Delivery of nebulized budesonide is affected by nebulizer type and breathing pattern.

The aim of this study was to determine the output in-vitro of budesonide from two different nebulizers under simulated breathing conditions. The BimboNeb and Nebula nebulizers were used to nebulize 2 mL of budesonide (500 microg) suspension. Particle size was determined by inertial impaction after a 5-min nebulization. Total outputs of the drug from both nebulizers were measured using a sinus flow pump to create simulated breathing conditions. Paediatric and adult breathing patterns were used, with drug output measured after 5 and 10 min nebulization. The mass median aerodynamic diameter of budesonide using the BimboNeb (4.5 microm) was significantly greater than that from the Nebula (3.4 microm) (P<0.01). With the simulated adult breathing pattern, the total drug output after 5 min with the BimboNeb (61.5 microg) was twice that from the Nebula (30.7 microg). For the paediatric breathing pattern, total outputs were very similar for both nebulizers. In all cases, nebulizing for 10 min produced greater drug outputs compared with those after 5 min, particularly for the paediatric breathing pattern. The amount of aerosolized drug available for inhalation needs to be assessed for each nebuliser used and the effect of the patient's breathing pattern should also be taken into account.

A randomised crossover trial of facemask efficacy.

The efficacy of different facemasks that can be used in the delivery of aerosol medication to children with recurrent wheeze or asthma was investigated. The results showed a statistically significant difference between some of the masks used, which has important implications for current clinical practice

The influence of inhaler selection on efficacy of asthma therapies.

Many different devices are available to aid inhalational drug delivery. Although each device is claimed to have advantages over its rivals, the evidence to support greater efficacy of a particular device is scanty. Most comparative studies are underpowered or flawed in their design. They may use inappropriate end-points, or involve healthy subjects, whose response may be very different from the patient with acute severe asthma. The dosage of drug used in a trial may be at the shallow part of the dose-response curve, masking differences in devices. Only in a few cases have clinical trials detected a significant difference between devices, and trials have rarely taken patient preference into account. The most efficacious device in practice is likely to be the one that the patient will use regularly and in accordance with a health care workers' recommendations.

Increased resting bronchial tone in normal subjects acclimatised to altitude.

BACKGROUND: Normal subjects frequently experience troublesome respiratory symptoms when acclimatised to altitude. Bronchial hyperresponsiveness (BHR) and full and partial flow-volume loops were measured before and after ascent to 5000 m altitude to determine if there are changes in resting bronchial tone and BHR that might explain the symptoms. METHODS: BHR to histamine was measured using a turbine spirometer to record partial and full flow-volume curves and expressed as log dose slopes. Twenty one subjects were tested at sea level and after acclimatisation at 5000 m altitude. RESULTS: No significant change in log dose slope measurements of forced expiratory volume in 1 second occurred after acclimatisation, and the maximal expiratory flow with 30% of forced vital capacity remaining (MEF(30%)) rose on the full loop and fell on the partial loop. Their ratio (full divided by partial) rose on average by 0.28 (95% confidence limits 0.14 to 0.42) from the mean (SD) sea level value of 0.87 (0.20). CONCLUSIONS: There is no increase in BHR in normal subjects acclimatised to altitude but an increase in resting bronchial tone occurs that could be released by deep inspiration. This may be the result of increased cholinergic tone.

Nasal peak inspiratory flow at altitude.

The present study investigated whether there are changes in nasal peak inspiratory flow (NPIF) during hypobaric hypoxia under controlled environmental conditions. During operation Everest III (COMEX '97), eight subjects ascended to a simulated altitude of 8,848 m in a hypobaric chamber. NPIF was recorded at simulated altitudes of 0 m, 5,000 m and 8,000 m. Oral peak inspiratory and expiratory flow (OPIF, OPEF) were also measured. Ambient air temperature and humidity were controlled. NPIF increased by a mean +/- SD of 16 +/- 12% from sea level to 8,000 m, whereas OPIF increased by 47 +/- 14%. NPIF rose by 0.085 +/- 0.03 L x s(-1) per kilometre of ascent (p<0.05), significantly less than the rise in OPIF and OPEF of 0.35 +/- 0.10 and 0.33 +/- 0.04 L x s(-1) per kilometre (p<0.0005). Nasal peak inspiratory flow rises with ascent to altitude. The rise in nasal peak inspiratory flow with altitude was far less than oral peak inspiratory flow and less than the predicted rise according to changes in air density. This suggests flow limitation at the nose, and occurs under controlled environmental conditions, refuting the hypothesis that nasal blockage at altitude is due to the inhalation of cold, dry air. Further work is needed to determine if nasal blockage limits activity at altitude.

Serial changes in spirometry during an ascent to 5,300 m in the Nepalese Himalayas.

The aims of the present study were to determine the changes in forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1) and peak expiratory flow (PEF), during an ascent to 5,300 m in the Nepalese Himalayas, and to correlate the changes with arterial oxygen saturation measured by pulse oximetry (SpO2) and symptoms of acute mountain sickness (AMS). Forty-six subjects were studied twice daily during an ascent from 2,800 m (mean barometric pressure 550.6 mmHg) to 5,300 m (mean barometric pressure 404.3 mmHg) during a period of between 10 and 16 days. Measurements of FVC, FEV1, PEF, SpO2, and AMS were recorded. AMS was assessed using a standardized scoring system. FVC fell with altitude, by a mean of 4% from sea level values [95% confidence intervals (CI) 0.9% to 7.4%] at 2,800 m, and 8.6% (95% CI 5.8 to 11.4%) at 5,300 m. FEV1 did not change with increasing altitude. PEF increased with altitude by a mean of 8.9% (95% CI 2.7 to 15.1%) at 2,800 m, and 16% (95% CI 9 to 23%) at 5,300 m. These changes were not significantly related to SpO2 or AMS scores. These results confirm a progressive fall in FVC and increase in PEF with increasing hypobaric hypoxia while FEV1 remains unchanged. The increase in PEF is less than would be predicted from the change in gas density. The fall in FVC may be due to reduced inspiratory force producing a reduction in total lung capacity; subclinical pulmonary edema; an increase in pulmonary blood volume, or changes in airway closure. The absence of a correlation between the spirometric changes and SpO2 or AMS may simply reflect that these measurements of pulmonary function are not sufficiently sensitive indicators of altitude-related disease. Further studies are required to clarify the effects of hypobaric hypoxia on lung volumes and flows in an attempt to obtain a unifying explanation for these changes.

An in vitro analysis of the output of budesonide from different nebulizers.

BACKGROUND: Inhaled corticosteroids are increasingly used in the treatment of asthma, and many different nebulizers are available to aerosolize steroid medications. There are few comparative data on their ability to do so. OBJECTIVE: Our purpose was to determine the particle size and mass output of budesonide nebulizer suspension from different nebulizers. METHODS: In vitro measurement of drug particle size and total drug output from 3 nebulizers (the Pari LC Plus, the Pari LC Star, and the Medicaid Ventstream) was performed under simulated breathing conditions. Nebulizers were charged with 2 mL (500 microg) of budesonide suspension. A sinus pump was used to draw aerosol from the nebulizers onto a filter during simulated inspiration at tidal volumes of 150 and 600 mL, mimicking pediatric and adult use. Aerosol particle size was determined separately by inertial impaction. RESULTS: The LC Plus nebulizer had the highest initial output rate and delivered the most budesonide at both breathing patterns. The maximal output rates of the Ventstream and LC Star nebulizers was half that of the LC Plus, but the LC Star nebulizer continued nebulization for longer and delivered twice as much budesonide as the Ventstream did. However, the Ventstream produced the smallest particles, mass median diameter 3.1 microm compared with 3.8 microm for the LC Star and 4.1 microm for the LC Plus. CONCLUSIONS: This study has identified differences among the nebulizers that would not have been apparent with current standards for nebulizer assessment. Incorporation of breathing simulation in the study imitates patient use and allows effective nebulization times to be predicted. The results suggest that the nebulizers studied would deliver different masses of budesonide to the lungs and to the upper airway. This may have important consequences in determining the efficacy and side effect profile of budesonide.

The output of budesonide from spacer devices assessed under simulated breathing conditions.

BACKGROUND: Spacer devices are increasingly used to aid inhalational therapy, and many different devices are available. Patient and spacer size and spacer static charge may affect drug delivery, but the optimum spacer size and method of reducing static charge is not certain. OBJECTIVE: We sought to determine the output of budesonide from 3 different spacer devices when assessed by using simulated breathing at different tidal volumes and to assess the effect of washing and handling the spacer on drug output. METHODS: Three spacer types were assessed: 2 polycarbonate spacers, the Aerochamber and the Nebuhaler, and the metal Nebuchamber or Non-Electrostatic-Spacer. Breathing was simulated by using a sinus flow pump. Metered-dose inhalers of budesonide 200 microg were actuated into the spacer, which was attached to the breathing simulator for 5 simulated breathing cycles. Budesonide was collected on a filter placed between the spacer and breathing simulator and was assayed by HPLC. Spacers were assessed after they had been washed briefly in water, after they had been washed briefly in cetrimide solution in an attempt to reduce their static charge, and after they had been handled to simulate normal use. In separate experiments budesonide particle size from the spacers was measured by using a multistage liquid impinger. RESULTS: Drug output from the Nebuchamber was greater than that from the other 2 spacers, especially at lower tidal volumes. With 150 mL of tidal volume, the Nebuchamber delivered 36% of the nominal dose to the filter versus 13% from the Nebuhaler and 7% from the Aerochamber. The output from the Aerochamber and Nebuhaler increased linearly with tidal volume, but this was not the case with the Nebuchamber, in which output was constant at tidal volumes of 150 mL and above. Compared with washing in tap water, neither washing the spacers in 0.1% cetrimide solution nor vigorous wiping with a paper towel changed their output. Thirty-eight percent of the drug from the Nebuchamber was contained in particles smaller than 4.7 microm in diameter compared with 47% from the Nebuhaler and 53% from the Aerochamber. CONCLUSIONS: The Nebuchamber increases in vitro budesonide delivery compared with the polycarbonate spacers tested but delivers a greater percentage of the drug in large particles. No increase in delivery with tidal volume was seen with the Nebuchamber, which would deliver a higher dose of drug per kilogram of body weight to smaller patients. Briefly washing the polycarbonate spacers in water or in a weak detergent solution, simulating household washing, did not make them as effective as the metal spacer. Further research is needed to determine a practical washing and handling method to reduce static charge on polycarbonate spacers.

New formulation metered dose inhaler increases breath alcohol levels.

A new, chlorofluorocarbon-free metered dose inhaler containing salbutamol, with small amounts of ethanol as a co-solvent, has recently been released. We evaluated the effect on breath alcohol levels of two inhalations from this metered dose inhaler. In 10 volunteers, breath alcohol levels rose to 17.9 micrograms 100 ml-1 breath after an inhalation with a good technique, and to 35 micrograms 100 ml-1 breath (the current legal limit for driving in the UK) after a poor inhalation. Breath alcohol levels were reduced by the use of a spacer device, and in all cases fell to near zero after 2 min. In patients who have just used this type of metered dose inhaler, breath alcohol measurements should be defferred for at least 2 min.

An in vitro analysis of the output of salbutamol from different nebulizers.

The objective of this study was to determine the particle size and mass output of salbutamol from different nebulizers used under simulated breathing conditions. Seven nebulizer/compressor combinations were assessed. Each nebulizer was charged with 5 mg salbutamol solution and connected to a breathing simulator operating at tidal volumes of 150 mL and 600 mL. Nebulizers were operated for 15 min. Salbutamol collected on the filters was measured by liquid chromatography. Aerosol particle size was determined separately by laser diffraction. The Pari LC Star nebulizer delivered the most salbutamol at both tidal volumes. The maximal output of the Medicaid Ventstream and Sidestream nebulizers was two-thirds that of the LC Star, and they delivered less salbutamol than the LC Star or LC Plus nebulizers. The Intersurgical Cirrus nebulizer delivered the least salbutamol at both tidal volumes, although there was only a small difference between the Cirrus and Ventstream or Sidestream nebulizers at 150 mL tidal volume. The LC Plus nebulizer produced larger particles, mass median diameter 5.3 microm, compared with 3.6-4.0 microm for the other nebulizers. In conclusion, there were large differences in the delivery of salbutamol between the nebulizers studied, even between nebulizers of apparently the same class, and this should be borne in mind by regulatory authorities, clinicians and researchers.

Cough frequency and cough receptor sensitivity to citric acid challenge during a simulated ascent to extreme altitude.

The aim of this study was to determine the frequency of cough and the citric acid cough threshold during hypobaric hypoxia under controlled environmental conditions. Subjects were studied during Operation Everest 3. Eight subjects ascended to a simulated altitude of 8,848 m over 31 days in a hypobaric chamber. Frequency of nocturnal cough was measured using voice-activated tape recorders, and cough threshold by inhalation of increasing concentrations of citric acid aerosol. Spirometry was performed before and after each test. Subjects recorded symptoms of acute mountain sickness and arterial oxygen saturation daily. Air temperature and humidity were controlled during the operation. Cough frequency increased with increasing altitude, from a median of 0 coughs (range 0-4) at sea level to 15 coughs (range 3-32) at a simulated altitude of 8,000 m. Cough threshold was unchanged on arrival at 5,000 m compared to sea level (geometric mean difference (GMD) 1.0, 95% confidence intervals (CI) 0.5-2.1, p=0.5), but fell on arrival at 8,000 m compared to sea level (GMD 3.3, 95% CI 1.1-10.3, p=0.043). There was no relationship between cough threshold and symptoms of acute mountain sickness, oxygen saturation or forced expiratory volume in one second. Temperature and humidity in the chamber were controlled between 18-24 degrees C and 30-60%, respectively. These results confirm an increase in cough frequency and cough receptor sensitivity associated with hypobaric hypoxia, and refute the hypothesis that high altitude cough is due to the inhalation of cold, dry air. The small sample size makes further conclusions difficult, and the cause of altitude-related cough remains unclear.

A comparative analysis of the particle size output of beclomethasone diproprionate, salmeterol xinafoate and fluticasone propionate metered dose inhalers used with the Babyhaler, Volumatic and Aerochamber spacer devices.

AIMS: To determine in vitro the effect of delay, inspiratory flow, and spacer washing on the drug output of metered dose inhalers (MDIs) used with different spacer devices. METHODS: The amount of drug in particles <5 microm diameter from MDI+spacer, sampling after a delay of up to 20 s, was measured using a Multistage Liquid Impinger. Drug output was also measured at different flow rates, and after washing the Babyhaler in household detergent. RESULTS: More fluticasone in small particles was recovered from the Babyhaler than the Volumatic or the Aerochamber spacers, and more beclomethasone and salmeterol was recovered from the Babyhaler and Volumatic spacers than from the Aerochamber. Washing the Babyhaler reduced the recovery of salmeterol, and did not alter the recovery of the other drugs tested. CONCLUSIONS: Spacer devices need to be fully evaluated for each drug prescribed for them.

Drug output from nebulizers is dependent on the method of measurement.

The objective of this study was to determine whether current regulatory methods for assessing the output of nebulizers are appropriate for the delivery of nebulized steroid suspensions to patients. We studied a conventional jet nebulizer (the Intersurgical Cirrus), an open-vent nebulizer (the Medicaid Sidestream) and a breath-enhanced nebulizer (the Pari LC Plus), using a constant sampling flow or a sinusoidal pump to represent the breathing pattern of children from 6 months to adulthood. Recovery of budesonide released from the nebulizers onto filters was reduced when using breathing simulation compared with constant flow, and this reduction was greatest for the conventional nebulizer (Cirrus, 103 microg with constant flow to 4.4 microg with a 50 mL tidal volume; Pari, 176 microg to 25 microg). The open-vent nebulizer deposited very little budesonide on the filter at lower tidal volumes (4.5 microg with a 50 mL tidal volume), possibly because the enhanced flow of aerosol laden air was greater than the inspiratory flow from the breathing simulator. The output of the LC plus was reduced at high flow, from 176 microg at 20 L x min(-1) to 93 microg at 60 L x min(-1). Overall, the measured output varied by up to 700%, depending on the method used. These results suggest that breathing patterns dramatically alter the measured output of different nebulizers and that breathing simulation should be included as part of their assessment.