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Allan L Coates

Publications and source records attributed to Allan L Coates.

At least 19 recordsLinked to original sources
PubMed2007

Calculating expected lung deposition of aerosolized administration of AAV vector in human clinical studies.

BACKGROUND: Cystic fibrosis is an autosomal recessive disease affecting approximately 1 in 2500 live births. Introducing the cDNA that codes for normal cystic fibrosis transmembrane conductance regulator (CFTR) to the small airways of the lung could result in restoring the CFTR function. A number of vectors for lung gene therapy have been tried and adeno-associated virus (AAV) vectors offer promise. The vector is delivered to the lung using a breath-actuated jet nebulizer. The purpose of this project was to determine the aerosolized AAV (tgAAVCF) particle size distribution (PSD) in order to calculate target doses for lung delivery. METHODS: A tgAAVCF solution was nebulized using the Pari LC Plus (n = 3), and the PSD was determined by coupling laser diffraction and inertial impaction (NGI) techniques. The NGI allowed for quantification of the tgAAVCF at each stage of impaction, ensuring that rAAV-CFTR vector is present and not empty particles. Applying the results to mathematical algorithms allowed for the calculation of expected pulmonary deposition. RESULTS: The mass median diameter (MMD) for the tgAAVCF was 2.78 +/- 0.43 microm. If the system works ideally and the patient only receives aerosol on inspiration, the patient would receive 47 +/- 0% of the initial dose placed in the nebulizer, with 72 +/- 0.73% of this being deposited beyond the vocal cords. CONCLUSIONS: This technology for categorizing the pulmonary delivery system for lung gene therapy vectors can be adapted for advanced aerosol delivery systems or other vectors.

Administration, Inhalation↗
PubMed2006

Controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: a randomized controlled trial.

CONTEXT: Children with croup are often treated with humidity even though this is not scientifically based, consumes time, and can be harmful. Although humidity using the traditional blow-by technique is similar to room air and no water droplets reach the nasopharynx, particles sized for laryngeal deposition (5-10 microm) could be beneficial. OBJECTIVE: To determine whether a significant difference in the clinical Westley croup score exists in children with moderate to severe croup who were admitted to the emergency department and who received either 100% humidity or 40% humidity via nebulizer or blow-by humidity. DESIGN AND SETTING: A randomized, single-blind, controlled trial conducted between 2001 and 2004 in a tertiary care pediatric emergency department. PARTICIPANTS: A convenience sample of 140 previously healthy children 3 months to 10 years of age with Westley croup score of more than 1 or 2 or higher (scoring system range, 0-17); 21 families refused participation. INTERVENTION: Thirty-minute administration of humidity using traditional blow-by technique (commonly used placebo, n = 48), controlled delivery of 40% humidity (optimally delivered placebo, n = 46), or 100% humidity (n = 46) with water particles of mass median diameter 6.21 microm. MAIN OUTCOME MEASURE: A priori defined change in the Westley croup score from baseline to 30 and 60 minutes in the 3 groups. RESULTS: Groups were comparable before treatment. At 30 minutes the difference in the improvement in the croup score between the blow-by and low-humidity groups was 0.03 (95% confidence interval [CI], -0.72 to 0.66), between low- and high-humidity groups, 0.16 (95% CI, -0.86 to 0.53), and between blow-by and high-humidity groups, 0.19 (95% CI, -0.87 to 0.49). Results were similar at 60 minutes. Differences between groups in pulse and respiratory rates and oxygen saturation changes were insignificant, as were proportions of excellent responders; proportions with croup score of 0 at study conclusion; and proportions receiving dexamethasone, epinephrine, or requiring additional medical care or hospitalization. CONCLUSIONS: One hundred percent humidity with particles specifically sized to deposit in the larynx failed to result in greater improvement than 40% humidity or humidity by blow-by technique. This study does not support the use of humidity for moderate croup for patients treated in the emergency department. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00230841.

Administration, Inhalation↗
PubMed2006

Resting and exercise cardiorespiratory function in survivors of congenital diaphragmatic hernia.

Our objective was to study exercise capacity and cardiorespiratory response to exertion in survivors of congenital diaphragmatic hernia (CDH). This was a cross-sectional cohort study of 23 CDH survivors, aged 10-16 years, and 23 gender- and age-matched controls. Exercise testing was performed on a cycle ergometer, with cardiac output measurements made using exponential CO2 rebreathing. Pretest cardiorespiratory assessment was done by echocardiography and pulmonary function testing. Statistical analysis was performed using Student's t-test, regression analysis, and longitudinal model computing with spatial covariance structure. No echocardiographic evidence for pulmonary hypertension was found at rest (right ventricular systolic pressures, 27 +/- 6 mmHg). Mean pulmonary artery diameter on the side of the CDH was significantly smaller than contralaterally, but was within normal range (z-score, 0 +/- 1.1 vs. 1.2 +/- 1.6, P < 0.01). Exercise capacity was mildly reduced in CDH compared to controls and predictive data (maximum workload, 77% +/- 12% vs. 91% +/- 16% of predicted, P < 0.01). Cardiorespiratory response to exertion was not significantly different between groups. In conclusion, most adolescent CDH survivors have nearly normal exercise capacity and cardiorespiratory response to exertion. This study may prove useful in comparisons with future cohorts comprising more severely affected individuals now surviving due to improved neonatal care.

Adolescent↗
PubMed2006

Nebulized therapies for childhood pulmonary hypertension: an in vitro model.

OBJECTIVES: Sildenafil, tezosentan, and prostacyclin reduce pulmonary vascular pressures in pulmonary hypertension, but have potential to vasodilate the systemic circulation. Nebulized vasodilators allow targeted drug delivery, high local drug concentrations, less systemic hypotension, and better matching of the lung's ventilation and perfusion. We aimed to estimate pulmonary deposition of these drugs from commonly employed nebulizers using in vitro techniques and to create a mathematical model to predict inspired mass of aerosol. DESIGN: Lung deposition was estimated by characterization of drug output and particle size distribution (PSD) of nebulizers using helium-neon laser diffraction techniques. A mathematical model for each device was created to estimate pulmonary deposition using patients' breathing patterns and was verified with a mechanical-breathing model. RESULTS: Total output and PSD were similar for the Hudson Updraft II and Whisperjet nebulizers, consisting of half the nebulizer's charge, with (1/4) of particles < or = 5 microm, in the respirable fraction (RF). Drug output increased with inspiratory flow for the Pari LC Star. Differences were noted in device performance, depending on the drug tested. Estimated pulmonary deposition (mean, 95% CI) was 8.1 (7.2, 9.0)% of the initial drug charge for the Hudson Updraft II, 6.4 (5.8, 7.0)% for the Whisperjet, and 33.0 (28.3, 37.9)% for the Pari LC Star. A mechanical model was consistent with our mathematical model. CONCLUSIONS: All drugs could be nebulized, but expected pulmonary deposition varied depending on the nebulizer and drug.

Adolescent↗
PubMed2006

The price of success in the management of congenital diaphragmatic hernia: is improved survival accompanied by an increase in long-term morbidity?

BACKGROUND: The impact of "gentle ventilation" (GV) strategies on morbidity and mortality of patients with congenital diaphragmatic hernia (CDH) in our institution has not been determined. This study reviews the primary and secondary outcomes of our patients with CDH treated with the GV approach. METHOD: We performed a retrospective chart review of respiratory, neurologic, nutritional, and musculoskeletal morbidities in patients with CDH treated at a single institution between 1985 and 1989 with conventional ventilation (CV) compared with those treated from 1996 to 2000 with GV. RESULTS: There were 77 CV-treated and 66 GV-treated patients with CDH, with 51% survival in the CV cohort compared with 80% in the GV group (chi(2), P < .05). At 3-year follow-up, we found no statistically significant differences in the frequency of respiratory (38% of CV patients, 50% of GV patients), neurologic (29% of CV patients, 34% of GV patients), or musculoskeletal morbidity (46% of CV vs 29% of GV-treated patients). There was a difference in nutritional morbidity as indicated by the increased frequency of gastrostomy tube use in the GV-treated patients (34%) compared with the CV patients (8%; chi2, P < .05). CONCLUSION: The implementation of GV techniques has significantly decreased mortality in infants with CDH. This has been associated with a documented increase in nutritional morbidity among survivors.

Hernia, Diaphragmatic↗
PubMed2006

Comparison of three valved holding chambers for the delivery of fluticasone propionate-HFA to an infant face model.

The purpose of this study was to compare three valved holding chambers (VHC) with facemasks attached. One VHC (AeroChamber Max[TM] with medium mask) was made with materials that dissipate surface electrostatic charge, and the others (OptiChamber Advantage and ProChamber[TM] with pediatric facemask) were made from non-conducting materials. The OptiChamber Advantage and ProChamber VHCs were each washed with an ionic detergent and drip dried before testing to minimize surface electrostatic charge. The AeroChamber Max VHCs were tested "out of the package" and also after wash, rinse, and drying. An infant face model incorporating an electrostatic filter in the oral cavity was connected to a breath simulator using a standard waveform for a small child. The fit of each VHC with facemask was demonstrated by agreement of inspiratory flow measurements between a pneumotachograph connected to the system with those set on the simulator. An HFA-fluticasone propionate metered dose inhaler (MDI; 125 microg/dose) was inserted into the VHC, two actuations were delivered, and the filters were subsequently assayed using high-pressure liquid chromatography (HPLC). Testing and sample assay order was randomized, and HPLC assays were undertaken blinded. Drug delivery efficiency expressed as a percentage of the total dose of fluticasone propionate (250 microg) for the AeroChamber Max VHC "out-of-the-package" was 22.0(0.7)% (mean [99% CI]) and 21.2(1.5)% when pre-washed/rinsed. Results for the pre-washed ProChamber and OptiChamber Advantage VHCs were 10.2(0.55)% and 8.8(1.9)%, respectively. The more efficient delivery of medication via VHCs made from electrostatic charge dissipative materials should be considered when choosing doses for small children.

Administration, Inhalation↗
PubMed2006

High-dose inhaled fluticasone does not replace oral prednisolone in children with mild to moderate acute asthma.

BACKGROUND: Inhaled corticosteroids are not as effective as oral corticosteroids in school-aged children with severe acute asthma. It is uncertain how inhaled corticosteroids compare with oral corticosteroids in mild to moderate exacerbations. PRIMARY OBJECTIVE: The purpose of this work was to determine whether there is a significant difference in the percentage of predicted forced expiratory volume in 1 second in children with mild to moderate acute asthma treated with either inhaled fluticasone or oral prednisolone. METHODS: This was a randomized, double-blind controlled trial conducted between 2001 and 2004 in a tertiary care pediatric emergency department. We studied a convenience sample of 69 previously healthy children 5 to 17 years of age with acute asthma and forced expiratory volume in 1 second at 50% to 79% predicted value; 41 families refused participation. Albuterol was given in the emergency department and salmeterol was given after discharge to all patients, as well as either 2 mg of fluticasone via metered dose inhaler and valved holding chamber in the emergency department plus 500 microg twice daily via Diskus for 10 doses after discharge (fluticasone group, N = 35) or 2 mg/kg of oral prednisolone in the emergency department plus 5 daily doses of 1 mg/kg of prednisolone after discharge (prednisolone group, N = 34). We measured a priori defined absolute change in percent predicted forced expiratory volume in 1 second from baseline to 4 and 48 hours in the 2 groups. RESULTS. At 240 minutes, the forced expiratory volume in 1 second increased by 19.1% +/- 12.7% in the fluticasone group and 29.8% +/- 15.5% in the prednisolone group. At 48 hours, this difference was no longer significant (estimated difference: 4.0 +/- 3.4; P = .14). The relapse rates by 48 hours were 12.5% and 0% in the fluticasone group and prednisolone group, respectively. CONCLUSION: Airway obstruction in children with mild to moderate acute asthma in the emergency department improves faster on oral than inhaled corticosteroids.

Administration, Inhalation↗
PubMed2005

How many infective viral particles are necessary for successful mass measles immunization by aerosol?

OBJECTIVES: This study characterized the performance of the "Classical Mexican Device", which immunized 4 million children against measles, demonstrating the efficacy of aerosol vaccination. METHODS: Using plaque-forming units to quantify virus, the particle size distribution (Next Generation Pharmaceutical Impactor) and rate of output coupled with age specific patterns of breathing allowed the calculation of expected pulmonary deposition. RESULTS: The estimated immunization dose for infants was 30 pfu's, for small children 50, and for older children and adolescents it was 130 and 225, respectively. CONCLUSIONS: These performance characteristics can be used to develop newer battery operable devices that are licensable.

Adolescent↗
PubMed2005

Aerosol delivery of an enhanced helper-dependent adenovirus formulation to rabbit lung using an intratracheal catheter.

BACKGROUND: Poor transduction of the ciliated airway epithelium and inefficient airway delivery of viral vectors are common difficulties encountered in lung gene therapy trials with large animals and humans. METHODS: We delivered a helper-dependent adenovirus vector, incorporating a human epithelial cell-specific expression cassette, to rabbit lung. An intratracheal device was used to aerosolize a moderate dose of virus (5 x 10(11) particles), mixed with the enhancing agent LPC (L-alpha-lysophosphatidylcholine), directly into the airways. Lung mechanics, body weight and temperature, transgene expression and histopathology were studied at day 5. RESULTS: Transgene expression was seen in the epithelium of large and small airways, from trachea to terminal bronchioles, with a strong tendency toward the right lung. All cell types of the surface epithelium were transduced. Extensive transduction of the epithelium (66% of cells in trachea) was obtained using virus formulated in isotonic 0.1% LPC, while virus formulated in 0.01% LPC transduced fewer cells (24% in trachea). A transient decrease in dynamic lung compliance was observed immediately following aerosol delivery. Fever and mild-to-moderate patchy pneumonia without edema were also observed. CONCLUSION: These data demonstrate a strategy for efficient and effective transduction of airway epithelium in a large animal.

Adenoviridae↗
PubMed2005

Long-term pulmonary morbidity in survivors of congenital diaphragmatic hernia.

Our objective was to study long-term respiratory outcomes of congenital diaphragmatic hernia (CDH) treated in the perinatal period. This was a cohort study with 26 adolescent survivors and age- and gender-matched controls. Medical histories were retrieved from hospital charts and questionnaires. Pulmonary function testing included measurement of maximum inspiratory and expiratory pressures (MIPS and MEPS) and maximum voluntary ventilation (MVV). Unpaired two-tailed t-test and nonlinear regression were used for statistical analysis. Significant differences were found in forced expiratory volume in one second (FEV(1)) (79% +/- 16% vs. 94% +/- 10%, P < 0.001), FEF(25-75) (62% +/- 24% vs. 84% +/- 15%, P < 0.001), FRC (114% +/- 20% vs. 95% +/- 13%, P < 0.001), RV/TLC (31% +/- 10% vs. 22% +/- 6%, P < 0.001), MVV (74% +/- 16% vs. 90% +/- 13%, P < 0.001), and MIPS (69% +/- 19% vs. 84% +/- 16%, P < 0.01), with numbers indicating percent predicted of reference values +/- SD. Reduction of MVV was not independent from FEV1 (r = 0.83). Forty-eight percent of patients vs. 4% of controls showed significant improvement of FEV1 after bronchodilators (86% +/- 15 vs. 98% +/- 10, P < 0.01). Forty-six percent of patients had abnormalities of the chest wall or spinal column such as pectus excavatum, pectus carinatum, and scoliosis, mostly mild or moderate. In conclusion, long-term respiratory outcome in adolescent CDH is associated with mild to moderate airway obstruction, a high prevalence of response to bronchodilators, and decreased inspiratory muscle strength. This should guide follow-up scheduling and should be taken into account for perioperative and critical care management.

Adolescent↗
PubMed2005

Fetal response to maternal exercise in pregnancies with uteroplacental insufficiency.

OBJECTIVE: The purpose of this study was to determine the fetal response to submaximal maternal exercise at 22 to 26 weeks in pregnancies with abnormal uterine artery Doppler. STUDY DESIGN: This was a prospective comparison of singleton pregnancies with uteroplacental vascular insufficiency (UPVI) (mean uterine pulsatility index [PI] values >1.45 [n = 12]) and those with normal uterine artery Doppler (n = 23). Maternal and fetal cardiovascular responses to 5 minutes of steady state cycling at 10% and at 15% of predicted work rate maximum were studied. RESULTS: Umbilical artery Doppler deteriorated after exercise in patients with UPVI (pre PI 1.4 [0.35-2.14], post PI 1.64 [0.45-2.18]). Three (25%) had transient absent-end diastolic flow (AEDF) in umbilical artery, 2 of which developed early-onset intrauterine growth restriction (IUGR) with AEDF. Fetal cardiac output studies remained stable during the examinations. CONCLUSION: Submaximal steady state exercise had a transient deleterious effect in a subset of women with uteroplacental vascular insufficiency destined to develop early-onset IUGR.

Adult↗
PubMed2005

Use of the next generation pharmaceutical impactor for particle size distribution measurements of live viral aerosol vaccines.

Aerosol administration of live measles vaccine virus has proven to be extremely efficacious in field trials using an industrial compressor coupled to a disposable nebulizer (IPI). To develop a new system for administration, it is necessary to characterize the operating characteristics of the old system. There are no standardized techniques for measuring particle size of live biological agents. This study evaluated the Next Generation Pharmaceutical Impactor's (NGI) ability to particle size wet aerosols in an effort to measure the particle size distribution of live measles vaccine from the IPI nebulizer. As a control albuterol was aerosolized using a Pari LC Star, since the soluble albuterol is evenly distributed throughout the droplets and laser diffraction measurements should agree with those from the NGI, as long as the NGI is cooled to prevent heat transfer to the aerosol. Albuterol was also used as a control for the IPI using quantitative ultraviolet spectrophotometry. There was close agreement in MMD (mean +/- 95% CI) for the LC Star, measured by laser diffraction (3.24 +/- 0.06 microm) and the NGI (2.93 +/- 0.22 microm) and the IPI (4.26 +/- 0.17 and 4.26 +/- 0.24 microm, respectively). For the measles vaccine assayed for plaque forming units, there were significant differences between the NGI MMD (6.14 +/- 0.39 microm) compared to laser diffraction (4.95 +/- 0.16 microm) indicating that the vaccine is not evenly distributed among the droplets of various sizes. This is likely clumping of the virus due to gelatin in the formulation. These data indicate that the NGI is capable of particle sizing live biological agents.

Administration, Inhalation↗
PubMed2005

Bronchial constriction and inhaled colistin in cystic fibrosis.

STUDY OBJECTIVE: Inhaled colistin is used for the treatment of Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients despite reports of chest tightness and bronchospasm. The main objective of the study was to assess whether bronchospasm occurred in pediatric CF patients with or without clinical evidence of airway hyperreactivity. DESIGN AND METHODS: A prospective placebo-controlled clinical trial with crossover design was devised using challenge tests with 75 mg colistin in 4 mL saline solution and a placebo solution of the same osmolarity using a breath-enhanced nebulizer for administration. Subjects were recruited as follows: high risk (HR) for bronchospasm due to a personal history of recurrent wheezing, a family history of asthma and/or atopy, or bronchial lability, as demonstrated in pulmonary function tests; or low risk (LR) without these characteristics. RESULTS: The mean FEV(1) (expressed as the mean [+/- SD] fall from baseline) of the HR group (n = 12) fell 12 +/- 9% after placebo was administered, and fell 17 +/- 10% after colistin was administered. For the LR group (n = 8), the mean FEV(1) fell 9 +/- 4% following placebo administration and 13 +/- 8% following colistin administration. There was a greater number of subjects in the HR group compared to the LR group, which had a mean fall in FEV(1) of >/= 15% (p < 0.01) after inhaling colistin. The differences between placebo and colistin therapy in the LR group were not significant. CONCLUSION: The results demonstrated that colistin can cause bronchospasm, particularly in those patients with coexisting CF and asthma.

Administration, Inhalation↗
PubMed2004

Disease severity in siblings with cystic fibrosis.

Since cross-infection occurs between cystic fibrosis (CF) siblings, we hypothesized that subsequent siblings may acquire respiratory pathogens at an earlier age and have a more severe course of pulmonary disease. We studied a retrospective cohort of 31 sibling pairs from the CF database at the Hospital for Sick Children. Kaplan-Meier curves and modified log-rank tests were used to test sibling differences in age of acquisition of Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA), or any positive culture. Differences in disease severity outcomes were explored. Older siblings were more likely to have both SA and any CF pathogen first isolated from respiratory culture at an older age than younger siblings (P = 0.0050 and P = 0.0008, respectively, by modified log-rank tests). However, more of the older siblings were positive on first culture at time of diagnosis, introducing an age-of-diagnosis bias. Hospitalization rates, courses of oral antibiotics, FEV(1) % predicted, and weight and height measurements were not better in the older children. No differences in clinical parameters were found between older and younger siblings. The apparent finding of younger age at first isolation of pathogens from respiratory cultures in younger siblings is likely because many older siblings were already infected with these organisms at time of diagnosis.

Age of Onset↗
PubMed2004

Comparison of spirometric reference values.

Lung-function reference values play a vital role in the management of respiratory disorders. There are many proposed reference equations for pediatric spirometry. Recently, spirometric reference equations were proposed, using data from people aged 8-80 years living in the US compiled by the third National Health and Nutrition Examination Survey. Our objective was to compare the predictive value of wider age-range reference equations to established pediatric reference equations for the pediatric population. Spirometry, height, and weight were obtained from 70 normal children aged 6-18 years. The difference between measured and predicted values as suggested by different reference equations was compared. Predicted values from general equations significantly differed from those generated from pediatric equations and from measured values in this population. The difference between measured and predicted values from the wider age-range equations varied between 7-16% for forced expired volume in 1 sec (FEV1) and forced vital capacity (FVC). The difference between measured and predicted values for the pediatric equations varied between 1-4%. Although wider age-range equations provide continuity through age ranges, their predictive accuracy may be low in the pediatric age group, especially for the youngest, smallest children. Extrapolating reference equations beyond the age range of subjects used to generate then is not recommended.

Adolescent↗
PubMed2004

Comparison of breath-enhanced to breath-actuated nebulizers for rate, consistency, and efficiency.

OBJECTIVES: To evaluate differences between three new-generation nebulizers-Pari LC Star (Pari Respiratory Equipment; Mississauga, ON, Canada), AeroEclipse (Trudell Medical International, London, ON, Canada), and Halolite (Medic-Aid Limited, West Sussex, UK)-in terms of rate and amount of expected deposition as well as the consistency of the doses delivered. METHODS: The in vitro performance characteristics were determined and then coupled to the respiratory pattern of seven patients with cystic fibrosis (age range, 4 to 18 years) in order to calculate expected deposition. The Pari LC Star and AeroEclipse were characterized while being driven by the Pari ProNeb Ultra compressor (Pari Respiratory Equipment) for home use, and by a 50-psi medical air hospital source. The Halolite has its own self-contained compressor. Algorithms for the rate of output for the inspiratory flow were developed for each device. Patient flow patterns were divided into 5-ms epochs, and the expected deposition for each epoch was calculated from the algorithms. Summed over a breath, this allowed the calculation of the estimated deposition for each patient's particular pattern of breathing. RESULTS: The rate of deposition was highest for the Pari LC Star and lowest for the Halolite. Rate of deposition was independent of respiratory pattern for the Pari LC Star and AeroEclipse, but proportional to respiratory rate for the Halolite. The differences between the Pari LC Star and AeroEclipse were less when driven by the 50-psi source. The AeroEclipse had the least amount of drug wastage. As designed, the Halolite delivered a predetermined amount of drug very accurately, whereas expected deposition when run to dryness of the other two devices had significant variations. CONCLUSIONS: To minimize treatment time, the Pari LC Star would be best. To minimize drug wastage, the AeroEclipse would be best. To accurately deliver a specific drug dose, the Halolite would be best.

Cystic Fibrosis↗