Comparison of velocity-log data collected using impeller and electromagnetic flowmeters.

Previous studies have used flowmeters in environments that are within the expectations of their published ranges. Electromagnetic flowmeters have a published range from 0.1 to 79.0 m/min, and impeller flowmeters have a published range from 1.2 to 61.0 m/min. Velocity-log data collected in five long-screened production wells in the Pleasant Valley area of southern California showed that (1) electromagnetic flowmeter results were comparable within +/-2% to results obtained using an impeller flowmeter for comparable depths; (2) the measured velocities from the electromagnetic flowmeter were up to 36% greater than the published maximum range; and (3) both data sets, collected without the use of centralizers or flow diverters, produced comparable and interpretable results. Although either method is acceptable for measuring wellbore velocities and the distribution of flow, the electromagnetic flowmeter enables collection of data over a now greater range of flows. In addition, changes in fluid temperature and fluid resistivity, collected as part of the electromagnetic flowmeter log, are useful in the identification of flow and hydrogeologic interpretation.

Comparison of efficiency and preference of metal and plastic spacers in preschool children.

BACKGROUND: The metal NebuChamber valved holding chamber (VHC) has gained wide acceptance among children with asthma. Due to its nonelectrostatic properties and larger volume, the 250-mL, metal NebuChamber delivers a greater mass of aerosol to a filter at the mouth compared with the commonly used 150-mL polypropylene AeroChamber VHC. Such in vitro results have been used to suggest that this may provide increased efficacy with the NebuChamber. No comparative efficacy data exist for preschool children with asthma. OBJECTIVE: To compare efficiency and preference of metal and plastic spacers in preschool children. METHODS: Children with mild-to-moderate persistent asthma received 200 microg of budesonide twice daily by NebuChamber or AeroChamber, both with the mask provided in a randomized, 2-month, crossover trial. Symptom diary cards, beta-agonist use, and preference by children and parents were compared. RESULTS: Thirty children (mean +/- SD age, 4.3 +/- 0.3 years) completed the study. There was no difference between the AeroChamber and NebuChamber in clinical efficacy outcomes. There was no difference between the AeroChamber and NebuChamber in parents' view of ease of use, design, acceptability by the children, and overall satisfaction. CONCLUSIONS: Despite a greater total dose delivered to the mouth, the NebuChamber appears no more effective than the AeroChamber and it is not preferred by patients or parents. More parents chose to continue to use the NebuChamber after the study.

Time trends in personnel certification and turnover in the Collaborative Ocular Melanoma Study.

BACKGROUND: The purpose of this analysis was to examine and quantify the coordinating center workload in regard to certification and turnover of clinical personnel who participated in the Collaborative Ocular Melanoma Study (COMS). METHODS: The COMS was a set of multicenter, multidisciplinary randomized clinical trials conducted to evaluate radiotherapy for initial treatment of choroidal melanoma, a primary eye cancer. Patients were screened, enrolled, treated, and followed for mortality and clinical outcomes at 43 clinical centers in the United States and Canada, beginning late in 1986. Clinical centers were added to the COMS during three calendar periods. Training and certification of clinical personnel was performed by five resource centers and coordinated at the COMS coordinating center. A personnel database was maintained at the coordinating center for tracking certification progress, recertification, transfers and resignations. Certification records were analyzed for the period 1986 through 1998 when patient accrual and treatment were completed. RESULTS: Clinical personnel (929 individuals) were certified for one or more of nine distinct roles in the COMS, resulting in 1,342 certifications; 26% were certified for two or more positions. The total number certified for each role ranged from 114 to 208. Certifications per year ranged from 260 in 1987 to 35 in 1997. The certification workload at the coordinating center rose following addition of each group of new clinical centers. It also increased in 1995 as a result of recertification of current personnel mandated by the external data monitoring committee. CONCLUSIONS: This analysis documented that training and certification were continuing tasks, and not limited to initiation of the study. Resignations and reassignments of certified personnel were responsible for 642 decertifications.

Safety of inhaled corticosteroids delivered by plastic and metal spacers.

BACKGROUND: Because of its non-electrostatic properties the metal Nebuchamber (NC) valved holding chamber (VHC) delivers a greater mass of aerosol to the mouth than the polypropylene Aerochamber (AC) VHC. Delivery of more aerosol to the lungs may also increase systemic absorption of inhaled corticosteroids (ICS) and hypothalamo-pituitary-adrenal (HPA) suppression. METHODS: Thirty children (mean 4.3 (SD 0.3) years) received 200 micro g budesonide twice daily by NC or AC, both with the mask provided, in a randomised, two month crossover trial. Twenty four hour urinary free cortisol (UFC) was determined as a measure of HPA suppression. RESULTS: UFC decreased from 42.3 (7.8) nmol UFC/nmol creatinine control to 26.2 (2.4) (p = 0.06 v control) after AC, and to 24.5 (2.5) (p = 0.04 v control) after NC (p = 0.4 AC v NC). CONCLUSIONS: Despite a greater total dose delivered to the mouth, NC is not associated with greater HPA suppression when using 400 micro g/day budesonide under real life conditions in young children.

Protection against methacholine-induced bronchospasm: salbutamol pMDI versus Clickhaler DPI.

Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy. This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler) with a reference salbutamol pMDI (Ventolin). Adult asthma patients with airway hyperresponsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20) <4 mg x mL(-1)) were treated on separate days with 0, 100, 200 or 400 microg of salbutamol via the DPI or pMDI. Methacholine challenge was performed before and after salbutamol treatment and the PC20 ratios analysed by Finney's bioassay to test for therapeutic equivalence of the inhalers. Eighteen patients completed the study and showed significant dose-related responses to salbutamol. The relative potency of DPI:pMDI was 1.29 (90% confidence interval 1.04-1.63). There were no treatment differences in safety (cardiac frequency, blood pressure, adverse events). Methacholine-challenge methodology provides a sensitive bioassay and has demonstrated therapeutic equivalence of the salbutamol Clickhaler dry-powder inhaler with the conventional salbutamol pressurised metered-dose inhaler.

Aerosols for systemic delivery of macromolecules.

During the past 50 years, aerosol therapy with small molecules has become the mainstay for managing lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. During the past decade, a new therapeutic paradigm has evolved-the delivery of macromolecules into the systemic circulation through the lung. Systemic pulmonary therapy with proteins and peptides resulted from major developments in dry powder drug formulations and aerosol delivery technology. These new technologies will enable the treatment of systemic disease, such as diabetes mellitus, noninvasively by means of the deep lung. Within a decade, it is likely that many medications will be administered in this way.

Aerosol therapy with valved holding chambers in young children: importance of the facemask seal.

OBJECTIVE: Masks are an essential interface between valved holding chambers (VHCs), or spacers, and a small child's face for providing aerosol therapy. Clinical experience suggests that many young children do not cooperate with the VHC treatment or tolerate a mask of any kind. This might impair the mask-face seal and reduce the dose delivered to the child. The objective of this study was to evaluate the ability of parents to provide a good mask-face seal in infants and toddlers using 3 masks provided with commonly used pediatric VHCs and compare this with the seal obtained with the Hans Rudolph pediatric anesthesia mask. METHODS: A preliminary in vitro filter study was conducted to validate the assumption that reduced ventilation as a result of increased facemask leak reduces the drug aerosol dose delivered to the mouth. Facemask leak then was studied in vivo for NebuChamber, AeroChamber, BabyHaler, and Hans Rudolph masks by measuring ventilation with an in-line pneumotachograph while the facemask was held in place by experienced parents who were asked to demonstrate how they deliver medication to their children without any additional instruction. Thirty children (mean age: 3.2 +/- 1.4 years) performed 4 repeat studies with each mask. The first 10 patients performed the tests once again within 1 month. On the second occasion, the parents were coached continuously and encouraged to hold the mask tightly against the child's face. RESULTS: The AeroChamber and Hans Rudolph masks provided the best seal as reflected in the magnitude of the ventilation measured through them. The NebuChamber provided the poorest seal, with 45% less ventilation than the AeroChamber and Hans Rudolph masks. There was considerable intraindividual variability for all masks (24% to 48%); however, the variability with the NebuChamber mask was 2-fold greater than the other masks. All ventilatory volumes during the coached session were significantly greater than during the uncoached session. Variability during the coached session was significantly less (except for the BabyHaler, which remained unchanged). CONCLUSIONS: VHCs with masks designed for use with small children may provide a poor seal with the face, leading to reduced or more variable dose delivery. The facemask seal is critical for efficient aerosol delivery to infants and young children, and this should be stressed to parents.

Mortality from all cancers of asbestos factory workers in east London 1933-80.

OBJECTIVE: To give the observed and expected deaths due to cancer at all separate sites in asbestos workers in east London, and to analyse these for overall effect and exposure-response trend. METHODS: The mortality experience of a cohort of over 5000 men and women followed up for over 30 years since first exposure to asbestos has been extracted. RESULTS: There was a large excess of deaths due to cancer (537 observed, 222 expected). Most of these were due to cancer of the lung (232 observed, 77 expected) and pleural (52) and peritoneal (48) mesothelioma. The exposure-response trend for all these three causes was highly significant. There was also an excess of cancer of the colon (27 observed, 15 expected) which was significantly related to exposure. There were significant excesses of cancer of the ovary, of the liver, and of the oesophagus but with no consistent relation to exposure. CONCLUSIONS: The excess risk of cancer after exposure to asbestos was mainly due to cancer of the lung and mesothelioma. An exposure related excess of cancer of the colon was also detected but the possibility that some of these deaths may have been peritoneal mesotheliomas could not be excluded. There was no consistent evidence of exposure related excesses at any other site.

Laser resection of a pedunculated tracheal adenoma.

We report a case of tracheal adenoma presenting as hemoptysis and reversible airflow obstruction in an ex-smoker. A questionable defect in the tracheal air shadow on a posteroanterior chest radiograph was shown on CT to be a pedunculated, mid-tracheal tumor. Two-stage bronchoscopic laser resection resulted in an apparently normal tracheal mucosa. Results of postresection spirometry were normal.

Comparison of efficacy and safety between flunisolide/AeroChamber and budesonide/turbuhaler in patients with moderate asthma. AER-MD-04 Study Group.

BACKGROUND: There is a limited body of evidence comparing the clinical effects of different inhaled corticosteroids in the treatment of asthma. This study compared the safety and efficacy of inhaled flunisolide and budesonide, both with unique delivery systems that may affect clinical response. OBJECTIVE: This multicenter study was carried out to compare the efficacy and safety of flunisolide, administered via AeroChamber, with budesonide, administered via Turbuhaler, in the treatment of moderate asthma. METHODS: Patients with moderate asthma, defined as an FEV1 of 40% to 85% of predicted, underwent a 2-week run-in period during which beclomethasone, 750 microg twice daily by MDI, was administered, along with salbutamol prn. Patients (n = 176) were then randomized into two groups. One group received flunisolide administered via AeroChamber, 750 microg (3 puffs), twice daily. The second group received budesonide administered via Turbuhaler, 600 microg (3 puffs), twice daily. All patients took salbutamol prn. RESULTS: At the end of the 6-week treatment period, there were no significant differences (P > .05 for all comparisons) in efficacy between the groups as evaluated by any efficacy parameter. The treatment groups also did not differ significantly in the number of adverse events or in the incidence of oropharyngeal Candida infection. CONCLUSION: Flunisolide administered by AeroChamber and budesonide administered via Turbuhaler demonstrate similar efficacy and safety in the treatment of moderate asthma.

Lung deposition and clearance of inhaled (99m)Tc-heparin in healthy volunteers.

The purpose of this study was to quantify the lower respiratory tract (LRT) dose delivered by a single nebulization of (99m)technetium-labeled sodium heparin as well as its airway distribution, and kinetics of aerosol clearance, since inhaled heparin may be useful in the treatment of asthma. Fifteen healthy subjects (5 male, 10 female) inhaled heparin from a jet nebulizer loaded with 90,000 IU of (99m)Tc-heparin, driving flow rate 10 L/min. Lung scintigrams and blood samples were taken immediately and at several time points up to 24 h after inhalation. 15 +/- 3% (mean +/- SD) (mean 13,300 IU) of the heparin nebulizer charge reached the mouth, and 8 +/- 2% (mean 7,000 IU) was found in the LRT. Jet nebulizer residual was 48 +/- 6% (mean 43,000 IU), 32 +/- 4% (mean 29,000) was found on exhalation filters, and 5 +/- 2% in the tubing. (99m)Tc-heparin was distributed uniformly in the lungs, and clearance was biphasic. 39 +/- 8% of the LRT dose of (99m)Tc-heparin remained in the lungs 24 h after inhalation. 10.00 +/- 3.40% (687 +/- 310 IU) of the LRT dose or 0.76 +/- 0.35% of the nebulizer charge was found in the blood. Peak concentration in the blood was found 61 +/- 25 min after conclusion of inhalation, which took 15 min. We conclude that a small but significant fraction of nebulized heparin reaches the LRT. The inhaled heparin distributes uniformly in the lungs from which it clears slowly, making it suitable for local administration without induction of measurable changes in coagulation assays. Administration of the present single dose of heparin thus appears to be safe.

Dry powder versus intravenous and nebulized gentamicin in cystic fibrosis and bronchiectasis. A pilot study.

Aminoglycosides are a mainstay of therapy for patients with cystic fibrosis (CF) or non-CF bronchiectasis who are infected with Pseudomonas aeruginosa (Psa). Traditionally, aerosolized antibiotics are delivered by liquid nebulization. The objective of this study was to determine whether a gentamicin dry powder inhaler (DPI) is as microbiologically active and potentially safe as gentamicin inhaled via a small-volume nebulizer (SVN) or given intravenously. The study was done according to a randomized, single-dose, and triple crossover protocol. Ten patients with CF or non-CF bronchiectasis and chronically infected with Psa were recruited. Patients received a single dose of either gentamicin 160 mg via DPI or SVN, or gentamicin at 5 mg/kg by intravenous infusion. In seven of the 10 patients, the minimum inhibitory concentration (MIC) was achieved in sputum after DPI and SVN, with mean (95% confidence interval) gentamicin concentrations at 2 h after administration of 13.1 microgram/g sputum (range: 2.2 to 23.9 microgram/g) and 97.2 microgram/g sputum (range: 0.3 to 194.2 microgram/g), respectively, whereas gentamicin levels in the sputum after intravenous administration failed to reach the MIC. Gentamicin given by DPI and SVN significantly decreased the sputum Psa density (p < 0.05), by almost one order of magnitude. No significant decline in bacterial counts was observed after intravenous gentamicin. When gentamicin was inhaled, blood concentrations were minimal, and were below concentrations known to cause systemic toxicity. For treatment of Psa infections susceptible to gentamicin, gentamicin administration by DPI appeared to be as efficient as by SVN, despite the delivery of a 7-fold lower dose to the airways.

Inspiratory flow rates through a novel dry powder inhaler (Clickhaler) in pediatric patients with asthma.

Inspiratory flow profiles through a novel dry powder inhaler (DPI) (Clickhaler; Innovata Biomed Ltd, St. Albans, UK) were recorded in 17 pediatric patients (aged 7-16 years) with stable mild to moderate asthma. Most patients (n = 14) could generate high peak inspiratory flows (PIFs) (> 60 L/min) and high flows early in the flow profile. These flows have been shown to be adequate to deaggregate and deliver micronized drug with this delivery system.

Characterization of heparin aerosols generated in jet and ultrasonic nebulizers.

Inhaled heparin has been used for asthma treatment, but results have been inconsistent, probably due to highly varying lung doses. We determined the output per unit time and the particle size distributions of sodium heparin, calcium heparin, and low molecular weight (LMW) heparin formulations in five concentrations from Sidestream jet nebulizers (Medic-Aid, Bognor Regis, England) and an Ultraneb 2000 ultrasonic nebulizer (DeVilbiss, Langen, Germany). We also determined the inhaled mass and the estimated respirable mass for some combinations. For the jet nebulizer, output per minute increased with increasing concentration and flow rate, and particle size decreased from 3.64 to 2.01 microns (mass median diameter [MMD]). The percentage of particles less than 3 microns ranged from 41% to 74%. For the ultrasonic nebulizer, maximum output per minute was achieved at a concentration of 7000 i.u./mL; this maximum depended upon the viscosity and temperature of the solution. MMD was independent of formulation, temperature, or concentration and ranged from 5.61 to 7.03 microns. Sodium heparin/calcium heparin in a concentration of 20,000 i.u./mL in the jet nebulizer driven at 10 L/min produced the highest dose of heparin capable of reaching the lower respiratory tract. Mass balance was determined for these combinations with the jet nebulizer run until visible aerosol generation ceased. Of a loading dose of 80,000 i.u. of heparin, 45,000 i.u. remained in the dead space of the nebulizer, 20,000 i.u. was deposited on the exhalation filter, and 15,000 i.u. was captured on the inhalation filter (inhaled mass). This corresponds to a respirable mass of 10,000 i.u. of heparin with a high probability of reaching the lower respiratory tract in normal healthy adults.

A randomized controlled trial on the effect of inhaled corticosteroids on airways inflammation in adult cigarette smokers.

STUDY OBJECTIVE: To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers. DESIGN: This was a randomized, placebo-controlled, double-blinded clinical trial. SETTING: The subjects were recruited from the community by advertising. PARTICIPANTS: Seventy-one adults with a > or = 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily. INTERVENTION: Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days. MEASUREMENTS AND RESULTS: Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment. CONCLUSIONS: With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.