton, Todd M. Przybycien, Stephen Garoff, and Timothy E. Corcoran
- Subjects
Pulmonary and Respiratory Medicine ,1,2-Dipalmitoylphosphatidylcholine ,Swine ,Pharmaceutical Science ,02 engineering and technology ,Cystic fibrosis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pulmonary surfactant ,medicine ,Animals ,Surface Tension ,Pharmacology (medical) ,Lung ,Aerosolization ,Original Research ,Aerosols ,Marangoni effect ,Inhalation ,Mucins ,Biological Transport ,respiratory system ,021001 nanoscience & nanotechnology ,medicine.disease ,Anti-Bacterial Agents ,medicine.anatomical_structure ,030228 respiratory system ,chemistry ,Biochemistry ,Dipalmitoylphosphatidylcholine ,Tobramycin ,Biophysics ,Antibiotic transport ,0210 nano-technology - Abstract
Background: Secondary lung infections are the primary cause of morbidity associated with cystic fibrosis lung disease. Aerosolized antibiotic inhalation is potentially advantageous but has limited effectiveness due to altered airway aerodynamics and deposition patterns that limit drug access to infected regions. One potential strategy to better reach infected areas is to formulate aerosols with surfactants that induce surface tension gradients and drive postdeposition drug dispersal via Marangoni transport along the airway surface liquid (ASL). Since this relies on surfactant-induced surface tension reduction, the presence of endogenous lipid monolayers may hinder drug dispersal performance. Methods: Tobramycin solutions were formulated with dipalmitoylphosphatidylcholine (DPPC), a major component of endogenous pulmonary surfactant, to drive postdeposition aerosol dispersal across a model ASL based on a liquid layer or “subphase” of aqueous porcine gastric mucin (PGM) solution with predeposited DPPC monolayers to mimic the endogenous surfactant. In vitro subphase samples were collected from regions outside the aerosol deposition zone and assayed for tobramycin concentration using a closed enzyme donor immunoassay. The motion of a tracking bead across the subphase surface and the corresponding decrease in surface tension on aerosol deposition were tracked both with and without a predeposited DPPC monolayer. The surface tension/area isotherm for DPPC on PGM solution subphase was measured to aid in the interpretation of the tobramycin dispersal behavior. Results and Conclusions: Transport of tobramycin away from the deposition region occurs in aerosols formulated with DPPC whether or not predeposited lipid is present, and tobramycin concentrations are similar in both cases across biologically relevant length scales (∼8 cm). When DPPC is deposited from an aerosol, it induces ultralow surface tensions (
- Published
- 2018
20. Evolution and disappearance of solvent drops on miscible polymer subphases
- Author
-
Timothy E. Corcoran, Robert D. Tilton, Todd M. Przybycien, Stephen Garoff, Bradley W. Treece, and Amy Z. Stetten
- Subjects
chemistry.chemical_classification ,Materials science ,Capillary action ,Drop (liquid) ,Disjoining pressure ,Thermodynamics ,02 engineering and technology ,Polymer ,021001 nanoscience & nanotechnology ,01 natural sciences ,Article ,Capillary number ,Solvent ,Surface tension ,Colloid and Surface Chemistry ,chemistry ,0103 physical sciences ,Wetting ,010306 general physics ,0210 nano-technology - Abstract
Traditionally, an interface is defined as a boundary between immiscible phases. However, previous work has shown that even when two fluids are completely miscible, they maintain a detectable “effective interface” for long times. Miscible interfaces have been studied in various systems of two fluids with a single boundary between them. However, this work has not extended to the three-phase system of a fluid droplet placed on top of a miscible pool. We show that these three-phase systems obey the same wetting conditions as immiscible systems, and that their drop shapes obey the Augmented Young-Laplace Equation. Over time, the miscible interface diffuses and the shape of the drop evolves. We place 2-microliter drops of water atop miscible poly(acrylamide) solutions. The drop is completely wetted by the subphase, and then remains detectable beneath the surface for many minutes. An initial effective interfacial tension can be approximated to be on the order of 0.5 mN/m using the capillary number. Water and poly(acrylamide) are completely miscible in all concentrations, and yet, when viewed from the side, the drop maintains a capillary shape. Study of this behavior is important to the understanding of effective interfaces between miscible polymer phases, which are pervasive in nature.
- Published
- 2018
21. ATP12A promotes mucus dysfunction during Type 2 airway inflammation
- Author
-
Stefanie L. Coburn, Timothy E. Corcoran, John A. Leech, Thomas R. Kleyman, Mike M. Myerburg, Elisa M. Heidrich, Alison T. Lennox, Joseph M. Pilewski, and Sally E. Wenzel
- Subjects
0301 basic medicine ,Mucociliary clearance ,Respiratory Tract Diseases ,lcsh:Medicine ,Inflammation ,Respiratory Mucosa ,Article ,H(+)-K(+)-Exchanging ATPase ,03 medical and health sciences ,0302 clinical medicine ,Mediator ,medicine ,Humans ,lcsh:Science ,Cells, Cultured ,Gene knockdown ,Interleukin-13 ,Multidisciplinary ,Chemistry ,lcsh:R ,respiratory system ,Mucus ,3. Good health ,030104 developmental biology ,030228 respiratory system ,Mucociliary Clearance ,Interleukin 13 ,Immunology ,Respiratory Mechanics ,Respiratory epithelium ,lcsh:Q ,medicine.symptom ,Airway - Abstract
Allergic airway disease is known to cause significant morbidity due to impaired mucociliary clearance, however the mechanism that leads to the mucus dysfunction is not entirely understood. Interleukin 13 (IL-13), a key mediator of Type 2 (T2) inflammation, profoundly alters the ion transport properties of airway epithelium. However, these electrophysiological changes cannot explain the thick, tenacious airway mucus that characterizes the clinical phenotype. Here we report that IL-13 dramatically increases the airway surface liquid (ASL) viscosity in cultured primary human bronchial epithelial cells and thereby inhibits mucus clearance. These detrimental rheological changes require ATP12A, a non-gastric H+/K+-ATPase that secretes protons into the ASL. ATP12A knockdown or inhibition prevented the IL-13 dependent increase in ASL viscosity but did not alter the ASL pH. We propose that ATP12A promotes airway mucus dysfunction in individuals with T2 inflammatory airway diseases and that ATP12A may be a novel therapeutic target to improve mucus clearance.
- Published
- 2018
22. A Dynamic Model of Cystic Fibrosis Airway Epithelium Electrophysiology
- Author
-
Florencio Serrano Castillo, Timothy E. Corcoran, Monica E. Shapiro, Robert S. Parker, and Carol A. Bertrand
- Subjects
0301 basic medicine ,education.field_of_study ,Ussing chamber ,Chemistry ,Transport dynamics ,Population ,medicine.disease ,Cystic fibrosis ,Epithelium ,03 medical and health sciences ,Electrophysiology ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Control and Systems Engineering ,Biophysics ,medicine ,Respiratory epithelium ,education ,030217 neurology & neurosurgery - Abstract
Modeling the ion and liquid transport dynamics of the Cystic Fibrosis (CF) airway epithelium has the potential to provide valuable insight into the nature of biophysical processes not accessible experimentally We have developed a model that describes key elements of the airway epithelium’s electrophysiology as measured by short-circuit current (Isc) traces obtained under Ussing Chamber (UC) conditions. The model structure uses well established mathematical relations describing the transport of liquid and ions across the epithelium. The model was informed with data measured from primary human bronchial epithelial (HBE) cell cultures harvested from CF and non-CF donors. Fitted trajectories recapitulate experimental data with an average relative error of 3.28%, demonstrating the model’s ability to capture Isc dynamics. Multi-parameter distributions showed significant differences between the predicted ion permeabilities for each population, in accordance with literature trends. This suggests that model-informed parametric descriptions of patient groups could help supplement current experimental protocols, and help identify key dynamic differences relevant to the pathophysiology of CF.
- Published
- 2018
23. Transport of a partially wetted particle at the liquid/vapor interface under the influence of an externally imposed surfactant generated Marangoni stress
- Author
-
Stephen Garoff, Robert D. Tilton, Todd M. Przybycien, Timothy E. Corcoran, and Ramankur Sharma
- Subjects
Marangoni effect ,Chemistry ,Drop (liquid) ,Nanotechnology ,02 engineering and technology ,Mechanics ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Article ,0104 chemical sciences ,Physics::Fluid Dynamics ,Condensed Matter::Soft Condensed Matter ,symbols.namesake ,Colloid and Surface Chemistry ,Gibbs isotherm ,symbols ,Particle size ,Particle velocity ,Wetting ,0210 nano-technology ,Magnetosphere particle motion ,Particle deposition - Abstract
Marangoni flows offer an interesting and useful means to transport particles at fluid interfaces with potential applications such as dry powder pulmonary drug delivery. In this article, we investigate the transport of partially wetted particles at a liquid/vapor interface under the influence of Marangoni flows driven by gradients in the surface excess concentration of surfactants. We deposit a microliter drop of soluble (sodium dodecyl sulfate) aqueous surfactant solution or pure insoluble liquid (oleic acid) surfactant on a water subphase and observe the transport of a pre-deposited particle. Following the previous observation by Wang et al. [1] that a surfactant front rapidly advances ahead of the deposited drop contact line and initiates particle motion but then moves beyond the particle, we now characterize the two dominant, time- and position-dependent forces acting on the moving particle: (1) a surface tension force acting on the three-phase contact line around the particle periphery due to the surface tension gradient at the liquid/vapor interface which always accelerates the particle and (2) a viscous force acting on the immersed surface area of the particle which accelerates or decelerates the particle depending on the difference in the velocities of the liquid and particle. We find that the particle velocity evolves over time in two regimes. In the acceleration regime, the net force on the particle acts in the direction of particle motion, and the particle quickly accelerates and reaches a maximum velocity. In the deceleration regime, the net force on the particle reverses and the particle decelerates gradually and stops. We identify the parameters that affect the two forces acting on the particle, including the initial particle position relative to the surfactant drop, particle diameter, particle wettability, subphase thickness, and surfactant solubility. We systematically vary these parameters and probe the spatial and temporal evolution of the two forces acting on the particle as it moves along its trajectory in both regimes. We find that a larger particle always lags behind the smaller particle when placed at an equal initial distance from the drop. Similarly, particles more deeply engulfed in the subphase lag behind those less deeply engulfed. Further, the extent of particle transport is reduced as the subphase thickness decreases due to the larger velocity gradients in the subphase recirculation flows.
- Published
- 2017
24. Combining Inhalation by A Breath Actuated Nebuliser (BAN) With Exhalation Through An Oscillating Positive Expiratory Pressure Device (OPEP) Offers The Potential For Optimal Combined Therapy
- Author
-
Jason Suggett, Dominic Coppolo, Anthony Wesolowski, Timothy E. Corcoran, Vladimir Kushnarev, and Mark Nagel
- Subjects
Lung ,medicine.diagnostic_test ,Inhalation ,business.industry ,Exhalation ,Positive expiratory pressure ,Scintigraphy ,Diethylenetriaminepentaacetic acid ,Hypertonic saline ,medicine.anatomical_structure ,Anesthesia ,Medicine ,Combined therapy ,business - Abstract
Rationale: OPEP therapy when combined with nebulised drug delivery or hypertonic saline offers the potential to reduce combined treatment time. Aerosol deposition scintigraphy was undertaken to assess in vivo pulmonary deposition from a BAN (AEROECLIPSE* II) coupled to an OPEP device (Aerobika*) compared to deposition from the nebuliser alone. Methods: Eight healthy subjects received albuterol (2.5 mg/3mL) admixed with 2 mCi of Tc-DTPA (Technetium-99m bound to diethylenetriaminepentaacetic acid) administered using the BAN alone and again when the BAN was combined with the OPEP device. Regional doses were then determined from anterior and posterior gamma camera images collected after delivery. Lung perimeters were defined using Cobalt-57 transmission scans and applied to Tc-DTPA deposition images. Results were expressed as a percentage of baseline counts. Results: Average age of all 8 subjects (4 male, 4 female) was 33 years. Whole lung deposition was, on average, 31±13 vs 32±13% of loaded dose for BAN alone and BAN+OPEP respectively. Conclusions: The delivery of medication from the AEROECLIPSE* II BAN to the lungs was not significantly affected by the incorporation of the Aerobika* OPEP device. This therapy could offer the clinician the opportunity for combined aerosol/OPEP therapy (ie in cystic fibrosis patients) thereby reducing the time needed for the patient to take nebuliser and OPEP treatment separately.
- Published
- 2019
25. Aerosolization of Second-generation Triazoles: In Vitro Evaluation and Application in Therapy of Invasive Airway Aspergillosis
- Author
-
Carlo J. Iasella, Shahid Hussain, Christopher R. Ensor, Harisudhan Thanukrishnan, Joseph A. Nero, M. Hong Nguyen, Matthew R. Morrell, Raman Venkataramanan, Timothy E. Corcoran, John F. McDyer, and Cody A. Moore
- Subjects
Adult ,medicine.medical_specialty ,Posaconazole ,Antifungal Agents ,030230 surgery ,Aspergillosis ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,Galactomannan ,0302 clinical medicine ,Internal medicine ,Administration, Inhalation ,Bronchoscopy ,medicine ,Humans ,Respiratory Tract Infections ,Aerosolization ,Voriconazole ,Aerosols ,Transplantation ,medicine.diagnostic_test ,business.industry ,Triazoles ,medicine.disease ,Regimen ,Bronchoalveolar lavage ,chemistry ,Feasibility Studies ,030211 gastroenterology & hepatology ,Female ,Caspofungin ,business ,Invasive Fungal Infections ,medicine.drug ,Lung Transplantation - Abstract
BACKGROUND A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered. METHODS Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions. RESULTS Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (
- Published
- 2019
26. Flow regime transitions and effects on solute transport in surfactant-driven Marangoni flows
- Author
-
Stephen Garoff, Ningguan Sun, Robert D. Tilton, Timothy E. Corcoran, Todd M. Przybycien, Xin Zhang, and Steven V. Iasella
- Subjects
Materials science ,Marangoni effect ,Drop (liquid) ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Article ,0104 chemical sciences ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Dilution ,Biomaterials ,Surface tension ,Colloid and Surface Chemistry ,Pulmonary surfactant ,Chemical physics ,Critical micelle concentration ,Oil spill ,Dewetting ,0210 nano-technology - Abstract
Hypothesis Surfactant-driven Marangoni flow on liquid films is predicted to depend on subphase depth and initial surface tension difference between the subphase and deposited surfactant solution drop. Changes in flow behavior will impact transport of soluble species entrained in the Marangoni flow along the surface. In extreme cases, the subphase film may rupture, limiting transport. Understanding this behavior is important for applications in drug delivery, coatings, and oil spill remediation. Experiments A trans-illumination optical technique measured the subphase height profiles and drop content transport after drop deposition when varying initial subphase depth, surfactant concentration, and subphase viscosity. Findings Three distinct flow regimes were identified depending on the subphase depth and surfactant concentration and mapped onto an operating diagram. These are characterized as a “central depression” bounded by an outwardly traveling ridge, an “annular depression” bounded by a central dome and the traveling ridge, and an “annular dewetting” when the subphase ruptures. Well above the critical micelle concentration, transitions between regimes occur at characteristic ratios of gravitational and initial surface tension gradient stresses; transitions shift when surfactant dilution during spreading weakens the stress before the completion of the spreading event. Drop contents travel with the ridge, but dewetting hinders transport.
- Published
- 2019
27. A physiologically-motivated model of cystic fibrosis liquid and solute transport dynamics across primary human nasal epithelia
- Author
-
Robert S. Parker, Florencio Serrano Castillo, Monica E. Shapiro, Carol A. Bertrand, Michael M. Myerburg, and Timothy E. Corcoran
- Subjects
Adult ,Male ,Cystic Fibrosis ,030226 pharmacology & pharmacy ,Cystic fibrosis ,Models, Biological ,Permeability ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,In vivo ,medicine ,Humans ,Transcellular ,Cells, Cultured ,Pharmacology ,Ion Transport ,biology ,Chemistry ,Technetium ,Pentetic Acid ,medicine.disease ,Epithelium ,Cystic fibrosis transmembrane conductance regulator ,Nasal Mucosa ,medicine.anatomical_structure ,Permeability (electromagnetism) ,030220 oncology & carcinogenesis ,Paracellular transport ,Case-Control Studies ,biology.protein ,Biophysics ,Respiratory epithelium ,Female - Abstract
Cystic fibrosis (CF) disease is caused by mutations affecting the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in the mucosal side of epithelial tissue. In the airway, dysfunctional CFTR results in a transepithelial osmotic imbalance leading to hyperabsorption of airway surface liquid mucostasis, chronic inflammation, and eventual respiratory failure. Human nasal epithelial cell cultures from healthy and CF donors were used to perform studies of liquid and solute transport dynamics at an air/liquid interface in order to emulate the in vivo airway. Then, these results were used to inform a quantitative systems pharmacology model of airway epithelium describing electrically and chemically driven transcellular ionic transport, contributions of both convective and diffusive paracellular solute transport, and osmotically driven transepithelial water dynamics. Model predictions showed CF cultures, relative to non-CF ones, have increased apical and basolateral water permeabilities, and increase paracellular permeability and transepithelial chemical driving force for a radiolabeled tracer used to track small molecule absorption. These results provide a computational platform to better understand and probe the mechanisms behind the liquid hyperabsorption and small molecule retention profiles observed in the CF airway.
- Published
- 2019
28. Effect of ivacaftor on mucociliary clearance and clinical outcomes in cystic fibrosis patients with G551D-CFTR
- Author
-
Brian Flanagan, Michael P. Boyle, Scott H. Donaldson, Pradeep Bhambhvani, Joseph M. Pilewski, Agathe Ceppe, Pamela L. Zeitlin, William D. Bennett, Kirby L. Zeman, Beth L. Laube, Peter J. Mogayzel, Steven M. Rowe, Landon W. Locke, Michael M. Myerburg, and Timothy E. Corcoran
- Subjects
Adult ,Male ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Cystic Fibrosis ,Mucociliary clearance ,Cystic Fibrosis Transmembrane Conductance Regulator ,Quinolones ,Aminophenols ,Cystic fibrosis ,Ivacaftor ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Forced Expiratory Volume ,Internal medicine ,medicine ,Humans ,In patient ,Longitudinal Studies ,Prospective Studies ,030212 general & internal medicine ,Child ,Lung function ,Lung ,business.industry ,General Medicine ,respiratory system ,medicine.disease ,Respiratory Function Tests ,respiratory tract diseases ,Treatment Outcome ,Pulmonology ,medicine.anatomical_structure ,030228 respiratory system ,Mucociliary Clearance ,Mutation ,Chloride channel ,Female ,business ,Research Article ,medicine.drug - Abstract
Background The ability to restore cystic fibrosis transmembrane regulator (CFTR) function with effective small molecule modulators in patients with cystic fibrosis provides an opportunity to study relationships between CFTR ion channel function, organ level physiology, and clinical outcomes. Methods We performed a multisite, prospective, observational study of ivacaftor, prescribed in patients with the G551D-CFTR mutation. Measurements of lung mucociliary clearance (MCC) were performed before and after treatment initiation (1 and 3 months), in parallel with clinical outcome measures. Results Marked acceleration in whole lung, central lung, and peripheral lung MCC was observed 1 month after beginning ivacaftor and was sustained at 3 months. Improvements in MCC correlated with improvements in forced expiratory volume in the first second (FEV1) but not sweat chloride or symptom scores. Conclusions Restoration of CFTR activity with ivacaftor led to significant improvements in MCC. This physiologic assessment provides a means to characterize future CFTR modulator therapies and may help to predict improvements in lung function. Trial registration ClinicialTrials.gov, NCT01521338. Funding CFF Therapeutics (GOAL11K1).
- Published
- 2018
29. Deposition studies of aerosol delivery by nasal cannula to infants
- Author
-
Darragh J. Johnston, Daniel J. Weiner, Yuliya Domnina, Alexander Huber, Timothy E. Corcoran, Jiuann-Huey Lin, Joan Sanchez De Toledo, Michael Czachowski, Cecilia W. Lo, Phillip S. Adams, and Al Saville
- Subjects
Pulmonary and Respiratory Medicine ,Heart Defects, Congenital ,Male ,medicine.medical_specialty ,Mucociliary clearance ,medicine.disease_cause ,medicine ,Cannula ,Humans ,Particle Size ,Lung ,Nose ,Administration, Intranasal ,Aerosols ,business.industry ,Nebulizers and Vaporizers ,Infant, Newborn ,Infant ,respiratory system ,Cardiac surgery ,Oxygen ,Nebulizer ,Nasal Mucosa ,medicine.anatomical_structure ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Toxicity ,Female ,business ,Nasal cannula - Abstract
Aim Nasal cannulas are used to provide oxygen support for infants and have been considered as a means for delivering aerosols to the lungs. To measure mucociliary clearance in the lungs of infants with congenital heart defects, we delivered radiopharmaceutical aerosols via a nasal cannula. Here we report on the pulmonary and nasal deposition of these aerosols. Method A total of 18 infants (median age = 26 days; quartiles = 11-74 days) performed clearance measurements soon before or after corrective cardiac surgery. The regional aerosol deposition was assessed using gamma camera imaging. Results Cannula flow rate significantly affected pulmonary dosing. Flow rates useful for oxygen support were associated with low pulmonary deposition (2 L/min; mean, 4.5% of deposited dose; range, 2%-9%; n = 7) and high nasal deposition. Much lower cannula flow rates increased the pulmonary deposition (0.2 L/min; mean, 33.5% of deposited dose; range, 15%-51%; n = 5; P = 0.005 vs 2 L/min). The ratio of nose/lung dosing was approximately 26:1 at 2 L/min and 2:1 at 0.2 L/min. Bench studies demonstrated cannula output rates of 10.2 ± 1.7% (2 L/min) and 3.3 ± 0.4% (0.2 L/min) of the loaded nebulizer dose during a 2-minute delivery. Combining in vitro and in vivo results, we estimate that 0.46% of the loaded nebulizer dose reaches the lungs at 2 L/min vs 1.10% at 0.2 L/min during a 2-minute delivery. Conclusion With the delivery system used here, pulmonary aerosol delivery via nasal cannula was very inefficient at the flow rates required to provide oxygen support. Even at low flows, nasal deposition was substantial and local toxicity must be considered.
- Published
- 2018
30. Measurements of deposited aerosol dose in infants and small children
- Author
-
Timothy E. Corcoran
- Subjects
education.field_of_study ,Inhalation ,business.industry ,Population ,Review Article on Medical Aerosol in Acute and Critical Care ,General Medicine ,respiratory system ,medicine.disease_cause ,030226 pharmacology & pharmacy ,Cannula ,Metered-dose inhaler ,03 medical and health sciences ,Nebulizer ,0302 clinical medicine ,medicine.anatomical_structure ,030228 respiratory system ,Anesthesia ,Throat ,medicine ,Dosing ,education ,business ,Nasal cannula - Abstract
Pediatric patients are very dependent on inhaled aerosol medications. There are significant differences in how these aerosols deposit in the lungs of children vs. adults that may affect the efficacy of the therapies. Inefficient aerosol delivery to children, caused by factors such as high mouth and throat deposition during oral inhalation, significant losses within adjunct devices such as masks, and high rates of nasal deposition during cannula delivery, can lead to dosing that is difficult to control. Here we discuss the methods, such as deposition scintigraphy, that are used to assess inhaled dose in vivo and review previous studies where these techniques have been applied to measure dosing in children. This includes studies of nebulizers and metered dose inhalers and delivery through adjuncts such as facemasks and nasal cannulas. We discuss the factors that can lead to inefficient inhaled drug delivery and high levels of mouth and throat deposition in children. Finally, we propose areas of innovation to improve inhaled drug delivery to this population. There is a need for child-specific technologies for inhaled drug delivery. This includes the use of smart devices that can guide pediatric breathing patterns and better engage children during treatments, the use of smaller aerosols which are less likely to deposit in the upper airways after inhalation, and the design of better nasal cannula interfaces for aerosol delivery to infants.
- Published
- 2021
31. IN VITRO AND IN SILICO CHARACTERIZATION OF HUMAN NASAL EPITHELIAL ION AND LIQUID TRANSPORT MECHANISMS
- Author
-
Monica E. Shapiro, Robert S. Parker, Timothy E. Corcoran, Hannah R. Meyer, Carol A. Betrand, and Florencio Serrano Castillo
- Subjects
Chemistry ,In silico ,Genetics ,Biophysics ,Molecular Biology ,Biochemistry ,In vitro ,Biotechnology ,Characterization (materials science) ,Ion - Published
- 2018
32. Surfactant-induced Marangoni transport of lipids and therapeutics within the lung
- Author
-
Steven V. Iasella, Robert D. Tilton, Stephen Garoff, Todd M. Przybycien, Timothy E. Corcoran, and Amy Z. Stetten
- Subjects
Marangoni effect ,Polymers and Plastics ,Chemistry ,Drop (liquid) ,Vesicle ,02 engineering and technology ,Surfaces and Interfaces ,Inhaled air ,021001 nanoscience & nanotechnology ,01 natural sciences ,Article ,010305 fluids & plasmas ,Surface tension ,Colloid and Surface Chemistry ,Pulmonary surfactant ,0103 physical sciences ,Drug delivery ,Biophysics ,Physical and Theoretical Chemistry ,0210 nano-technology ,Complex fluid - Abstract
Understanding the fundamentals of surface transport on thin viscous films has important application in pulmonary drug delivery. The human lung contains a large-area interface between its complex fluid lining and inhaled air. Marangoni flows driven by surface tension gradients along this interface would promote enhanced distribution of inhaled therapeutics by carrying them from where they are deposited in the upper airways, along the fluid interface to deeper regions of the lung. Motivated by the potential to improve therapies for acute and chronic lung diseases, we review recent progress in modeling and experimental studies of Marangoni transport induced by the deposition of surfactant-containing microliter drops and liquid aerosols (picoliter drops) onto a fluid interface. The roles of key system variables are identified, including surfactant solubility, drop miscibility with the subphase, and the thickness, composition and surface properties of the subphase liquid. Of particular interest is the unanticipated but crucial role of aerosol processing to achieve Marangoni transport via phospholipid vesicle dispersions, which are likely candidates for a biocompatible delivery system. Progress in this field has the potential to not only improve outcomes in patients with chronic and acute lung diseases, but also to further our understanding of surface transport in complex systems.
- Published
- 2018
33. Surfactant Driven Post-Deposition Spreading of Aerosols on Complex Aqueous Subphases. 2: Low Deposition Flux Representative of Aerosol Delivery to Small Airways
- Author
-
Ramankur Sharma, Amsul Khanal, Timothy E. Corcoran, Stephen Garoff, Todd M. Przybycien, and Robert D. Tilton
- Subjects
Aerosols ,Pulmonary and Respiratory Medicine ,Surface-Active Agents ,Mucins ,Humans ,Pharmaceutical Science ,Pharmacology (medical) ,respiratory system ,Particle Size ,complex mixtures ,Lung ,Original Research - Abstract
Cystic fibrosis (CF) is associated with the accumulation of dehydrated mucus in the pulmonary airways. This alters ventilation and aerosol deposition patterns in ways that limit drug delivery to peripheral lung regions. We investigated the use of surfactant-based, self-dispersing aerosol carriers that produce surface tension gradients to drive two-dimensional transport of aerosolized medications via Marangoni flows after deposition on the airway surface liquid (ASL). We considered the post-deposition spreading of individual aerosol droplets and two-dimensional expansion of a field of aerosol droplets, when deposited at low fluxes that are representative of aerosol deposition in the small airways.We used physically entangled aqueous solutions of poly(acrylamide) or porcine gastric mucin as simple ASL mimics that adequately capture the full miscibility but slow penetration of entangled macromolecular chains of the ASL into the deposited drop. Surfactant formulations were prepared with aqueous solutions of nonionic tyloxapol or FS-3100 fluorosurfactant. Fluorescein dye served as a model "drug" tracer and to visualize the extent of post-deposition spreading.The surfactants not only enhanced post-deposition spreading of individual aerosol droplets due to localized Marangoni stresses, as previously observed with macroscopic drops, but they also produced large-scale Marangoni stresses that caused the deposited aerosol fields to expand into initially unexposed regions of the subphase. We show that the latter is the main mechanism for spreading drug over large distances when aerosol is deposited at low fluxes representative of the small airways. The large scale convective expansion of the aerosol field drives the tracer (drug mimic) over areas that would cover an entire airway generation or more, in peripheral airways, where sub-monolayer droplet deposition is expected during aerosol inhalation.The results suggest that aerosolized surfactant formulations may provide the means to maximize deposited drug uniformity in and access to small airways.
- Published
- 2015
34. Surfactant Driven Post-Deposition Spreading of Aerosols on Complex Aqueous Subphases. 1: High Deposition Flux Representative of Aerosol Delivery to Large Airways
- Author
-
Robert D. Tilton, Todd M. Przybycien, Stephen Garoff, Ramankur Sharma, Timothy E. Corcoran, and Amsul Khanal
- Subjects
Aerosols ,Pulmonary and Respiratory Medicine ,Aqueous solution ,Chromatography ,Marangoni effect ,Chemistry ,Pharmaceutical Science ,respiratory system ,Aerosol ,Surface-Active Agents ,Aerosol delivery ,Deposition (aerosol physics) ,Flux (metallurgy) ,Chemical engineering ,Pulmonary surfactant ,Humans ,Pharmacology (medical) ,Particle Size ,Lung ,Aerosol drug delivery ,Original Research - Abstract
Aerosol drug delivery is a viable option for treating diseased airways, but airway obstructions associated with diseases such as cystic fibrosis cause non-uniform drug distribution and limit efficacy. Marangoni stresses produced by surfactant addition to aerosol formulations may enhance delivery uniformity by post-deposition spreading of medications over the airway surface, improving access to poorly ventilated regions. We examine the roles of different variables affecting the maximum post-deposition spreading of a dye (drug mimic).Entangled aqueous solutions of either poly(acrylamide) (PA) or porcine gastric mucin (PGM) serve as airway surface liquid (ASL) mimicking subphases for in vitro models of aerosol deposition. Measured aerosol deposition fluxes indicate that the experimental delivery conditions are representative of aerosol delivery to the conducting airways. Post-deposition spreading beyond the locale of direct aerosol deposition is tracked by fluorescence microscopy. Aqueous aerosols formulated with either nonionic surfactant (tyloxapol) or fluorosurfactant (FS-3100) are compared with surfactant-free control aerosols.Significant enhancement of post-deposition spreading is observed with surfactant solutions relative to surfactant-free control solutions, provided the surfactant solution surface tension is less than that of the subphase. Amongst the variables considered--surfactant concentration, aerosol flow-rate, total deposited volume, time of delivery, and total deposited surfactant mass--surfactant mass is the primary predictor of maximum spread distance. This dependence is also observed for solutions deposited as a single, microliter-scale drop with a volume comparable to the total volume of deposited aerosol.Marangoni stress-assisted spreading after surfactant-laden aerosol deposition at high fluxes on a complex fluid subphase is capable of driving aerosol contents over significantly greater distances compared to surfactant-free controls. Total delivered surfactant mass is the primary determinant of the extent of spreading, suggesting a great potential to extend the reach of aerosolized medication in partially obstructed airways via a purely physical mechanism.
- Published
- 2015
35. Overnight delivery of hypertonic saline by nasal cannula aerosol for cystic fibrosis
- Author
-
Jennifer L. Goralski, Ryan T. Lacy, Joseph E. Godovchik, David R. Busick, Lawrence Weber, Karl H. Donn, Michael M. Myerburg, Timothy E. Corcoran, Landon W. Locke, Joseph M. Pilewski, Ashok Muthukrishnan, and Matthew R. Markovetz
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Adult ,Male ,Cystic Fibrosis ,Mucociliary clearance ,medicine.disease_cause ,Cystic fibrosis ,Article ,Pulmonary function testing ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Surveys and Questionnaires ,Administration, Inhalation ,Medicine ,Cannula ,Humans ,Lung ,Saline Solution, Hypertonic ,Cross-Over Studies ,Inhalation ,business.industry ,Nebulizers and Vaporizers ,Nasal Sprays ,Middle Aged ,medicine.disease ,Hypertonic saline ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Tolerability ,Mucociliary Clearance ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Female ,business ,Sleep ,Nasal cannula - Abstract
Aim: Inhaled hypertonic saline increases mucociliary clearance, improves pulmonary function, and decreases exacerbations in cystic fibrosis (CF) but contributes to the already significant treatment burden of CF. Overnight delivery of inhaled medications via a specially designed nasal cannula-aerosol device (Trans-nasal Pulmonary Aerosol Delivery [tPAD]) is an alternative approach. Here, we test whether overnight inhalation of hypertonic saline via tPAD improves mucociliary clearance and assess the tolerability of the device. Method: In this study, 12 CF subjects inhaled 7% hypertonic saline (HS) for 8 h overnight using the tPAD system. Safety and tolerability were assessed and measurements of mucociliary and absorptive clearance (MCC/ABS) were performed after the treatment. Comparisons were made versus sham treatment where the same subjects wore the nasal cannula overnight but did not receive aerosol. Results: Both the HS and sham treatments were well-tolerated. Only one subject did not complete the overnight HS treatment. There were no significant differences in MCC associated with HS inhalation at any time point (90 min, 3 h, 6 h) in any lung zone. Changes in FEV1 on both study days were similar. There were no differences in quality of sleep between HS and sham nights as assessed with the modified Leeds Sleep Evaluation Questionnaire (mLSEQ). Sino-Nasal Outcome Test (SNOT-14) questionnaires demonstrated significant increases (worsening) in 2/14 symptom categories with HS. Conclusions: The most likely cause for the failure to accelerate MCC was under-dosing of HS relative to the active transport of salt from the airways.
- Published
- 2017
36. Lung Deposition and Pharmacokinetics of Nebulized Cyclosporine in Lung Transplant Patients
- Author
-
B.A. Johnson, R. Niven, Timothy E. Corcoran, S. Dilly, and W. Verret
- Subjects
Adult ,Pulmonary and Respiratory Medicine ,Lung deposition ,Pharmaceutical Science ,Drug Administration Schedule ,Pharmacokinetics ,Administration, Inhalation ,Humans ,Medicine ,Pharmacology (medical) ,Dosing ,Radionuclide Imaging ,Lung ,Original Research ,Aged ,Ohio ,Aerosols ,business.industry ,Nebulizers and Vaporizers ,Stomach ,respiratory system ,Middle Aged ,Pennsylvania ,respiratory tract diseases ,Nebulizer ,Treatment Outcome ,medicine.anatomical_structure ,Anesthesia ,Cyclosporine ,Breathing ,Technetium Tc 99m Pentetate ,Transplant patient ,Drug Monitoring ,Radiopharmaceuticals ,business ,Immunosuppressive Agents ,Lung Transplantation - Abstract
Inhaled cyclosporine (CsA) is being investigated as a prophylaxis for lung transplant rejection. Lung deposition and systemic exposure of nebulized CsA in lung transplant patients was evaluated as part of the Phase 3 cyclosporine inhalation solution (CIS) trial (CYCLIST).Ten patients received 300 mg of CIS (62.5 mg/mL CsA in propylene glycol) admixed with 148 MBq of Tc-DTPA (technetium-99m bound to diethylenetriaminepentaacetic acid) administered using a Sidestream(®) disposable jet nebulizer. Deposition was assessed using a dual-headed gamma camera. Blood samples were collected over a 24-hr time period after aerosol dosing and analyzed for CsA levels. A pharmacokinetic analysis of the resulting blood concentration versus time profiles was performed.The average total deposited dose was 53.7 ± 12.7 mg. Average pulmonary dose was 31.8 ± 16.3 mg, and stomach dose averaged 15.5 ± 11.1 mg. Device performance was consistent, with breathing maneuvers influencing dose variation. Predose coaching with five of 10 patients reduced stomach deposition (22.6 ± 11.2 vs. 8.3 ± 5.2 mg; p=0.03). Blood concentrations declined quickly from a maximum of 372 ± 140 ng/mL to 15.3 ± 9.7 ng/mL at 24 hr post dose. Levels of AUC(0-24) [area under the concentration vs. time curve from 0 to 24 hr] averaged 1,493 ± 746 ng hr/mL. On a three times per week dose regimen, this represents5% of the weekly systemic exposure of twice per day oral administration.Substantial doses of CsA can be delivered to the lungs of lung transplant patients by inhaled aerosol. Systemic levels are small relative to typical oral CsA administration.
- Published
- 2014
37. Quantitative imaging of airway liquid absorption in cystic fibrosis
- Author
-
Joseph M. Pilewski, Matthew R. Markovetz, Lawrence Weber, Thomas J. Harding, Landon W. Locke, Michael M. Myerburg, Timothy E. Corcoran, Michael Czachowski, Robert S. Parker, Stefanie L. Brown, and Joseph A. Nero
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Spirometry ,Osmosis ,Pathology ,medicine.medical_specialty ,Cystic Fibrosis ,Mucociliary clearance ,Absorption (skin) ,Pharmacology ,Cystic fibrosis ,Article ,Young Adult ,In vivo ,Image Processing, Computer-Assisted ,Humans ,Medicine ,Child ,Radionuclide Imaging ,Cells, Cultured ,Aerosols ,medicine.diagnostic_test ,business.industry ,Middle Aged ,Pentetic Acid ,respiratory system ,Fluid transport ,medicine.disease ,Mucus ,Hypertonic saline ,Treatment Outcome ,Case-Control Studies ,Mutation ,Technetium Tc 99m Sulfur Colloid ,cardiovascular system ,Female ,Radiopharmaceuticals ,business ,circulatory and respiratory physiology - Abstract
New measures are needed to rapidly assess emerging treatments for cystic fibrosis (CF) lung disease. Using an imaging approach, we evaluated the absorptive clearance of the radiolabeled small molecule probe diethylene triamine penta-acetic acid (DTPA) as an in vivo indicator of changes in airway liquid absorption. DTPA absorption and mucociliary clearance rates were measured in 21 patients with CF (12 adults and nine children) and nine adult controls using nuclear imaging. The effect of hypertonic saline on DTPA absorption was also studied. In addition, in vitro studies were conducted to identify the determinants of transepithelial DTPA absorption. CF patients had significantly increased rates of DTPA absorption compared with control subjects but had similar mucociliary clearance rates. Treatment with hypertonic saline resulted in a decrease in DTPA absorption and an increase in mucociliary clearance in 11 out of 11 adult CF patients compared with treatment with isotonic saline. In vitro studies revealed that ∼ 50% of DTPA absorption can be attributed to transepithelial fluid transport. Apically applied mucus impedes liquid and DTPA absorption. However, mucus effects become negligible in the presence of an osmotic stimulus. Functional imaging of DTPA absorption provides a quantifiable marker of immediate response to treatments that promote airway surface liquid hydration.
- Published
- 2014
38. Physiologically-Based Model of Fluid Absorption and Mucociliary Clearance in Cystic Fibrosis
- Author
-
Carol A. Bertrand, Robert S. Parker, Florencio Serrano Castillo, Monica E. Shapiro, and Timothy E. Corcoran
- Subjects
Pathology ,medicine.medical_specialty ,Mucociliary clearance ,Chemistry ,food and beverages ,Absorption (skin) ,Specific adsorption ,respiratory system ,medicine.disease ,030226 pharmacology & pharmacy ,Cystic fibrosis ,Mucus ,03 medical and health sciences ,0302 clinical medicine ,030228 respiratory system ,Control and Systems Engineering ,otorhinolaryngologic diseases ,medicine ,Airway - Abstract
Dehydration of mucus in the lungs of cystic fibrosis (CF) patients can inhibit mucociliary clearance (MCC), resulting in mucus build-up and blockages. Prior mathematical models have shown differences in MCC from the large airways and airway surface liquid (ASL) absorption dynamics between CF and non-CF patients. The model developed here captures MCC and ASL absorption dynamics over 250 minutes with higher accuracy than previous models.
- Published
- 2018
39. Quasi-Immiscible Spreading of Aqueous Surfactant Solutions on Entangled Aqueous Polymer Solution Subphases
- Author
-
Timothy E. Corcoran, Robert D. Tilton, Todd M. Przybycien, Ramankur Sharma, Stephen Garoff, and Ellen R. Swanson
- Subjects
chemistry.chemical_classification ,Aqueous solution ,Materials science ,Chromatography ,Marangoni effect ,Polymers ,Surface Properties ,Drop (liquid) ,Sodium Dodecyl Sulfate ,Water ,Polymer ,Surface pressure ,Article ,Contact angle ,Surface tension ,Surface-Active Agents ,Pulmonary surfactant ,Chemical engineering ,chemistry ,Hydrodynamics ,Surface Tension ,Fluorescein ,General Materials Science - Abstract
Motivated by the possibility of enhancing aerosol drug delivery to mucus-obstructed lungs, the spreading of a drop of aqueous surfactant solution on a physically entangled aqueous poly(acrylamide) solution subphase that mimics lung airway surface liquid was investigated. Sodium dodecyl sulfate was used as the surfactant. To visualize spreading of the drop and mimic the inclusion of a drug substance, fluorescein, a hydrophilic and non-surface active dye, was added to the surfactant solution. The spreading progresses through a series of events. Marangoni stresses initiate the convective spreading of the drop. Simultaneously, surfactant escapes across the drop’s contact line within a second of deposition and causes a change in subphase surface tension outside the drop on the order of 1 mN/m. Convective spreading of the drop ends within 2–3 seconds of drop deposition, when a new interfacial tension balance is achieved. Surfactant escape depletes the drop of surfactant and the residual drop takes the form of a static lens of non-zero contact angle. On longer time scales, the surfactant dissolves into the subphase. The lens formed by the water in the deposited drop persists for as long as 3 minutes after the convective spreading process ends due to the long diffusional timescales associated with the underlying entangled polymer solution. The persistence of the lens suggests that the drop phase behaves as if it were immiscible with the subphase during this time period. Whereas surfactant escapes the spreading drop and advances on the subphase/vapor interface, hydrophilic dye molecules in the drop do not escape, but remain with the drop throughout the convective spreading. The quasi-immiscible nature of the spreading event suggests that the chemical properties of the surfactant and subphase are much less important than their physical properties, consistent with prior qualitative studies of spreading of different types of surfactants on entangled polymer subphases: the selection of surfactant for pulmonary delivery applications may be limited only by physical and toxicological considerations. Further, the escape of surfactant from individual drops may provide an additional spreading mechanism in the lung as hydrodynamic and/or surface pressure repulsions may drive individual droplets apart after deposition.
- Published
- 2013
40. Enabling Marangoni flow at air-liquid interfaces through deposition of aerosolized lipid dispersions
- Author
-
Grace Moraca, Stephanie Tristram-Nagle, Robert D. Tilton, Stephen Garoff, Todd M. Przybycien, Timothy E. Corcoran, and Amy Z. Stetten
- Subjects
0301 basic medicine ,1,2-Dipalmitoylphosphatidylcholine ,Swine ,Acrylic Resins ,02 engineering and technology ,Phase Transition ,Article ,Biomaterials ,Surface tension ,03 medical and health sciences ,Colloid and Surface Chemistry ,Adsorption ,Pulmonary surfactant ,Deposition (phase transition) ,Animals ,Surface Tension ,Aerosolization ,Unilamellar Liposomes ,Aerosols ,Chromatography ,Marangoni effect ,Aqueous solution ,Chemistry ,Vesicle ,Mucins ,Water ,Pulmonary Surfactants ,021001 nanoscience & nanotechnology ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,Solutions ,030104 developmental biology ,Chemical engineering ,0210 nano-technology ,Dimyristoylphosphatidylcholine ,Rheology - Abstract
It has long been known that deposited drops of surfactant solution induce Marangoni flows at air-liquid interfaces. These surfactant drops create a surface tension gradient, which causes an outward flow at the fluid interface. We show that aqueous phospholipid dispersions may be used for this same purpose. In aqueous dispersions, phospholipids aggregate into vesicles that are not surface-active; therefore, drops of these dispersions do not initiate Marangoni flow. However, aerosolization of these dispersions disrupts the vesicles, allowing access to the surface-active monomers within. These lipid monomers do have the ability to induce Marangoni flow. We hypothesize that monomers released from broken vesicles adsorb on the surfaces of individual aerosol droplets and then create localized surface tension reduction upon droplet deposition. Deposition of lipid monomers via aerosolization produces surface tensions as low as 1 mN/m on water. In addition, aerosolized lipid deposition also drives Marangoni flow on entangled polymer solution subphases with low initial surface tensions (~ 34 mN/m.) The fact that aerosolization of phospholipids naturally found within pulmonary surfactant can drive Marangoni flows on low surface tension liquids suggests that aerosolized lipids may be used to promote uniform pulmonary drug delivery without the need for exogenous spreading agents.
- Published
- 2016
41. Autophobing on Liquid Subphases Driven by the Interfacial Transport of Amphiphilic Molecules
- Author
-
Timothy E. Corcoran, Roomi Kalita, Ramankur Sharma, Robert D. Tilton, Todd M. Przybycien, Stephen Garoff, and Ellen R. Swanson
- Subjects
Amphiphilic molecule ,Chemistry ,Drop (liquid) ,Surfaces and Interfaces ,Condensed Matter Physics ,Article ,Surface tension ,Contact angle ,Sessile drop technique ,Chemical physics ,Monolayer ,Amphiphile ,Electrochemistry ,Surface Tension ,Organic chemistry ,General Materials Science ,Dimethylpolysiloxanes ,Wetting ,Volatilization ,Hydrophobic and Hydrophilic Interactions ,Spectroscopy - Abstract
We investigated the phenomenon of incomplete wetting of a high-energy liquid subphase by drops of pure amphiphilic molecules as well as drops of amphiphile solutions that are immiscible with the subphase. We show that amphiphiles escape across the contact line of the drop, move on the subphase/vapor interface, and form a submonolayer or full monolayer external to the drop. If this monolayer is sufficiently dense, then it can reduce the surface tension of the subphase, raise the contact angle of the drop, and prevent the drop from fully wetting the subphase. This phenomenon is called autophobing and has been extensively studied on solid substrates. For the liquid subphase studied here, we measure the surface tensions of the three relevant interfaces before and after the drop is deposited. The measured surface tension external to the drop shows that amphiphiles can move across the contact line and form a monolayer outside of the drop. In some cases, at equilibrium, the monolayer is in a sufficiently packed state to create the nonwetting condition. In other cases, at equilibrium the monolayer density is insufficient to lower the surface tension enough to achieve the nonwetting condition. Unlike on solid substrates where the formation of the monolayer external to the drop is kinetically hindered, the amphiphiles can move rapidly across the liquid subphase by Marangoni-driven surface transport, and local equilibrium is achieved. However, because the amphiphile inventory and subphase area are limited, the achievement of autophobing on a liquid subphase depends not only on the instrinsic subphase/amphiphile interaction but also on the total amphiphile inventory and area of the liquid subphase.
- Published
- 2012
42. Imaging the Postdeposition Dispersion of an Inhaled Surfactant Aerosol
- Author
-
Stephen Garoff, Timothy E. Corcoran, Kristina Thomas, Robert D. Tilton, Todd M. Przybycien, and Joseph M. Pilewski
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Time Factors ,Calfactant ,Cystic Fibrosis ,medicine.medical_treatment ,Pharmaceutical Science ,Pilot Projects ,Cystic fibrosis ,Young Adult ,Drug Delivery Systems ,Pulmonary surfactant ,Administration, Inhalation ,medicine ,Humans ,Pharmacology (medical) ,Particle Size ,Radionuclide Imaging ,Lung ,Saline ,Original Research ,Aerosols ,Biological Products ,Inhalation ,Chemistry ,Nebulizers and Vaporizers ,Pulmonary Surfactants ,Penetration (firestop) ,Middle Aged ,respiratory system ,medicine.disease ,Surgery ,Aerosol ,Airway Obstruction ,Technetium Tc 99m Sulfur Colloid ,Female ,Airway ,medicine.drug ,Biomedical engineering - Abstract
Aerodynamic forces provide the primary means of distributing aerosol medications within the lungs. Partial airway obstructions can limit both air flow and aerosol penetration into diseased zones. We hypothesize that low surface tension additives may help to disperse aerosol medications after deposition in the airways, improving dose uniformity and drug delivery to underventilated regions. To test this, we performed a pilot scintigraphy study of surfactant and saline deposition and postdeposition dispersion.Because inhaled antibiotics for cystic fibrosis provide an example of where self-dispersing medications may be useful, we administered calfactant and saline aerosols with added Technetium 99m sulfur colloid (Tc-SC; 100 nm filtered) on different days in randomized order to eight cystic fibrosis (CF) subjects (average FEV(1)%, p=85 ± 12%). Nebulized delivery was matched (similar aerosol sizes and volume delivery rates, fixed breathing patterns). Tc-SC distribution in the lungs was imaged continuously for 30 min after delivery.Both aerosols were well tolerated. Aerosol distribution was mostly peripheral (58/42%) and initially similar for saline and surfactant. Changes in whole lung counts after 30 min were also similar. Peripheral lung activity decreased more rapidly on average with calfactant though the difference versus saline was not statistically significant. Central to peripheral count ratio decreased with saline and increased with calfactant and c/p changes approached significance (-0.05 ± 0.16 vs. 0.10 ± 0.10; p=0.07 Wilcoxon).Our results lack statistical significance, but suggest that inhaled calfactant increased peripheral clearance, due to either surfactant-based dispersion or mucociliary effects. Further studies are needed to define the potential for low surface tension carriers to improve drug delivery.
- Published
- 2012
43. Pseudomonas infection and mucociliary and absorptive clearance in the cystic fibrosis lung
- Author
-
Landon W. Locke, Daniel J. Weiner, Michael M. Myerburg, Timothy E. Corcoran, Lawrence Weber, Ryan T. Lacy, Matthew R. Markovetz, Robert S. Parker, Joseph M. Pilewski, Ashok Muthukrishnan, and Michael Czachowski
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Cystic Fibrosis ,Mucociliary clearance ,Respiratory System ,medicine.disease_cause ,Cystic fibrosis ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pseudomonas infection ,Administration, Inhalation ,Medicine ,Humans ,Pseudomonas Infections ,Longitudinal Studies ,Radionuclide Imaging ,Aerosols ,Lung ,Inhalation ,business.industry ,Pseudomonas aeruginosa ,food and beverages ,respiratory system ,Middle Aged ,medicine.disease ,Mucus ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Mucociliary Clearance ,Disease Progression ,Female ,Radiopharmaceuticals ,business ,Airway - Abstract
Airway surface liquid hyperabsorption and mucus accumulation are key elements of cystic fibrosis lung disease that can be assessed in vivo using functional imaging methods. In this study we evaluated experimental factors affecting measurements of mucociliary clearance (MCC) and small-molecule absorption (ABS) and patient factors associated with abnormal absorption and mucus clearance.Our imaging technique utilises two radiopharmaceutical probes delivered by inhalation. Measurement repeatability was assessed in 10 adult cystic fibrosis subjects. Experimental factors were assessed in 29 adult and paediatric cystic fibrosis subjects (51 scans). Patient factors were assessed in a subgroup with optimal aerosol deposition (37 scans; 24 subjects). Paediatric subjects (n=9) underwent initial and 2-year follow-up scans. Control subjects from a previously reported study are included for comparison.High rates of central aerosol deposition influenced measurements of ABS and, to a lesser extent, MCC. Depressed MCC in cystic fibrosis was only detectable in subjects with previous Pseudomonas aeruginosa infection. Cystic fibrosis subjects without P. aeruginosa had similar MCC to control subjects. Cystic fibrosis subjects had consistently higher ABS rates.We conclude that the primary experimental factor affecting MCC/ABS measurements is central deposition percentage. Depressed MCC in cystic fibrosis is associated with P. aeruginosa infection. ABS is consistently increased in cystic fibrosis.
- Published
- 2015
44. The potential for delivery of particulate matter through positive airway pressure devices (CPAP/BPAP)
- Author
-
Timothy E. Corcoran, Patrick J. Strollo, Nina O’Connell, David A. Kristo, and Kristina Thomas
- Subjects
medicine.medical_treatment ,complex mixtures ,law.invention ,HEPA ,law ,Humans ,Medicine ,Continuous positive airway pressure ,Particle Size ,Aerosolization ,Filtration ,Sleep Apnea, Obstructive ,Continuous Positive Airway Pressure ,Inhalation ,business.industry ,Nebulizers and Vaporizers ,Dust ,Equipment Design ,respiratory system ,Particulates ,Aerosol ,Nebulizer ,Otorhinolaryngology ,Anesthesia ,Technetium Tc 99m Pentetate ,Particulate Matter ,Neurology (clinical) ,business ,Biomedical engineering - Abstract
Airborne particulate matter may induce health risk with inhalation. Special concerns exist for deployed military personnel with inhaled particulate matter in desert environments. Continuous positive airway pressure (CPAP) used in obstructive sleep apnea may facilitate inhalation of particulate matter. We evaluated the ability of commercial CPAP filter systems to eliminate inhalation of particulate matter. An ultrasonic medical nebulizer (DeVilbliss Ultraneb, DeVilbliss, Somerset, PA) atomized liquid producing “respirable” aerosol. Technetium-99m diethylene triamine pentaacetic acid dissolved in water was also aerosolized to quantify aerosol inhalation. A high efficiency particulate air (HEPA) filter placed at the patient–hose connection port in the bilevel positive airway pressure (BPAP) device captured the aerosol inbound to the patient. The HEPA filter provided a means to quantify aerosol dose delivered to a simulated patient. Commercial foam and ultrafine filters were assessed with aerosol to determine the simulated patient exposure. Foam and ultrafine filters used together allowed 1.5% or less of aerosol volume to pass through the BPAP system. Foam filters alone allowed an average of 18.9% of aerosol delivered to pass through the BPAP system. Foam and ultrafine filters used together in BPAP systems provide excellent aerosol filtration in this laboratory simulation of BPAP use.
- Published
- 2011
45. Intrapulmonary Disposition of Amphotericin B After Aerosolized Delivery of Amphotericin B Lipid Complex (Abelcet; ABLC) in Lung Transplant Recipients
- Author
-
Kenneth R. McCurry, Diana L. Pakstis, Bruce E. Johnson, Shahid Husain, Timothy E. Corcoran, Sean M. Studer, Shimin Zhang, Kathleen A. Shutt, Blair Capitano, Maria Crespo, M.E. Carey, David L. Paterson, Raman Venkataramanan, and Joseph M. Pilewski
- Subjects
Male ,medicine.medical_specialty ,Antifungal Agents ,medicine.medical_treatment ,Respiratory Mucosa ,Aspergillosis ,Gastroenterology ,Drug Administration Schedule ,Pharmacokinetics ,Tandem Mass Spectrometry ,Amphotericin B ,Internal medicine ,Administration, Inhalation ,Bronchoscopy ,medicine ,Humans ,Lung transplantation ,Tissue Distribution ,Prospective Studies ,Respiratory system ,Lung ,Chromatography, High Pressure Liquid ,Aerosols ,Invasive Pulmonary Aspergillosis ,Transplantation ,Inhalation ,business.industry ,Middle Aged ,medicine.disease ,medicine.anatomical_structure ,Anesthesia ,Female ,business ,Bronchoalveolar Lavage Fluid ,Lung Transplantation ,medicine.drug - Abstract
Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients. However, no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients.We prospectively determined the concentrations of amphotericin B in the epithelial lining fluid (ELF) and plasma after aerosolized nebulization (AeroEclipse), of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients. One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject. High-performance liquid chromatography and high-performance liquid chromatography-MS-MS were used to measure amphotericin B.Concentrations of amphotericin B in ELF (median, 25-75 IQR) were at 4 hr (n=5) 7.20 μg/mL (1.3-17.6), 24 hr (n=6) 8.26 μg/mL (3.9-82.7), 48 hr (n=5) 2.15 μg/mL (1.4-5.5), 72 hr (n=4) 1.25 μg/mL (0.75-5.5), 96 hr (n=6) 0.86 μg/mL (0.55-1.4), 120 hr (n=4) 1.04 μg/mL (0.44-1.6), 144 hr (n=1), 4.25 μg/mL, 168 hr (n=3) 1.14 μg/mL, and 192 hr (n=1) 1 μg/mL. The plasma concentration of the drug remained below 0.08 μg/mL at all time points. During the study, the side effects noted included wheezing, coughing, and 12% decline in forced expiratory volume in 1 sec.We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated.
- Published
- 2010
46. Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway
- Author
-
Raymond A. Frizzell, Michael M. Myerburg, Joseph M. Pilewski, Timothy E. Corcoran, Kristina Thomas, Ashok Muthukrishnan, and Lawrence Weber
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,Pathology ,medicine.medical_specialty ,Adolescent ,Cystic Fibrosis ,Mucociliary clearance ,animal diseases ,Pilot Projects ,Respiratory Mucosa ,Absorption (skin) ,Cystic fibrosis ,Article ,Young Adult ,In vivo ,medicine ,Humans ,Radionuclide Imaging ,Aerosols ,Lung ,business.industry ,organic chemicals ,Indium Radioisotopes ,Respiratory disease ,Pentetic Acid ,respiratory system ,medicine.disease ,Respiratory Function Tests ,medicine.anatomical_structure ,Linear Models ,cardiovascular system ,Female ,business ,Clearance rate ,Biomarkers ,Zones of the lung ,circulatory and respiratory physiology - Abstract
Biomarkers providing in vivo quantification of the basic elements of cystic fibrosis (CF) lung disease are needed. A study was performed to determine whether the absorption of a small radiolabelled hydrophilic molecule (Indium-111 (In-)DTPA) would be increased in CF airways. DTPA clearance has been used previously to assess epithelial permeability and may also be useful for quantifying liquid absorption. The absorptive clearance rate of DTPA was quantified in 10 CF and 11 control subjects using a novel aerosol technique. Subjects inhaled an aerosol containing nonabsorbable technetium-99m sulfur colloid (Tc-SC) particles and In-DTPA. Tc-SC clearance from the lung is exclusively mucociliary, while In-DTPA is cleared by both absorption and mucociliary clearance. The difference between the In-DTPA and Tc-SC clearance rates estimates In-DTPA absorption. Tc-SC (mucociliary) clearance was similar in central and peripheral zones in CF and non-CF lungs. Total In-DTPA clearance was increased in both zones in CF lungs. The absorptive component of In-DTPA clearance was increased in the airway-dominated central lung zones in CF (42% x h( -1) versus 32% x h(-1), p = 0.03). The absorption of In-DTPA is increased in the CF airway. Further study is needed to understand the relative roles of fluid absorption, inflammation and other mechanisms potentially affecting epithelial permeability and DTPA absorption.
- Published
- 2009
47. Recent Developments in Heliox Therapy for Asthma and Bronchiolitis
- Author
-
In K. Kim and Timothy E. Corcoran
- Subjects
medicine.medical_specialty ,Asthma exacerbations ,Inhalation ,business.industry ,Acute viral bronchiolitis ,medicine.disease ,Heliox ,Nebulizer therapy ,respiratory tract diseases ,Bronchiolitis ,Pediatrics, Perinatology and Child Health ,Emergency Medicine ,medicine ,Oxygen gas ,Intensive care medicine ,business ,Asthma - Abstract
Helium and oxygen gas mixtures (heliox) have become an area of renewed interest in pediatric emergency and critical care for the treatment of acute asthma exacerbations and bronchiolitis. After a review of recent literature on heliox, this article will provide an overview of delivery techniques. This article will primarily focus on heliox inhalation therapy and heliox-driven nebulizer therapy for acute asthma exacerbations. The emergence of heliox inhalation therapy for acute viral bronchiolitis will also be addressed.
- Published
- 2009
48. Aerosol Delivery through Nasal Cannulas: An In Vitro Study
- Author
-
Amy L. Marcinkowski, Al Saville, Abhiram R. Bhashyam, Timothy E. Corcoran, Matthew T. Wolf, Joseph A. Carcillo, and Kristina Thomas
- Subjects
Adult ,Pulmonary and Respiratory Medicine ,Pharmaceutical Science ,medicine.disease_cause ,Models, Biological ,Catheterization ,Aerosol delivery ,medicine ,Humans ,Pharmacology (medical) ,Particle Size ,Child ,Administration, Intranasal ,Aerosols ,business.industry ,Lasers ,Nebulizers and Vaporizers ,digestive, oral, and skin physiology ,Age Factors ,Infant ,Humidity ,respiratory system ,Metered-dose inhaler ,Cannula ,Aerosol ,Nebulizer ,Anesthesia ,Breathing ,Nasal administration ,business ,Nasal cannula - Abstract
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.
- Published
- 2008
49. Aerosol Delivery through Nasal Cannulas: AnIn VitroStudy
- Author
-
Abhiram R. Bhashyam, Matthew T. Wolf, Amy L. Marcinkowski, Al Saville, Kristina Thomas, Joseph A. Carcillo, and Timothy E. Corcoran
- Subjects
Pulmonary and Respiratory Medicine ,Pharmacology (medical) - Published
- 2008
50. Imaging in Aerosol Medicine
- Author
-
Timothy E. Corcoran
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Quantification methods ,Computed tomography ,Critical Care and Intensive Care Medicine ,Scintigraphy ,Administration, Inhalation ,Medicine ,Humans ,Lung ,Aerosols ,Tomography, Emission-Computed, Single-Photon ,medicine.diagnostic_test ,business.industry ,General Medicine ,Aerosol ,Positron emission tomography ,Mucociliary Clearance ,Positron-Emission Tomography ,Radiology ,History of use ,Molecular imaging ,Radiopharmaceuticals ,business ,Preclinical imaging ,Biomedical engineering - Abstract
Imaging techniques have been used extensively to study the delivery of inhaled medications. Deposition scintigraphy involves the quantification of deposited aerosol dose and is performed using 2-dimensional planar or 3-dimensional positron emission tomography (PET) or single-photon-emission computed tomography (SPECT) imaging techniques. Planar techniques have an extensive history of use, and quantification methods are well established. SPECT and PET techniques can provide better dose localization, but quantification is more complex, and the techniques are in more limited use. Aerosols have also been used to deliver radiopharmaceutical probes for the imaging of lung physiology. These studies include measurements of ventilation, mucus and cough clearance, and, more recently, liquid absorption in the airways. Clearance measurements have been used to assess therapeutic response in conditions such as cystic fibrosis. Future directions in aerosol-based imaging are likely to include use of novel probes to measure new physiological processes in the lung, more thorough integration of anatomical imaging, and use of multiple probes to simultaneously image drug and disease or interacting physiological processes.
- Published
- 2015
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.