Are the Reference Values for the Provocative Concentration of Methacholine Appropriate for Children?

Background: Preliminary data in a randomly selected pediatric cohort study in 8-year-olds suggested a rate of positivity to a methacholine challenge test that was unexpectedly high, roughly 30%. The current recommendation for a negative methacholine test is a 20% decrease in the forced expiratory volume in one second at a dose greater than 400 µg. This was derived from studies in adults using the obsolete English Wright nebulizer. One explanation for the high incidence of positivity in the study in 8-year-olds could be that children deposit more methacholine on a µg/kg basis than adults, due to differences in their breathing patterns. The purpose of this study was to determine if pediatric breathing patterns could result in a higher dose of methacholine depositing in the lungs of children based on µg/kg body weight compared with adults. Methods: An AeroEclipse Breath Actuated nebulizer delivered methacholine aerosol, generated from a 16 mg/mL solution, for one minute, using age-appropriate breathing patterns for a 70 kg adult and a 30 and 50 kg child produced by a breathing simulator. Predicted lung deposition was calculated from the collected dose of methacholine on a filter placed at the nebulizer outport, multiplied by the fraction of the aerosol mass contained in particles ≤5 µm. The dose of methacholine on the inspiratory filter was assayed by high performance liquid chromatography (HPLC). Particle size was measured using laser diffraction technology. Results: The mean (95% confidence intervals) predicted pulmonary dose of methacholine was 46.1 (45.4, 46.8), 48.6 (45.3, 51.9), and 36.1 (34.2, 37.9) µg/kg body weight for the 30 kg child, 50 kg child, and 70 kg adult, respectively. Conclusions: On a µg/kg body weight, the predicted pulmonary dose of methacholine was greater with the pediatric breathing patterns than with the adult pattern.

Outcomes from the first mouth cancer awareness and clinical check-up day in the Dublin Dental University Hospital.

PURPOSE OF THE STUDY: To increase public awareness about mouth cancer, the Dublin Dental University Hospital (DDUH) hosted an awareness day and free mouth check-up in September 2010. The messages of information, self-examination and risk management, and the importance of early detection, were available to all attendees. The role of general dental and medical practitioners in examination of the mouth was stressed. MATERIAL AND METHODS: A questionnaire regarding knowledge about the causes of and risk factors for mouth cancer, and a clinical check-up, were completed. RESULTS: A total of 1,661 individuals (675 male, 986 female) were examined. The mean age was 59.6 years. Just over one-third (36.5%) of those examined required no action, and slightly less (30%) were advised to return to their general dental or medical practitioner (GDP/GMP). Some 21% were advised about self-examination of the mouth, and 8% about smoking cessation. Of the remainder, 52 people (3.5%) were sent for a second opinion. Of these, 30 individuals were referred for further investigation, including biopsy in 27 cases. Following biopsy, five individuals were diagnosed with carcinoma in situ or carcinoma. CONCLUSIONS: The diagnosis of five people with mouth cancers, who may not otherwise have been identified for early treatment, highlights the need for regular mouth examination. It is inappropriate that such an exercise would remain the preserve of the dental teaching hospitals, and it is vital that all dentists take on the responsibility for regular mouth checks for all of their patients. More should be done to encourage those identified as high risk to visit their dentist. There is a need for recognition of the additional resources required for the detection and timely management of such cancers.

A novel, versatile valved holding chamber for delivering inhaled medications to neonates and small children: laboratory simulation of delivery options.

BACKGROUND: Delivery of bronchodilator to infants and small children from a pressurized metered-dose inhaler with valved holding chamber (pMDI-VHC) is limited by airway narrowness, short respiratory cycle time, and small tidal volume (V(T)). There is a need for a versatile, efficient VHC, given the variety of treatment modalities. METHODS: We tested the AeroChamber Mini VHC (the internal geometry of which is optimized for aerosol delivery, and which accepts a pMDI canister that has a dose counter) in experiments to determine differences in the delivery of hydrofluoroalkane-propelled albuterol (90 microg/actuation) during: mechanical ventilation via endotracheal tube (ETT); manual resuscitation via ETT; and spontaneous breathing via face mask. We tested 5 units of the AeroChamber Mini VHC per test. We simulated the tidal breathing of a premature neonate (V(T) 6 mL), a term neonate (V(T) 20 mL), and a child approximately 2 years old (V(T) 60 mL). We collected the aerosol on an electret filter and quantitatively assayed for albuterol. RESULTS: The total emitted mass of albuterol per actuation that exited the VHC was marginally greater during spontaneous breathing (12.1 +/- 1.8 microg) than during manual resuscitation (10.0 +/- 1.1 microg) (P = .046). Albuterol delivery via mechanical ventilation, though comparable with the premature-neonate model (3.3 +/- 1.2 microg), the term-neonate model (3.8 +/- 2.1 microg), and the 2-y-old-child model (4.2 +/- 2.3 microg) (P = .63), was significantly lower than in the spontaneous-breathing and manual-resuscitation models (P < .001). In the neonatal models the total emitted mass was similar with the spontaneous-breathing model (6.0 +/- 1.0 microg with the premature-neonate model, 10.5 +/- 0.7 microg with the term-neonate model) and the manual-resuscitation model (5.5 +/- 0.3 microg premature-neonate model, 10.7 +/- 0.9 microg term-neonate model) (P > or = .46 via one-way analysis of variance). CONCLUSION: The reduced delivery of albuterol during mechanical ventilation (compared to during spontaneous breathing and manual resuscitation via ETT) was probably associated with the saturated atmosphere in the breathing circuit (37 degrees C, relative humidity > 99%), compared to the ambient air (22 +/- 1 degrees C, 44 +/- 7% relative humidity). The AeroChamber Mini VHC may provide a versatile alternative to VHCs that are designed exclusively for one aerosol treatment modality.

Relative precision of inhaler aerodynamic particle size distribution (APSD) metrics by full resolution and abbreviated andersen cascade impactors (ACIs): part 1.

The purpose of this study was to compare relative precision of two different abbreviated impactor measurement (AIM) systems and a traditional multi-stage cascade impactor (CI). The experimental design was chosen to provide separate estimates of variability for each impactor type. Full-resolution CIs are useful for characterizing the aerosol aerodynamic particle size distribution of orally inhaled products during development but are too cumbersome, time-consuming, and resource-intensive for other applications, such as routine quality control (QC). This article presents a proof-of-concept experiment, where two AIM systems configured to provide metrics pertinent to QC (QC-system) and human respiratory tract (HRT-system) were evaluated using a hydrofluoroalkane-albuterol pressurized metered dose inhaler. The Andersen eight-stage CI (ACI) served as the benchmark apparatus. The statistical design allowed estimation of precision with each CI configuration. Apart from one source of systematic error affecting extra-fine particle fraction from the HRT-system, no other bias was detected with either abbreviated system. The observed bias was shown to be caused by particle bounce following the displacement of surfactant by the shear force of the airflow diverging above the collection plate of the second impaction stage. A procedure was subsequently developed that eliminated this source of error, as described in the second article of this series (submitted to AAPS PharmSciTech). Measurements obtained with both abbreviated impactors were very similar in precision to the ACI for all measures of in vitro performance evaluated. Such abbreviated impactors can therefore be substituted for the ACI in certain situations, such as inhaler QC or add-on device testing.

Relative precision of inhaler aerodynamic particle size distribution (APSD) metrics by full resolution and abbreviated andersen cascade impactors (ACIs): part 2--investigation of bias in extra-fine mass fraction with AIM-HRT impactor.

The purpose of this study was to resolve an anomalously high measure of extra-fine particle fraction (EPF) determined by the abbreviated cascade impactor possibly relevant for human respiratory tract (AIM-HRT) in the experiment described in Part 1 of this two-part series, in which the relative precision of abbreviated impactors was evaluated in comparison with a full resolution Andersen eight-stage cascade impactor (ACI). Evidence that the surface coating used to mitigate particle bounce was laterally displaced by the flow emerging from the jets of the lower stage was apparent upon microscopic examination of the associated collection plate of the AIM-HRT impactor whose cut point size defines EPF. A filter soaked in surfactant was floated on top of this collection plate, and further measurements were made using the same pressurized metered-dose inhaler-based formulation and following the same procedure as in Part 1. Measures of EPF, fine particle, and coarse particle fractions were comparable with those obtained with the ACI, indicating that the cause of the bias had been identified and removed. When working with abbreviated impactors, this precaution is advised whenever there is evidence that surface coating displacement has occurred, a task that can be readily accomplished by microscopic inspection of all collection plates after allowing the impactor to sample ambient air for a few minutes.

The importance of nonelectrostatic materials in holding chambers for delivery of hydrofluoroalkane albuterol.

INTRODUCTION: Electrostatic attraction of aerosolized particles to the inner walls of an aerosol holding chamber (HC) made from a nonconducting material can reduce medication delivery, particularly if there is a delay between actuation and inhalation. OBJECTIVE: Compare total emitted mass and fine-particle mass (mass of particles < 4.7 microm) of hydrofluoroalkane-propelled albuterol from similar-sized HCs manufactured from conductive material (Vortex), charge-dissipative material (AeroChamber Max), and nonconductive material (OptiChamber Advantage, ProChamber, Breathrite, PocketChamber, and ACE), with and without wash/rinse pretreatment of the HC interior with ionic detergent, and with 2-s and 5-s delays between actuation and inhalation. METHODS: All the HCs were evaluated (1) directly from their packaging (with no wash/rinse pretreatment) and (2) after washing with ionic detergent and rinsing and drip-drying. We used an apparatus that interfaced between the HC mouthpiece and the induction port of an 8-stage Andersen cascade impactor to simulate a poorly coordinated patient, with delays of 2 s and 5 s between actuation and inhalation/sampling, at 28.3 L/min. RESULTS: With the 2-s delay, the delivered fine-particle mass per actuation, before and after (respectively) wash/rinse pretreatment was: AeroChamber Max: 23.8 +/- 4.8 microg, 21.5 +/- 3.2 microg; Vortex: 16.2 +/- 1.7 microg, 15.5 +/- 2.0 microg; OptiChamber Advantage: 2.6 +/- 1.2 microg, 6.7 +/- 2.3 microg; ProChamber: 1.6 +/- 0.4 microg, 5.1 +/- 2.5 microg; Breathrite: 2.0 +/- 0.9 microg, 3.2 +/- 1.8 microg; PocketChamber: 3.4 +/- 1.6 microg, 1.7 +/- 1.6 microg; ACE: 4.5 +/- 0.9 microg, 5.4 +/- 2.9 microg. Similar trends, but greater reduction in aerosol delivery, were observed with the 5-s delay. Significantly greater fine-particle mass was delivered from HCs made from conducting or charge-dissipative materials than from those made from nonconductive polymers, even after wash/rinse pretreatment (p < 0.01). The fine-particle mass was also significantly greater from the AeroChamber Max than from the Vortex, irrespective of wash/rinse pretreatment or delay interval (p < 0.01). CONCLUSION: HCs made from electrically conductive materials emit significantly greater fine-particle mass, with either a 2-s or 5-s delay, than do HCs made from nonconducting materials, even with wash/rinse pretreatment.

The delivery of chlorofluorocarbon-propelled versus hydrofluoroalkane-propelled beclomethasone dipropionate aerosol to the mechanically ventilated patient: a laboratory study.

UNLABELLED: We describe a laboratory investigation comparing the delivery of chlorofluorocarbon (CFC)- and hydrofluoroalkane (HFA)-formulated beclomethasone dipropionate (BDP) by metered-dose inhaler and holding chamber (AeroChamber HC MV) in a simulation of a mechanically ventilated adult patient. METHODS: We equipped each HC MV (n = 5) with an 8.0 mm diameter endotracheal tube (ETT), locating the HC MV in the inspiratory limb of a breathing circuit linked to a mechanical ventilator set to simulate tidal breathing at tidal volume = 830 mL, respiratory rate = 15 breaths/min, inspiratory-expiratory ratio of 1:2.1, peak inspiratory pressure = 20 cm H(2)O. Temperature and humidity settings were 35+/-1 degrees C and 100% relative humidity (close to body conditions). We compared delivery of 5-actuations of CFC- and HFA-BDP (both 50 microg/actuation), measuring total emitted mass captured by a filter at the distal end of the ETT. In a separate study, we inserted the distal end of the ETT within the entry cone of a cascade impactor so that the aerosol particle size distribution could be determined with the circuit at similar environmental conditions as described previously. We made benchmark measurements with circuit temperature and humidity at room ambient conditions (21+/-1 degrees C and 54+/-5% RH respectively). RESULTS: Total emitted mass (5 measurements/device) was significantly greater for HFA-BDP (14.1+/-1.1 microg/actuation) compared with CFC-BDP (2.4+/-0.8 microg/actuation) (paired t test, p < 0.001). More HFA-BDP (2.7 +/- 0.2 microg/actuation) was lost from the delivery system during exhalation (0.9 +/- 0.4 microg/actuation for CFC-BDP) (p < 0.001). The mass median aerodynamic diameter (MMAD) increased from 1.2 microm (room ambient) to 2.8 microm (higher temperature and humidity conditions) for HFA-BDP. In contrast, MMAD for CFC-BDP remained close to 4.6 microm under either condition, but particles finer than about 4.0 microm increased in size when the circuit was saturated. CONCLUSIONS: Total emitted mass for HFA-BDP was increased by a factor of 5.8 compared with CFC-BDP, due largely to the finer particle size distribution of the HFA-based solution formulation. Additional water vapor required to operate the breathing circuit at close to body conditions resulted in fine particle growth with both formulations.

An in vitro study to investigate the use of a breath-actuated, small-volume, pneumatic nebulizer for the delivery of methacholine chloride bronchoprovocation agent.

BACKGROUND: Current American Thoracic Society and American Association for Respiratory Care guidelines for the delivery of aerosol agents such as methacholine chloride (MC) for bronchoprovocation testing require the use of pneumatic jet nebulizers that have well-defined droplet size and mass output. A recently developed disposable, breath-actuated nebulizer (AeroEclipse) may offer bronchoprovocation testers an alternative to existing devices. METHODS: We studied the performance of 5 AeroEclipse nebulizers with regard to mass of MC delivered with various MC solution concentrations and numbers of inhalations, using a model of adult tidal breathing. Each nebulizer was operated with compressed air (8 L/min at 50 psig) and an initial fill of 2 mL. MC solutions with mass concentrations of 0.25, 0.98, 3.85, and 15.70 mg/mL were tested. The total mass of MC delivered was determined after 5, 10, and 15 complete breathing cycles, by assaying the MC collected on a filter placed at the nebulizer mouthpiece. The aerosol droplet size distribution, fine droplet fraction (FDF) (percentage of droplets < 4.8 microm diameter), and fine droplet mass (FDM) (mass of droplets < 4.8 microm diameter) were determined by laser diffractometry, using physiologically normal saline as a surrogate for MC solution. RESULTS: The mean +/- SD FDM collected in 5 breathing cycles was 654 +/- 29 microg with the 15.70 mg/mL solution, 158 +/- 9 microg with the 3.85 mg/mL solution, 37 +/- 3 microg with the 0.98 mg/mL solution, and 7 +/- 2 microg with the 0.25 mg/mL solution. FDM showed a linear correlation (r(2) = 0.9999) with MC concentration, within the range studied. FDM also showed a linear correlation (r(2) = 0.999) with the number of breathing cycles. For instance, with the 15.70 mg/mL solution, FDM was 654 +/- 29 microg with 5 breathing cycles, 1,228 +/- 92 microg with 10 breathing cycles, and 1,876 +/- 132 microg with 15 breathing cycles. CONCLUSIONS: Although the bronchoprovocation test procedure had to be slightly modified from the guidelines to accommodate the operation of the AeroEclipse's breath-actuation feature, our measurements indicate that a predictable dose of MC, within the useful range for bronchoprovocation testing, can be delivered to an adult patient breathing tidally. The green indicator on the AeroEclipse could be used to coach the patient to inhale for a specific period, thereby controlling MC delivery per breathing cycle.

Aerodynamic particle size analysis of aerosols from pressurized metered-dose inhalers: comparison of Andersen 8-stage cascade impactor, next generation pharmaceutical impactor, and model 3321 Aerodynamic Particle Sizer aerosol spectrometer.

The purpose of this research was to compare three different methods for the aerodynamic assessment of (1) chloroflurocarbon (CFC)--fluticasone propionate (Flovent), (2) CFC-sodium cromoglycate (Intal), and (3) hydrofluoroalkane (HFA)--beclomethasone dipropionate (Qvar) delivered by pressurized metered dose inhaler. Particle size distributions were compared determining mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD), and fine particle fraction <4.7 microm aerodynamic diameter (FPF(<4.7 microm)). Next Generation Pharmaceutical Impactor (NGI)-size distributions for Flovent comprised finer particles than determined by Andersen 8-stage impactor (ACI) (MMAD = 2.0 +/- 0.05 micro m [NGI]; 2.8 +/- 0.07 microm [ACI]); however, FPF(<4.7 microm) by both impactors was in the narrow range 88% to 93%. Size distribution agreement for Intal was better (MMAD = 4.3 +/- 0.19 microm (NGI), 4.2 +/- 0.13 microm (ACI), with FPF(<4.7 microm) ranging from 52% to 60%. The Aerodynamic Particle Sizer (APS) undersized aerosols produced with either formulation (MMAD = 1.8 +/- 0.07 micro m and 3.2 +/- 0.02 micro m for Flovent and Intal, respectively), but values of FPF(<4.7 microm)from the single-stage impactor (SSI) located at the inlet to the APS (82.9% +/- 2.1% [Flovent], 46.4% +/- 2.4% [Intal]) were fairly close to corresponding data from the multi-stage impactors. APS-measured size distributions for Qvar (MMAD = 1.0 +/- 0.03 micro m; FPF(<4.7 micro m)= 96.4% +/- 2.5%), were in fair agreement with both NGI (MMAD = 0.9 +/- 0.03 micro m; FPF(<4.7 microm)= 96.7% +/- 0.7%), and ACI (MMAD = 1.2 +/- 0.02 microm, FPF(<4.7 microm)= 98% +/- 0.5%), but FPF(<4.7 microm) from the SSI (67.1% +/- 4.1%) was lower than expected, based on equivalent data obtained by the other techniques. Particle bounce, incomplete evaporation of volatile constituents and the presence of surfactant particles are factors that may be responsible for discrepancies between the techniques.