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Coronavirus disease 2019 (COVID-19) has negatively affected the delivery of respiratory diagnostic services across the world due to the potential risk of disease transmission during lung function testing. Community prevalence, reoccurrence of COVID-19 surges and the emergence of different variants of SARS-CoV-2 have impeded attempts to restore services. Finding consensus on how to deliver safe lung function services for both patients attending and for staff performing the tests are of paramount importance.This international statement presents the consensus opinion of 23 experts in the field of lung function and respiratory physiology balanced with evidence from the reviewed literature. It describes a robust roadmap for restoration and continuity of lung function testing services during the COVID-19 pandemic and beyond.Important strategies presented in this consensus statement relate to the patient journey when attending for lung function tests. We discuss appointment preparation, operational and environmental issues, testing room requirements including mitigation strategies for transmission risk, requirement for improved ventilation, maintaining physical distance and use of personal protection equipment. We also provide consensus opinion on precautions relating to specific tests, filters, management of special patient groups and alternative options to testing in hospitals.The pandemic has highlighted how vulnerable lung function services are and forces us to re-think how long-term mitigation strategies can protect our services during this and any possible future pandemic. This statement aspires to address the safety concerns that exist and provide strategies to make lung function tests and the testing environment safer when tests are required.

This cohort study assesses the association between intravenous magnesium therapy administered in the emergency department and subsequent hospitalization among pediatric patients with refractory acute asthma in Canada., Key Points Question Is receipt of intravenous (IV) magnesium sulfate therapy in the emergency department associated with subsequent hospitalization among children with refractory acute asthma after adjustment for patient-level characteristics? Findings In this secondary analysis of a randomized clinical trial of 816 children who experienced moderate to severe respiratory distress after stabilization therapy and inhaled magnesium therapy or placebo, 88.4% of those who received IV magnesium therapy were hospitalized compared with 29.0% of those who did not receive this therapy. After adjustment, children who received IV magnesium therapy had greater odds of hospitalization compared with those who did not receive this therapy. Meaning The findings suggest that, after adjustment of patient-level characteristics, receipt of IV magnesium in the emergency department is associated with subsequent hospitalization among children with asthma., Importance Despite guidelines recommending administration of intravenous (IV) magnesium sulfate for refractory pediatric asthma, the number of asthma-related hospitalizations has remained stable, and IV magnesium therapy is independently associated with hospitalization. Objective To examine the association between IV magnesium therapy administered in the emergency department (ED) and subsequent hospitalization among pediatric patients with refractory acute asthma after adjustment for patient-level variables. Design, Setting, and Participants This post hoc secondary analysis of a double-blind randomized clinical trial of children with acute asthma treated from September 26, 2011, to November 19, 2019, at 7 Canadian tertiary care pediatric EDs was conducted between September and November 2020. In the randomized clinical trial, 816 otherwise healthy children aged 2 to 17 years with Pediatric Respiratory Assessment Measure (PRAM) scores of 5 points or higher after initial therapy with systemic corticosteroids and inhaled albuterol with ipratropium bromide were randomly assigned to 3 nebulized treatments of albuterol plus either magnesium sulfate or 5.5% saline placebo. Exposures Intravenous magnesium sulfate therapy (40-75 mg/kg). Main Outcomes and Measures The association between IV magnesium therapy in the ED and subsequent hospitalization for asthma was assessed using multivariable logistic regression analysis. Analyses were adjusted for year epoch at enrollment, receipt of IV magnesium, PRAM score after initial therapy and at ED disposition, age, sex, duration of respiratory distress, previous intensive care unit admission for asthma, hospitalizations for asthma within the past year, atopy, and receipt of oral corticosteroids within 48 hours before arrival in the ED, nebulized magnesium, and additional albuterol after inhaled magnesium or placebo, with site as a random effect. Results Among the 816 participants, the median age was 5 years (interquartile range, 3-7 years), 517 (63.4%) were boys, and 364 (44.6%) were hospitalized. A total of 215 children (26.3%) received IV magnesium, and 190 (88.4%) of these children were hospitalized compared with 174 of 601 children (29.0%) who did not receive IV magnesium. Multivariable factors associated with hospitalization were IV magnesium receipt from 2011 to 2016 (odds ratio [OR], 22.67; 95% CI, 6.26-82.06; P

Importance While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown. Objective To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy. Design, Setting, and Participants A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed. Interventions Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408). Main Outcomes and Measures The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes. Results Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, −4.2%; absolute risk difference 95% [exact] CI, −11% to 2.8%];P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, −0.23 to 0.50];P = .46); respiratory rate (0.17 breaths/min [95% CI, −1.32 to 1.67];P = .82); oxygen saturation (−0.04% [95% CI, −0.53% to 0.46%];P = .88); systolic blood pressure (0.78 mm Hg [95% CI, −1.48 to 3.03];P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11];P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%). Conclusions and Relevance Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma. Trial Registration ClinicalTrials.gov Identifier:NCT01429415

Background Tidal volumes standardized to predicted body weight are recommended for adult mechanical ventilation, but children are frequently ventilated by using measured body weight. The goal of this study was to examine the difference in FVC (in milliliters per kilogram [mL/kg]) by using measured body weight compared with predicted body weight in children. Methods This retrospective analysis included outpatient pulmonary function tests (PFTs) from two datasets. Dataset one included 6- to 19-year-old patients undergoing PFTs from the nationally representative Canadian Health Measures Survey. Dataset two included 6- to 20-year-old patients undergoing PFTs at a freestanding children's hospital. FVC mL/kg values were analyzed against BMI z scores to show changes in FVC vs BMI between measured and predicted weight. Results Dataset one included 5,394 PFTs from the Canadian survey. FVC from measured weight decreased as the BMI z score group increased. The median FVC from measured weight was 81.4 mL/kg in the lowest BMI z score group and 51.7 mL/kg in the highest BMI z score group. FVC from predicted weight increased slightly with increasing BMI z score group. Dataset two included 8,472 patient PFTs from clinical measurement. A decline in median FVC from measured weight (from 69.4 to 37.6 mL/kg) as BMI z score group increased was also seen. Conclusions FVC differs significantly when standardizing to measured weight vs predicted weight. Obese children have lung volumes reflecting their predicted body weight from height. Children with low or normal BMI have lung volumes reflecting measured body weight. These findings suggest that targeting tidal volume by using the lower of measured and predicted body weights would be the most lung-protective strategy.

Background: The American Thoracic Society committee on Proficiency Standards for Pulmonary Function Laboratories has recognized the need for a standardized reporting format for pulmonary function tests. Although prior documents have offered guidance on the reporting of test data, there is considerable variability in how these results are presented to end users, leading to potential confusion and miscommunication.Methods: A project task force, consisting of the committee as a whole, was approved to develop a new Technical Standard on reporting pulmonary function test results. Three working groups addressed the presentation format, the reference data supporting interpretation of results, and a system for grading quality of test efforts. Each group reviewed relevant literature and wrote drafts that were merged into the final document.Results: This document presents a reporting format in test-specific units for spirometry, lung volumes, and diffusing capacity that can be assembled into a report appropriate fo...

Spirometry plays a major role in the diagnosis and assessment of severity of lung disease. Determining which lung function values are normal and which are below the lower limit of normal depends on reference equations derived from an appropriate population.The purpose of this study was to derive spirometric reference equations for the Canadian population.The Canadian Health Measures Survey consisted of a respiratory questionnaire, urinary cotinine measurements, and spirometry performed in the sitting position with rigorous quality control standards. Of the 16,606 respondents between 6 and 79 years of age, 11,145 were eliminated for positive responses to the respiratory questionnaire, tobacco exposure, or inability to provide high-quality spirograms. Of the remaining 5,461, roughly half were less than 18 years of age. Quantile regression was used to derive predictive (median) and lower limit of normal equations for males and females for FEV1, FVC, and FEV1/FVC ratio for those with ages greater and less than 18 years.The resulting equations were compared with those from the Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey (NHANES) III by using an ideal subject on the 50th percentile for height and between the ages of 6 and 79 years; the comparison showed minor and inconsistent discrepancies among the predictive equations. A plot of residuals (predicted minus measured value for each subject) suggested a marginally better fit compared with the GLI and NHANES III equations, although differences among the equations were small and unlikely to have any clinical significance.This study provides spirometric reference equations for the Canadian population that were measured under the recommended clinical conditions and with rigorous quality control.

Objectives The Vapotherm system delivers high humidity to the airway of patients by using semipermeable tubules where heated liquid water is in contact with air. The humidified air is conducted to the patient via a heated tube. Preliminary clinical observations in infants with croup suggested that epinephrine added to the water supplying the humidity was delivered successfully in the vapor phase. The purpose of this study was to evaluate the efficiency of the delivery of epinephrine in the vapor phase and to develop the feasibility criteria for a clinical pilot study. Design Thirty milligrams of epinephrine in a 1-L bag of sterile water was used as the humidification source for a Vapotherm 2000i. The output of the heated circuit was condensed and collected into a small Erlenmeyer flask via a metal coil while the whole collection system was submerged in an ice slurry to maintain the outflow temperature from the flask between 0°C and 2°C. The in vitro system was tested at 40°C with flows of 5, 10, and 15 L/min and L-epinephrine concentrations of 15, 30, and 60 mg/L. Each test was duplicated at each of the six conditions. Setting Academic children's hospital research laboratory. Patients None. Interventions None. Measurements and main results The system recovered more than 90% of the water vapor from the fully saturated air at 40°C. The epinephrine concentration recovery quantified by ultraviolet-visible spectrophotometry was 23.9% (27.5-20.4%) (mean and range) of the initial concentration. At flows of 5, 10, and 15 L/min, the delivery of epinephrine would be 1.8, 3.6, and 4.2 μg/min, respectively, which is in the therapeutic range used for parenteral infusion in young children. Conclusions The Vapotherm system can be used to deliver epinephrine in pharmacological doses to the respiratory system as a vapor and thus as an alternative to droplets by conventional nebulization.

A major challenge in developing gene-based therapies for airway diseases such as cystic fibrosis (CF) is sustaining therapeutic levels of transgene expression over time. This is largely due to airway epithelial cell turnover and the host immunogenicity to gene delivery vectors. Modern gene editing tools and delivery vehicles hold great potential for overcoming this challenge. There is currently not much known about how to deliver genes into airway stem cells, of which basal cells are the major type in human airways. In this study, helper-dependent adenoviral (HD-Ad) vectors were delivered to mouse and pig airways via intranasal delivery, and direct bronchoscopic instillation, respectively. Vector transduction was assessed by immunostaining of lung tissue sections, which revealed that airway basal cells of mice and pigs can be targeted in vivo. In addition, efficient transduction of primary human airway basal cells was verified with an HD-Ad vector expressing green fluorescent protein. Furthermore, we successfully delivered the human CFTR gene to airway basal cells from CF patients, and demonstrated restoration of CFTR channel activity following cell differentiation in air-liquid interface culture. Our results provide a strong rationale for utilizing HD-Ad vectors to target airway basal cells for permanent gene correction of genetic airway diseases.

Recently, this international task force reported the general considerations for bronchial challenge testing and the performance of the methacholine challenge test, a “direct” airway challenge test. Here, the task force provides an updated description of the pathophysiology and the methods to conduct indirect challenge tests. Because indirect challenge tests trigger airway narrowing through the activation of endogenous pathways that are involved in asthma, indirect challenge tests tend to be specific for asthma and reveal much about the biology of asthma, but may be less sensitive than direct tests for the detection of airway hyperresponsiveness. We provide recommendations for the conduct and interpretation of hyperpnoea challenge tests such as dry air exercise challenge and eucapnic voluntary hyperpnoea that provide a single strong stimulus for airway narrowing. This technical standard expands the recommendations to additional indirect tests such as hypertonic saline, mannitol and adenosine challenge that are incremental tests, but still retain characteristics of other indirect challenges. Assessment of airway hyperresponsiveness, with direct and indirect tests, are valuable tools to understand and to monitor airway function and to characterise the underlying asthma phenotype to guide therapy. The tests should be interpreted within the context of the clinical features of asthma.

While the FEV1 had been recognized as an excellent indicator of disability, it is not very sensitive to early and mild disease. In cystic fibrosis (CF) small airway disease is believed to be one of the early hallmarks and indices such as the FEF25-75 and FEF75 have been proposed as sensitive markers of early disease. The site of early disease in asthma is not as well worked out. Recently a study of more than 20,000 spirometries found that neither of these indices added anything to the FEV1 /FVC but that study was not disease specific and contained both adults and children and the adults were the most numerous. To see if this would be true in children, 1,175 spirograms from children 6 to 18 years of age with CF or asthma whose FEV1 and FVC were above the lower limit of normal were taken from sequential studies. The data expressed in z scores was plotted with either the FEF25-75 or FEF75 plotted against FEV1 /FVC. In both diseases, but particularly in asthma, the FEV1 /FVC was more likely to be abnormal than either of the other two indices for suggesting that for children, early, or mild disease will be more apparent using the FEV1 /FVC than any other index.

The two American Thoracic Society recommended aerosol delivery devices for methacholine challenge testing are both obsolete and often very difficult to acquire, leading to the test being done with a number of nonstandardized nebulizers. Of the two recommended devices, one is the English Wright nebulizer used in the 2-min tidal breathing method, and the other is the DeVilbiss 646 nebulizer used in the five-breath dosimeter method. The purpose of this study was to evaluate the in vitro performance of potential alternative devices that would be economically viable and would minimize environmental contamination. One device was the disposable breath-actuated AeroEclipse(®) II BAN as a potential delivery system for the 2-min tidal breathing, and the second was the automated system by VIASYS as an alternative to either the 2-min tidal breathing or the five-breath dosimeter method.A breath simulator mimicked an adult or small child breathing pattern, and a slow inhalation for the five-breath method was generated by a spirometry calibration syringe. Methacholine (Provocholine™) was eluted from filters at the "mouth" and assayed by high-pressure liquid chromatography.In 12 sec, the AeroEclipse II BAN would be expected to have a pulmonary deposition equivalent to the 2-min tidal breathing with the English Wright, whereas the VIASYS system would take approximately 40 sec for the equivalent delivery. The per-breath delivery of the VIASYS and the DeVilbiss 646 was approximately the same, whereas one breath from the AeroEclipse II BAN was the equivalent of five from the DeVilbiss 646.These data will allow for planning in vivo studies to develop methacholine challenge protocols using modern aerosol delivery systems.

and expertise that is not readily available in all centers. Other fitness parameters such as peak anaerobic power, measures of power and strength may be simpler to deliver in the clinic. The relationship between these measures and established outcomes such as forced expiratory volume in one second (FEV1) and peak aerobic power (VO2peak) in CFremains unclear. Therefore we evaluated (a) aerobic fitness, (b) anaerobic fitness, and (c) upper and lower body muscle strength to determine their relationship to FEV1 and VO2peak in children with CF. Methods: Eightytwopatients(7‐18years)withCF(40female)fromtheCFclinicatTheHospitalforSickChildrenin Toronto performed a maximal incremental cycling test to exhaustion. Anaerobic power (W) for 10 and 30sec cycling trials as well as vertical jump (VJ) and hand grip strength (HG) were compared to FEV1 and VO2peak. Results: Absolute VO2peak (R 2 ¼0.16, P

Summary Background Aerosolized liposomal Amphotericin B may reduce the incidence of invasive pulmonary Aspergillosis in adults with chemotherapy-induced prolonged neutropenia with less nephrotoxicity. The breath-actuated AeroEclipse® BAN nebulizer is very efficient and minimizes environmental drug contamination since no aerosol is produced, unless the patient is inspiring through the device. Our aim is to develop an appropriate delivery system suitable for children that does not disrupt the liposomes due to the shear forces in nebulization. Methods This is an in vitro experimental study in vitro. Six ml of 4 mg/ml liposomal Amphotericin B solution (AmBisome®; Astellas Pharma Inc., Markham, Ontario, CA) was nebulized with the breath-actuated nebulizer (AeroEclipse®; Trudell Medical International, Canada) and captured by the glass liquid impinger. Sodium dodecyl sulfate was used as detergent to disrupt the liposomes in control samples. Gel filtration, electron microscopy, and high performance liquid chromatography (HPLC) were used to compare the size and shape of the liposomes, and amount of the drug before and after nebulization. The aerosol particle size was obtained by the laser diffraction. Results After nebulization, 97.5% of amphotericin B was captured by the liquid impinger and detected by HPLC. Gel filtration and electron microscopy demonstrated that the drug remained in its liposomal configuration after nebulization. The mass median diameter (MMD) was 3.7 μm and 66% of aerosol particles were less than 5 μm in diameter. Conclusions We demonstrated that liposomal Amphotericin B can be nebulized successfully without disrupting the liposomes and minimize drug loss by using the breath-actuated nebulizer. Pediatr Pulmonol. 2014; 49:574–580. © 2013 Wiley Periodicals, Inc.

Background Up to 30 % of children with acute asthma are refractory to initial therapy, and 84 % of this subpopulation needs hospitalization. Finding safe, noninvasive, and effective strategies to treat this high-risk group would substantially decrease hospitalizations, healthcare costs, and the psycho-social burden of the disease. Whereas intravenous magnesium (Mg) is effective in severe refractory asthma, its use is sporadic due to safety concerns, with the main treatment goal being to prevent intensive care unit admission. In contrast, nebulized Mg is noninvasive, allows higher pulmonary drug concentrations, and has a much higher safety potential due to the lower rate of systemic delivery. Previous studies of inhaled Mg show disparate results due to the use of unknown/inefficient delivery methods and other methodological flaws. Methods/Design The study is a randomized double-blind controlled trial in seven Canadian pediatric Emergency Departments (two-center pilot 2011 to 2014, Canada-wide November 2014 to December 2017). The trial will include 816 otherwise healthy children who are 2 to 17 years old, having had at least one previous wheezing episode, have received systemic corticosteroids, and have a Pediatric Respiratory Assessment Measure (PRAM) ≥ 5 points after three salbutamol and ipratropium treatments for a current acute asthma exacerbation. Eligible consenting children will receive three experimental treatments of nebulized salbutamol with either 600 mg of Mg sulfate or placebo 20 min apart, using an Aeroneb Go nebulizer, which has been shown to maximize pulmonary delivery while maintaining safety. The primary outcome is hospitalization within 24 h of the start of the experimental therapy for persistent respiratory distress or supplemental oxygen. Secondary outcomes include all-cause hospitalization within 24 h, PRAM, vital signs, number of bronchodilator treatments by 240 min, and the association between the difference in the primary outcome between the groups, age, gender, baseline PRAM, atopy, and “viral induced wheeze” phenotype (Fig. 1). Discussion If effective, inhaled Mg may represent an effective strategy to minimize morbidity in pediatric refractory acute asthma. Unlike previous works, this trial targets nonresponders to optimized initial therapy who are the most likely to benefit from inhaled Mg. Future dissemination of results will include knowledge translation, incorporation into a Cochrane Review, presentation at scientific meetings, and a peer-reviewed publication. Trial registration NCTO1429415, registered 2 September 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1151-x) contains supplementary material, which is available to authorized users.

Importance Reliance on pulse oximetry has been associated with increased hospitalizations, prolonged hospital stay, and escalation of care. Objective To examine whether there is a difference in the proportion of unscheduled medical visits within 72 hours of emergency department discharge in infants with bronchiolitis who have oxygen desaturations to lower than 90% for at least 1 minute during home oximetry monitoring vs those without desaturations. Design, Setting, and Participants Prospective cohort study conducted from February 6, 2008, to April 30, 2013, at a tertiary care pediatric emergency department in Toronto, Ontario, Canada, among 118 otherwise healthy infants aged 6 weeks to 12 months discharged home from the emergency department with a diagnosis of acute bronchiolitis. Main Outcomes and Measures The primary outcome was unscheduled medical visits for bronchiolitis, including a visit to any health care professional due to concerns about respiratory symptoms, within 72 hours of discharge in infants with and without desaturations. Secondary outcomes included examination of the severity and duration of the desaturations, delayed hospitalizations within 72 hours of discharge, and the effect of activity on desaturations. Results A total of 118 infants were included (mean [SD] age, 4.5 [2.1] months; 69 male [58%]). During a mean (SD) monitoring period of 19 hours 57 minutes (10 hours 37 minutes), 75 of 118 infants (64%) had at least 1 desaturation event (median continuous duration, 3 minutes 22 seconds; interquartile range, 1 minute 54 seconds to 8 minutes 50 seconds). Among the 118 infants, 59 (50%) had at least 3 desaturations, 12 (10%) had desaturation for more than 10% of the monitored time, and 51 (43%) had desaturations lasting 3 or more minutes continuously. Of the 75 infants who had desaturations, 59 (79%) had desaturation to 80% or less for at least 1 minute and 29 (39%) had desaturation to 70% or less for at least 1 minute. Of the 75 infants with desaturations, 18 (24%) had an unscheduled visit for bronchiolitis as compared with 11 of the 43 infants without desaturation (26%) (difference, −1.6%; 95% CI, −0.15 to ∞; P = .66). One of the 75 infants with desaturations (1%) and 2 of the 43 infants without desaturations (5%) were hospitalized within 72 hours (difference, −3.3%; 95% CI, −0.04 to 0.10; P = .27). Among the 62 infants with desaturations who had diary information, 48 (77%) experienced them during sleep or while feeding. Conclusions and Relevance The majority of infants with mild bronchiolitis experienced recurrent or sustained desaturations after discharge home. Children with and without desaturations had comparable rates of return for care, with no difference in unscheduled return medical visits and delayed hospitalizations.

BACKGROUND: As the use of intravenous magnesium sulfate (MgSO4) for the treatment of refractory asthma is becoming more common, the incidence of MgSO4-related systemic hypotension is also rising. One option is to deliver MgSO4 via aerosol, but compared to most inhaled medications, which are active in the microgram dose range, the MgSO4 dose requirement is in the milligram range. This, along with inefficient aerosol delivery systems, may be the reason that some studies have found lack of efficacy with aerosol MgSO4. In preparation for a multicenter study of inhaled MgSO4 in asthmatic children 2–17 years old, we conducted an in vitro study to choose the best MgSO4 nebulizer system that would be effective over the entire age range. METHODS: We tested the Pari LC Star jet nebulizer, Omron MicroAir vibrating-mesh nebulizer, and the Aeroneb Go vibrating-mesh nebulizer with the Idehaler valve-less holding chamber. Aerosol delivery was via face mask. RESULTS: The Pari LC Star had an appropriate particle size distribution but a very slow aerosol output rate. The Omron MicroAir had an even slower output rate and a larger particle size distribution, which would be inappropriate for smaller children. In vitro lung deposition with the Aeroneb Go with Idehaler was 16.0 ± 0.4 mg/min in older children and approximately a fifth of that in toddlers. CONCLUSIONS: The Aeroneb Go with Idehaler was chosen for the multicenter clinical study.

Previous studies have reported differences in muscle function and metabolism between patients with cystic fibrosis (CF) and healthy controls (HC), but it is currently unknown whether these abnormalities are specific to CF or also seen in other airway diseases. In this study, we used magnetic resonance spectroscopy (MRS) during exercise to assess muscle metabolism in CF patients. Twenty patients with CF and 20 age, gender, and habitual activity-matched HCs and a respiratory disease comparison group with primary ciliary dyskinesia (PCD; n = 10) were studied. Phosphorus MRS (P-MRS) was used to characterize muscle bioenergetic metabolism at rest and after high-, moderate-, and low-intensity exercise. CF patients exhibited lower resting ATP/phosphocreatine (PCr) ratio and significantly higher end-exercise pH values compared with both HC and PCD patients. Both CF and PCD patients demonstrated significantly slower PCr recovery time constants after high-intensity exercise. Our results suggest that not only there are specific abnormalities of muscle metabolism in CF patients but also there is a nonspecific impact of respiratory disease on muscle function.

Poor adherence to recommended therapy in cystic fibrosis (CF) is often because of the time demands of therapy. Tobramycin (TOBI ® , 300 mg at 60 mg/ml) inhaled from the PARI LC PLUS ® nebulizer requires about 20 min. This study determined if equivalent levels of pulmonary deposition could be achieved in shorter time using 1.5 ml of 100 mg/ml tobramycin solution delivered by an investigational eFlow ® nebulizer. Sixteen males with stable CF, 8 children and 8 adults, and an FEV 1 > 45% predicted inhaled both preparations on two occasions with 99m Tc-DTPA added to the tobramycin. Blood samples were taken for quantification of tobramycin in the serum. The PARI LC PLUS ® delivered 45.4 (39.3-51.6), mean and 95% CI, mg to the lungs in 17.0 ± 2.5min (mean ± SD) with serum levels of 1,089 ± 388 μg/L. The investigational eFlow ® delivered 46.3(40.3―51.7) mg in 4.0 ± 1.0 min with blood levels of 909 ± 458 μg/L. Only the time of delivery was significantly different with P< 0.0001 (paired t-test). Tolerability of the treatment was comparable for both inhalation regimes, but the shorter treatment was preferred by all patients. These results demonstrate the possibility of delivering equivalent levels of tobramycin much faster into the lungs of CF patients when using eFlow ® , a very efficient electronic nebulizer.

Regular exercise and habitual physical activity are important for patients with cystic fibrosis (CF). Research has demonstrated the benefits of aerobic, anaerobic, and strength exercise training programs for health and quality of life, however, the CF patient is faced with unique barriers and challenges to participation. Recently, increased levels of habitual physical activity have been shown to slow the decline in lung function in patients with CF, and regular participation in a variety of activities may result in greater adherence in the long term. Research is now available to justify the incorporation of exercise into the routine care of patients with CF. This paper provides the background and rationale for the implementation of exercise and habitual physical activity recommendations by the health care team. Education of health care providers regarding the importance of exercise and habitual physical activity for patients with CF is needed in order for exercise and physical activity to be incorporated as key components of clinical practice and into the lives of patients with CF.

Age-related reference ranges are useful for assessing growth in children. The LMS method is a popular technique for constructing growth charts that model the age-changing distribution of the measurement in terms of the median, coefficient of variation and skewness. Here the methodology is extended to references that depend on body size as well as age, by exploiting the flexibility of the generalised additive models for location, scale and shape (GAMLSS) technique. GAMLSS offers general linear predictors for each moment parameter and a choice of error distributions, which can handle kurtosis as well as skewness. A key question with such references is the nature of the age-size adjustment, additive or multiplicative, which is explored by comparing the identity link and log link for the median predictor. There are several measurements whose reference ranges depend on both body size and age. As an example, models are developed here for the first four moments of the lung function variables forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in terms of height and age, in a data set of 3598 children and adults aged 4 to 80 years. The results show a strong multiplicative association between spirometry, height and age, with a large and nonlinear age effect across the age range. Variability also depends nonlinearly on age and to a lesser extent on height. FEV1 and FVC are close to normally distributed, while FEV1/FVC is appreciably skew to the left. GAMLSS is a powerful technique for the construction of such references, which should be useful in clinical medicine. Copyright © 2008 John Wiley & Sons, Ltd.

Summary. Rationale: Cystic fibrosis (CF) leads to pathological changes in organs that express the cystic fibrosis transmembrane conductance regulator (CFTR), including secretory cells of the digestive tract and the pancreas. Maintaining nutritional sufficiency is challenging for CF patients and therefore accurate monitoring is important for their clinical management. Purpose: The objectives of this study were to evaluate the effectiveness of skinfold measurements as an accurate method for determining body composition (fat mass (FM) and lean body mass (LBM)) of this population, using dual-energy X-ray absorptiometry (DEXA) as a gold standard comparison and to determine the most accurate equation for this calculation in children with CF. Methods: Fifty-five pediatric patients with CF participated in the study. FM and LBM calculated via four methods: Slaughter, Durnin, Durenberg (2-site and 4-site). The relationship between the methods and DEXA results were estimated by intraclass-correlation coefficient (ICC) and Bland and Altman analyses. Results: The Slaughter method was the most accurate (ICC of 0.92 for FM and 0.99 for LBM) and displayed the least bias over the range of FM and LBM in CF patients. In addition, the results of Bland Altman analyses comparing each skinfold method to DEXA, revealed that the results were evenly distributed along the range of values for the Slaughter calculation, whereas the other three methods under and over estimated % fat results at the upper and lower ends of the range respectively. Conclusion: We therefore conclude that the Slaughter method may be used for body composition assessment of pediatric CF patients. This provides clinical teams with a simple, accurate and non-invasive method that can be used to monitor nutritional status in pediatric

Rationale: Corticosteroid therapy is not routinely recommended in true bronchiolitis. However, since bronchiolitis and the first asthma attack are impossible to distinguish, some infants with the first wheezing episode receive corticosteroids. Optimal duration of corticosteroid therapy in this scenario is unknown. This study compared efficacy of multiple administrations and a single dose of dexamethasone in bronchiolitis. Methods: In this randomized double blind trial, previously healthy outpatients 2–23 months of age with bronchiolitis and Respiratory Disease Assessment Instrument (RDAI) score 6 or more received 1 mg/kg of oral dexamethasone in the Emergency Department. Prior to discharge at 4 hr they were randomized to either 4 daily doses of dexamethasone 0.15 mg/kg or placebo equivalent. Primary outcome was the proportion of subsequent hospitalizations or prescribed trials of bronchodilator/corticosteroid therapy for dyspnea by day 6 in the groups. Secondary outcomes were changes in the RDAI to day 6, and proportions with unscheduled visits by days 6 and 28. Results: The rate of primary outcome in the single dose group (SDG, N = 64) was 9/64 or 14.1% versus 7/61 or 11.5% in the multiple dose group (MDG, N = 61) [95% CI 0.09; 0.14]. Twelve (18.8%) children in the SDG had unscheduled medical visits by day 6 versus 11 (18.0%) children in the MDG [95% CI 0.13; 0.14]. On day 6 the RDAI decreased from 9.5 ± 2.1 to 2.1 ± 2.4 in the SDG and from 9.8 ± 2.2 to 1.6 ± 2.3 in the MDG [95% CI 0.36; 2.06]. Between days 7–28, 24/64 (37.5%) SDG infants returned for care versus 20/61 (32.8%) of the MDG [95% CI 0.12; 0.21]. Conclusions: Our study suggests that, in outpatients with bronchiolitis who receive dexamethasone, continuation of this agent beyond the initial dose does not provide significant benefit. Pediatr Pulmonol. 2008; 43:844–850. © 2008 Wiley-Liss, Inc.

Background Patients with cystic fibrosis spend as much 30 min a day inhaling tobramycin. Could a new rapid system deposit the equivalent amount of tobramycin faster? Methods Six healthy adult males inhaled 5 ml (300 mg) of tobramycin from a breath enhanced nebulizer and either 125 mg (n = 3) or 150 mg (n = 3) from a vibrating membrane system with a large or small aerosol mixing chamber respectively. A radiolabel was added to the solution and shown to “track” with the tobramycin. Imaging was done with a dual headed gamma camera. Because the radiolabel will be cleared by mucociliary action during administration, algorithms were developed to allow the comparison of a slower system to a faster one. Results Both formulations were well tolerated. The lung deposition was 16.6 ± 3.2% (mean ± SD) of the charge dose delivered in 10.9 ± 1.0 min for the breath enhanced nebulizer versus 32.0 ± 5.1% delivered in 2.5 ± 0.4 min from the vibrating membrane system. The absolute pulmonary delivery of tobramycin was 49.9 ± 9.6 versus 43.9 ± 4.8 mg for the two systems respectively, differences that were statistically significant (pair t-test) but unlikely to be clinically significant. There was a similar deposition of tobramycin for the 125 and 150 mg dose. Conclusions It is possible to deliver an equivalent amount of tobramycin in a shorter period of time with the new vibrating membrane system and a more concentrated formulation. These data will allow the design of a comparison in patients with CF. Pediatr Pulmonol. 2008; 43:753–759. © 2008 Wiley-Liss, Inc.

Purpose To understand potential benefits of exercise in the cystic fibrosis (CF) population, there needs to be accurate methods to quantify it. The Habitual Activity Estimation Scale (HAES) questionnaire has been shown to be a feasible tool to measure physical activity however the reliability and validity have yet to be determined in the CF population. Methods Fourteen (seven male, seven female) patients aged 16.2 ± 4.2 years with CF participated in this study. Participants were clinically stable at the time of the study and participating in their habitual physical activity. To assess reliability, patients completed the HAES and a validated 3-day activity diary, and wore an ActiGraph™ Accelerometer for two consecutive weeks. Validity was assessed by comparing the activity results of each of the three instruments over a single week time period. Results ICC estimates of reliability for the HAES, diary, and accelerometer were 0.72 (P

Rationale: The Third National Health and Nutrition Examination Survey (NHANES III) reference is currently recommended for interpreting spirometry results, but it is limited by the lack of subjects younger than 8 years and does not continuously model spirometry across all ages. Objectives: By collating pediatric data from other large-population surveys, we have investigated ways of developing reference ranges that more accurately describe the relationship between spirometric lung function and height and age within the pediatric age range, and allow a seamless transition to adulthood. Methods: Data were obtained from four surveys and included 3,598 subjects aged 4–80 years. The original analyses were sex specific and limited to non-Hispanic white subjects. An extension of the LMS (lambda, mu, sigma) method, widely used to construct growth reference charts, was applied. Measurements and Main Results: The extended models have four important advantages over the original NHANES III analysis as follows: (1) they extend the reference data down to 4 years of age, (2) they incorporate the relationship between height and age in a way that is biologically plausible, (3) they provide smoothly changing curves to describe the transition between childhood and adulthood, and (4) they highlight the fact that the range of normal values is highly dependent on age. Conclusions: The modeling technique provides an elegant solution to a complex and longstanding problem. Furthermore, it provides a biologically plausible and statistically robust means of developing continuous reference ranges from early childhood to old age. These dynamic models provide a platform from which future studies can be developed to continue to improve the accuracy of reference data for pulmonary function tests.

In quantifying aerosol delivery, the drug is often mixed with a radiolabel such as (99m)Tc-DTPA whose deposition is used as a proxy for the drug. (99m)Tc-DTPA deposited in the lung is cleared by a combination of absorption into the pulmonary circulation and mucociliary clearance. If administration is not instantaneous, the image will not include that clearance during administration, a problem raised if comparing devices with different administration times. However, if rates of clearance are measured, it will be possible to "correct" the initial image for the clearance that occurred during administration and before counting. Five adult males inhaled a 5-mL solution containing (99m)Tc-DTPA from a breath enhanced jet nebulizer (LC Plus)over the course of 10 min and a 1.25-mL solution from a vibrating membrane device (eFlow), which was delivered in 2.5 min. Quality assurance was the radioactivity count balance (RCB) defined as the difference in the total radioactivity pre-nebulization less post, divided by pre, and expressed as a percentage. Attenuation calculations used a (57)Co flood source (Macey and Marshall). The "correction" for the clearance of (99m)Tc-DTPA was 0.91 +/- 0.04 (mean +/- SD) for the LC Plus) and 0.96 +/- 0.02 for the eFlow). RCB was -0.6 +/- 3.5% for the LC Plus and -4.7 +/- 6.4% for the eFlow, implying acceptable accuracy. For the LC Plus, lung deposition was 15.9(13.4, 18.4)% (mean and 95% CI) of the charge dose, and for the eFlow it was 32.0(29.0, 35.0)%. This technique gave an acceptable level of accuracy for quantitative planar imaging and allowed the comparison of delivery from devices with very different rates of delivery.

Udgivelsesdato: 2007-Mar

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 µm. 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. Copyright © 2006 John Wiley & Sons, Ltd.

The American Thoracic Society guidelines (1999) for methacholine challenge tests (MCTs) using the 2-minute tidal breathing protocol were developed for the now-obsolete English-Wright (EW) nebulizer. In addition, the guideline recommendation to use the provocative concentration of methacholine causing a 20% drop in FEV1 (PC20) rather than the provocative dose of methacholine causing a 20% drop in FEV1 (PD20) for determining the level of bronchial hyperresponsiveness has been challenged.To determine if cumulative dose or concentration of methacholine delivered to the airways is the determinant for airway responsiveness and to validate use of the AeroEclipse* II BAN (Aero; Trudell Medical International, London, ON, Canada) nebulizer compared with use of the reference standard EW nebulizer.Subjects with asthma (10-18 yr old) participated in randomized, controlled cross-over experiments comparing four MCT protocols using standard methacholine concentrations, but varying: (1) methacholine starting concentration (testing for cumulative effect); (2) nebulizer (EW versus Aero); and (3) inhalation time. PD20 was calculated using nebulizer output rate, inhalation time, and preceding doses delivered. ANOVA analyses were used to compare geometric means of PC20 and PD20 between protocols.A total of 32 subjects (17 male) participated. PC20 differed when starting concentration varied (0.46 vs. 0.80 mg/ml; P0.0001), whereas PD20 did not (0.06 vs. 0.08 mg). PC20 differed with the EW versus the Aero nebulzer with 30-second inhalation (1.19 vs. 0.43 mg/ml; P=0.0006) and the EW versus the Aero nebulizer with 20-second inhalation (1.91 vs. 0.89 mg/ml; P=0.0027), whereas PD20 did not (0.07 vs. 0.06 mg and 0.11 vs. 0.09 mg, respectively).In MCTs, the cumulative dose (PD20), not the PC20, determines bronchial responsiveness. Modern nebulizers may be used for the test if clinical interpretation is based on PD20. Clinical trial registered with www.clinicaltrials.gov (NCT01288482).

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 μg 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.

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.

Over the past year, a series of papers have reviewed the literature concerning assessment and interpretation of lung function in infants and young children with chronic lung disease of infancy. This manuscript, which represents the final paper in that series, summarizes the findings to date and highlights key areas for future research. Despite the huge literature in this field, interpretation of results and their use in guiding clinical management are still limited by difficulties in 'normalizing data' according to body size and maturation and selection of appropriate control groups. Furthermore, sensitive tests that more closely reflect the underlying pathophysiology of 'new' bronchopulmonary dysplasia, together with simple and reliable methods of assessing lung maturity at birth and true oxygen requirements at specified time points are urgently required. Research in this field is also challenged by the need to separate the independent effects of genetic predisposition, gene-environment interactions, preterm delivery, neonatal respiratory disorders and various treatment strategies on the growing lung. The extent to which disruption of lung growth following premature exposure to the extra-uterine environment leads to an earlier or more aggravated decline in respiratory function in later adult life remains to be elucidated. Whatever its origin, given the increasing survival of smaller and more immature infants, the long term sequelae of neonatal lung disease, are likely to continue to change, requiring ongoing, carefully designed longitudinal studies. Future research strategies need to encompass a multicenter, multi-disciplinary, collaborative approach with closer links between clinicians and basic scientists, to ensure that the most relevant research questions are addressed using appropriate methodology and that findings are implemented into clinical practice in a more timely fashion.

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 ¼ of particles ≤5 µm, 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. Pediatr Pulmonol. 2006; 41: 666–673. © 2006 Wiley-Liss, Inc.

[⇓][1] SERIES “ATS/ERS TASK FORCE: STANDARDISATION OF LUNG FUNCTION TESTING” Edited by V. Brusasco, R. Crapo and G. Viegi Number 4 in this Series [1]: #F4

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.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.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% (p0.01) after inhaling colistin. The differences between placebo and colistin therapy in the LR group were not significant.The results demonstrated that colistin can cause bronchospasm, particularly in those patients with coexisting CF and asthma.

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.

Maximal voluntary ventilation (MVV) may be determined directly by the sprint method or calculated from pulmonary function data, using the functions MVV = forced expired volume in 1 sec (FEV1) × 35 or MVV = FEV1 × 40. The purpose of this paper was to test the validity of the equation over a wide range of lung function in children. Cystic fibrosis (CF), a chronic lung disease where children typically have a wide range of pulmonary function, was chosen as the study requirement. Spirometric data from 332 children with CF who underwent pulmonary function testing between 1987–2000 were stratified according to disease severity, and box-plots comparing the ratio of MVV to FEV1 for each category were generated. As results indicated that the equation underestimates true MVV proportionally to the degree of airflow limitation, a new function to predict MVV for this population was derived and tested. The new equation was derived using data from patients who were tested on odd-numbered days (group A). The validity of the new equation was then tested on the patients tested on even-numbered days (group B). To test its validity, the results were compared to the “gold standard” sprint values using a Bland and Altman plot. MVV was expressed as a function of FEV1 and predicted FEV1: MVV = 27.7(FEV1) + 8.8(PredFEV1) (R2 = 0.98, P

With all pulmonary function diagnostic and respiratory therapy equipment, cross-infection has always been a concern, especially in the cystic fibrosis population, in whom pulmonary function tests are done routinely. The aim of this study was to identify and compare the bacterial removal efficiency (BRE, ability of a filter to remove microorganisms) of six different filters used in hospital settings: Microgard (MG), Spirobac (SB), PALL (PL), and KOKO (KK), used in the pulmonary function laboratory; and Clear-Guard (CG) and Respigard (RG), used in ventilator circuits. Filters were tested in both saturated and nonsaturated conditions. A Pseudomonas aeruginosa suspension of 1 x 10(4) to 1 x 10(8) CFU/mL was nebulized onto each filter. A blood agar plate was held immediately downstream from the filter. Colony-forming units (CFU) were then counted after 24 hr of incubation. A peak flow was applied across the spirometry filters. Bacterial thresholds of the filters were also identified (concentration of bacteria at which a filter no longer has 100% BRE). There was a significant difference in BRE among the six filters in saturated states when challenged with 1 x 10(4) CFU/mL (MG, KK, CG, and RG, 100%; SB, 98.8%; PL, 42.7%; P = 0.003). There was no significant difference between saturated and nonsaturated states, or after application of a peak flow. Filter thresholds were significantly different (KK 1 x 10(8), MG 1 x 10(7), CG 1 x 10(6), RG 1 x 10(5), and SB and PL

This international task force report updates general considerations for bronchial challenge testing and the performance of the methacholine challenge test. There are notable changes from prior recommendations in order to accommodate newer delivery devices. Rather than basing the test result upon a methacholine concentration (provocative concentration (PC20) causing a 20% fall in forced expiratory volume in 1 s (FEV1)), the new recommendations base the result upon the delivered dose of methacholine causing a 20% fall in FEV1(provocative dose (PD20)). This end-point allows comparable results from different devices or protocols, thus any suitable nebuliser or dosimeter may be used, so long as the delivery characteristics are known. Inhalation may be by tidal breathing using a breath-actuated or continuous nebuliser for 1 min (or more), or by a dosimeter with a suitable breath count. Tests requiring maximal inhalations to total lung capacity are not recommended because the bronchoprotective effect of a deep breath reduces the sensitivity of the test.

Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation during sleep secondary to a blunted response to hypercapnia and hypoxia. The current case report describes developmentally normal four-year-old monozygotic twin boys who presented in infancy with variable presentations and clinical severity of congenital central hypoventilation syndrome. Both were managed with noninvasive positive pressure ventilation.

To the Editors: A few questions have been raised following the publication in 2005 of the joint American Thoracic Society (ATS)/European Respiratory Society (ERS) series of documents on standardising lung function testing and these are answered below. The following questions and answers pertain to the standardisation document for spirometry 1. ### Start of test criteria Should blows be rejected solely on the basis of a poor back extrapolated volume (EV)? #### Reply Usually. The forced vital capacity (FVC) may be usable, but the forced expiratory volume in 1 s (FEV1) is likely to be falsely high or low. #### Rationale The acceptability criteria for spirometry were designed to help technologists improve the subject’s technique in order to get the best and most reliable result. EV is important for determining that a fast start to the blow was achieved and this is crucial for getting the best values for FEV1 and peak expiratory flow (PEF). ### End of test criteria In the original document, there was an error in table 5. #### Reply In table 5, the within-manoeuvre criteria for a satisfactory completion of a blow should have read “Duration of ≥6 s (3 s for children) and a plateau in the volume–time curve, or if the subject cannot or should not continue to exhale.” The original table had “or” in twice, whereas the accompanying text was correct, as above. #### Rationale The end of test (EOT) criteria are applied in order to ensure that efforts are made to achieve the best estimate of FVC. When a subject cannot meet the plateau criterion (

Inhaled mannitol has been developed for bronchial challenge testing in adults. This study determined if mannitol could identify children with active asthma and responsive to methacholine, and whether mannitol challenge was faster to complete than methacholine challenge. Twenty-five children (aged 6-13 years) responsive to methacholine and 10 nonasthmatic children unresponsive to methacholine were studied. The methacholine challenge (Cockcroft protocol) was followed by a mannitol challenge on separate days. Twenty-one asthmatic children were positive to mannitol. Three taking inhaled corticosteroids with borderline methacholine responsiveness did not respond to mannitol, and one could not complete the mannitol challenge due to cough. The geometric mean (GM) and 95% confidence interval (CI) for PD(15) for mannitol was 39 mg (19, 78), and PC(20) for methacholine was 0.6 mg/mL (0.35-1.02) (r(p) = 0.75, p < 0.001, n = 21). Responses to mannitol were repeatable: GM PD(15) for the first challenge was 29 mg (CI: 17,50), and for the second challenge, 33 mg (CI: 20, 55) (P = 0.44, n = 9). Mannitol was faster to administer than methacholine (median (range)) 14 min (5-32) vs. 29 min (19-49), respectively (P < 0.001). Time to recover to baseline FEV(1) spontaneously and after bronchodilator administration was similar for both challenges. There were no significant falls in arterial oxygen saturations. During mannitol challenge, the mean (SD) fall in FEV(1) in nonasthmatic children was 3.1% (2.9). We conclude that mannitol identifies children with airway hyperresponsiveness and is faster to perform than the methacholine challenge.

The ability to predict drug deposition of inhaled drugs used in cystic fibrosis (CF) is important if there is a need to target specific doses of drug to the lungs of individual patients. The gold standard of measuring pulmonary deposition is the quantification of an aerosolized radiolabel either mixed with the drug solution or tagged directly to the compound of interest. Accuracy of the quantification could be assured if there is agreement between the amount of radioactivity before and after administration. Before administration, the radiolabel is concentrated in the well of the nebulizer, whereas after administration, it is distributed throughout the nebulizer, the expiratory filter and connectors, and the upper airway, stomach, trachea, and lung. Not only is the geometry of the distribution that is presented to the gamma camera different, but there are different attenuation factors for the various body tissues. The primary aim of this study was to evaluate the accuracy of the quantification of deposition. Secondary goals were to compare in vitro nebulizer performance with that measured in vivo during the deposition study. Eighty milligrams of tobramycin and technetium bound to human serum albumin was administered to 10 normal adults using a Pari LC Jet Plus (Pari Respiratory Equipment, Inc., Richmond, VA) breath-enhanced nebulizer. Techniques were developed that allowed for the accounting of 99 +/- 2% of the initial radioactivity. The fraction of the rate of lung deposition to total body deposition was the in vivo respirable fraction (0.62 +/- 0.07), which closely agreed with in vitro measurements of respirable fraction (0.62 +/- 0.04). Drug output measured from the change in weight and concentration in the nebulizer systematically overestimated drug output measured by the deposition study. The results indicate that 11.8 of the initial 80 mg would be deposited in the lungs. This technique could be adapted to accurately quantify the amount of deposition on any inhaled therapeutic agent, but caution must be used when extrapolating performance of a nebulizer on the bench to expected deposition in patients.