Integrated multidisciplinary community service for chronic obstructive pulmonary disease reduces hospitalisations.

BACKGROUND: Hospitalisations for chronic obstructive pulmonary disease (COPD) exacerbation affect patient outcomes and healthcare costs. The long-term impact of an integrated COPD disease-management approach on hospitalisation remains controversial. AIM: The aim of this study was to evaluate whether a multidisciplinary community service reduces respiratory hospitalisations for COPD patients. METHODS: A total of 346 patients was followed for a mean duration of 27.3 months. The number of admissions, total bed days for respiratory (COPD exacerbation or pneumonia) or general medical causes and length of stay (LOS) per respiratory admission was compared before and after referral with the service. A secondary multivariate analysis examined which clinical parameters best predict benefit from such service. RESULTS: The total respiratory admission and hospital bed days after referral were reduced by 31% (288 vs 417, P < 0.001) and 40.4% (1637 vs 2746, P < 0.0001) respectively, compared with the equivalent duration prior. The average LOS for each respiratory admission was also significantly reduced after referral (6.61 vs 5.70, P = 0.02). Overall, 55% patients experienced a reduction in admission frequency and hospital days. The impact on admission frequency and hospital days was the greatest in those with an at least moderate disease (GOLD ≥2, odds ratio (OR): 3.2, 95% confidence interval (CI): 1.2, 8.9; P = 0.019) and those who completed pulmonary rehabilitation (PR) (OR: 1.7, 95% CI: 1.1, 2.8; P = 0.04). In contrast, general medical admissions increased, one-third attributable to a cardiovascular cause both before and after referral. CONCLUSIONS: The implementation of COPD multidisciplinary community service was associated with reduced respiratory hospitalisations in the long term. Patients with moderate or severe disease and who are able to complete PR are much more likely to benefit.

Reducing electrostatic charge on spacer devices and bronchodilator response.

AIMS: Plastic spacers are widely used with pressurized metered dose inhalers (pMDI). Reducing electrostatic charge by washing spacers with detergent has been shown to greatly improve in vitro and in vivo drug delivery. We assessed whether this finding is associated with an improved bronchodilator response in adult asthmatics. METHODS: Twenty subjects (age 18-65 years) with a known bronchodilator response inhaled in random order salbutamol from a pMDI (Ventolin) through an untreated new spacer (Volumatic) and through a detergent washed spacer. Patients received the following doses of salbutamol via pMDI at 20 min intervals: 100 microg, 100 microg, 200 microg, 400 microg, 800 microg. Spirometry, heart rate and blood pressure were checked prior to each dose and 20 min after the last dose. RESULTS: There were no differences between baseline forced expiratory volume in 1 s (FEV1) using either spacer (2.61+/-0.56 and 2.52+/-0.45 l, untreated and treated with detergent, respectively; mean +/- s.d.). The provocation dose required to cause a clinically significant improvement of 10% in FEV1 (PD10) was significantly lower when the detergent treated spacer was used (1505 +/-1335 and 430+/-732 microg, untreated and treated, respectively, P<0.002). CONCLUSIONS: We have demonstrated an improvement in bronchodilator response, in adult asthmatics, after reducing the electrostatic charge in a spacer device by washing it with ordinary household detergent. This finding stresses the importance of an optimal choice of delivery device for asthma medication.

Lung deposition from the Turbuhaler in children with cystic fibrosis.

Drug delivery to patients using dry powder inhalers, such as the Turbuhaler, is believed to be influenced by the inspiratory flow used. Clinical studies have indicated that this delivery system can be used effectively by children. However, it is not known how the total and weight-corrected dose delivered to the airways varies with age. A deposition study using technetium-99m (99mTc)-labelled budesonide was performed in order to determine the effect of age on delivery. Twenty one children with cystic fibrosis, aged 4-16 yrs, were recruited. They were clinically stable with normal lung function. Initially, a gamma camera scan was taken in front of a flood source containing 37 MBq of 99mTc. Subsequently, subjects inhaled through a low resistance inspiratory filter connected to a commercially available Turbuhaler. Immediately afterwards they inhaled from a noncommercial Turbuhaler containing budesonide labelled with 99mTc, and then underwent anterior and posterior gamma camera scans. Both Turbuhaler inhalers were attached to a portable spirometer and the peak inspiratory flow through the Turbuhaler was recorded for each inhalation. The total body dose was calculated from the dose deposited on the inspiratory filter connected to the commercial Turbuhaler. Analysis of the gamma camera images provided information on the proportion of the radiolabel delivered to the lungs compared to that deposited in the upper airway and stomach. As expected, a highly significant positive correlation was noted between the peak inspiratory flow generated by the patient through the Turbuhaler and the dose delivered to the lung. Similarly, there was a highly significant positive correlation between age and "total lung dose". However, when total lung dose was corrected for body weight, there was a nonsignificant negative correlation with age. This study suggests that the "weight-corrected lung dose" achieved when children aged > 6 yrs use the Turbuhaler, is largely independent of age. It would appear that the flow-dependent properties of this device are such that the reduced peak inspiratory flow generated by younger children results in a lower dose to the lungs, but that this is off-set by their lower body weight. This is unlikely to be a property of other devices with different flow/drug delivery characteristics.

Aerosol delivery to wheezy infants: a comparison between a nebulizer and two small volume spacers.

Inhalation therapy for wheezy infants with either a nebulizer or a pressurized metered-dose inhaler (pMDI) through a spacer is common practice. The aim of our study was to compare aerosol delivery to wheezy infants from a nebulizer and from a pMDI via two small volume spacers. Twenty wheezy infants (aged 4-12 months) were recruited. They inhaled salbutamol from a Pari-Baby nebulizer, from a detergent-coated Babyhaler, and from a Nebuchamber in random order. A filter was placed between the inhalation systems and the patients. The amount of salbutamol deposited on the filter was measured using an ultraviolet spectrophotometer and was expressed as a percentage of the total nebulized or actuated doses. The mean total nebulized dose for the Pari-Baby (1030 micrograms) was higher (P < 0.001) than the mean actuated dose from a pMDI for the Babyhaler (374 micrograms) and for the Nebuchamber (378 micrograms). Mean drug deposition on the filter was 40.2% (150 micrograms) of the total actuated dose for the detergent-coated Babyhaler and 40.7% (154 micrograms) of the total actuated dose for the Nebuchamber. There was no significant difference in drug deposition on the filter between the two spacers. Mean drug deposition on the filter was 25.3% (260 micrograms) of the total nebulized dose for the Pari-Baby nebulizer. There was no weight dependence in drug deposition on the filter for the two spacers, but, drug deposition increased with the subject's weight for the nebulizer. We have shown that aerosol delivery to wheezy infants from a pMDI through small volume spacers is effective and that a higher percentage of the total amount of salbutamol is delivered than from a nebulizer. The weight dependence in drug deposition for the nebulizer can be of clinical relevance.

Progressive massive fibrosis in the absence of lung nodulation.

Progressive massive fibrosis is a well-recognized complication of long-term industrial dust exposure. Typically, it occurs in a setting of background parenchymal nodulation. We wish to report a case occurring in the absence of lung nodules.

Effect of electrostatic charge, flow, delay and multiple actuations on the in vitro delivery of salbutamol from different small volume spacers for infants.

BACKGROUND: A study was undertaken to determine the influences of electrostatic charge, flow, delay, and multiple actuations on the in vitro delivery of salbutamol generated by a pressurised metered dose inhaler (pMDI) from small volume spacers used in infants. METHODS: Ten actuations from a salbutamol pMDI were drawn at different flow rates after either single or multiple actuations, with or without delay, through either static or reduced static spacers. An ionic detergent was used to reduce the charge of plastic spacers (Babyhaler, Babyspacer, Aerochamber, Nebuhaler). Electrostatic charge was measured using an electrometer. A multistage liquid impinger was used to determine the particle size distribution of the output of the pMDI through the spacers. RESULTS: Electrostatic charge on the surface of plastic spacers had the greatest influence on delivery, causing a decrease in drug delivery. Reducing charge by coating the surface with ionic detergent resulted in an increase of 46.5-71.1% (p < 0.001) in small (< 6.8 microns) particle delivery from small volume plastic spacers. Lower flow, delay, and multiple actuations resulted in decreased delivery from static spacers. Lower flow resulted in a decrease of 15% in small (< 9.6 microns) particle delivery. Delay and multiple actuations resulted in a decrease of 40.7% and 76.0%, respectively, in small (< 6.8 microns) particle delivery. The influences of lower flow, delay, and multiple actuations were greatly reduced or even eliminated by reducing charge. However, multiple actuations still resulted in a significant decreased delivery (p < 0.05). The reduced static Nebuhaler had a higher delivery than all small volume spacers. CONCLUSIONS: Electrostatic charge has a major influence on the delivery of salbutamol from small volume spacers. Using a metal spacer or ionic detergent coating of plastic spacers resulted in no or reduced charge and hence in improved delivery. Lower flow, delay, and multiple actuations played a major part only in static spacers.

Electrostatic charge on a plastic spacer device influences the delivery of salbutamol.

The aim of this study was to determine whether electrostatic charge on a plastic spacer decreases the delivery of salbutamol from a pressurized metered-dose inhaler (pMDI) and, if so, to find an optimal and practical treatment to remove the charge. Ten single actuations from a salbutamol pMDI were drawn through different Volumatic spacers at a constant flow of 60 L.min-1. The efficacies of different methods of removing charge were tested, including detergent coating of the spacers. A multistage liquid impinger was used to determine the particle size distribution of the output of the pMDI through the Volumatic spacers. The electrostatic charge on the inner surface of the spacers was measured both quantitatively with an electrometer, and qualitatively by the attraction of a thin strip of cellulose membrane to the wall of the spacer. Each experiment was repeated four times. Ionic detergent coating of the spacers removed the charge for at least 24 h. This resulted in an increase of 55-70% in small particle (< 6.8 microns) delivery compared to delivery from new spacers with high charge. We have demonstrated that electrostatic charge plays a major role in the delivery of salbutamol through plastic spacers. Adequate treatment with ionic detergent removes the charge and improves drug delivery.

The pulmonary deposition of two aerosol preparations of nedocromil sodium delivered by MDI assessed by single photon emission computed tomography.

The pulmonary deposition and pharmacokinetics of fine and coarse radioactive aerosols of nedocromil sodium, of mass median aerodynamic diameters 16 microns and 24 microns respectively, delivered by metered dose inhaler (MDI) have been investigated. The corresponding geometric standard deviations of the particle size distributions were 5.32 and 3.93. Pulmonary deposition was assessed by both planar radionuclide scintigraphy and multi-modality three dimensional imaging using single photon emission computed tomography (SPECT) and x-ray computed tomography (CT). The three dimensional data were analysed by transformation to a hemispherical shape based on the fractional radial distance of each point in the lung from the centre to the corresponding extrapolated point on the periphery. This enabled parameters on the variation of both concentration of deposition and total amount deposited with penetration distance to be calculated. For both planar and SPECT data the central to peripheral concentration ratio (C/P ratio) was calculated. The three dimensional C/P ratio showed a median value (3.21) which was significantly higher than for the planar imaging (2.03) (p < 0.001). The parameter used to express the variation of total amount deposited was the median dose position. This showed that for both aerosols 50% of the dose was deposited at sites with a percentage central to peripheral distance of greater than 68%. There was a trend for total percentage of the fine aerosol in the lungs to be higher than for the coarse and for its deposition to be more peripheral. In addition the mean concentrations in blood were measured to be greater for the fine aerosol. However these differences were relatively small and none were individually statistically significant. The technique of combined SPECT and CT imaging was shown to be valuable in obtaining more accurate information on pulmonary distribution of inhaled aerosol deposition. The merits, limitations and potential applications of the technique are discussed.

Factors affecting total and "respirable" dose delivered by a salbutamol metered dose inhaler.

BACKGROUND: Many factors contribute to the high variability of doses delivered to the lungs of patients using metered dose inhalers (MDIs). Relatively little attention has been paid to the contribution to this variability of the way in which the MDI is handled before the inhalation manoeuvre. Instruction leaflets often recommend procedures at odds with those used for in vitro testing of the device. The standard protocol for in vitro assessment of salbutamol MDIs involves shaking the MDI vigorously for 30 seconds and wasting the first two actuations. Subsequent actuations are introduced into the testing device at five second intervals. Patient instructions do not include a recommendation to waste the first two actuations and recommend a delay of one minute between actuations. A series of experiments was performed to determine whether such differences might be important. METHODS: The total and "respirable" doses delivered by a salbutamol MDI (Ventolin, Allen & Hanburys) under various conditions were assessed with a multistage liquid impinger. The quantity of drug deposited on each stage was measured by an ultraviolet spectrophotometric method. The effect on the delivered dose of not shaking the canister, not wasting the first two doses, waiting 30 seconds between actuations, and using multiple rapid actuations was assessed by comparing the results with those obtained using the standard in vitro testing protocol. RESULTS: Compared with a standard protocol, it was found that not shaking the MDI before use reduced the total and "respirable" dose by 25.5% and 35.7%, respectively. The dose delivered when actuating the MDI at 30 second intervals was no different from that when intervals was no different from that when intervals of five seconds were used. Two actuations separated by one second had no effect on the total dose but reduced the "respirable" dose by 15.8%, while four rapid actuations reduced the total and "respirable" doses by 8.2% and 18.2%, respectively. Storing the MDI stem down reduced the total and "respirable" dose delivered in the first actuation by 25.0% and 23.3% despite shaking the MDI before use. CONCLUSIONS: MDIs containing drug in suspension must be shaken before use to resuspend the drug contained in the MDI, but shaking does not alter the composition of the suspension in the metering chamber and hence the dose in the first actuation remains low. Very rapid actuations can reduce the dose delivered per actuation, but salbutamol MDIs can be actuated immediately after a 10 second breath holding pause without affecting the dose delivered.

A new method of quantification of the pulmonary regional distribution of aerosols using combined CT and SPECT and its application to nedocromil sodium administered by metered dose inhaler.

Aerosols of nedocromil sodium labelled with 99Tcm were delivered on 20 separate occasions to healthy male volunteers. Planar and single photon emission computerized tomography (SPECT) gamma scintigraphy were immediately performed to assess the pulmonary regional distribution of delivered aerosol. On a separate occasion volunteers were imaged using X-ray computed tomography (CT). Alignment of SPECT and CT images was performed using marked anatomical features and the anterior and lateral skin outlines. CT images provided data for attenuation correction and were used to define the anatomical lung volume. Central to peripheral (CP) ratios of deposited activity were calculated from volumes of interest in coronal and transverse sections of the right lung. These were compared with CP ratios obtained from planar images obtained immediately following aerosol inhalation. Volumetric CP ratio correlated significantly with immediate planar CP ratio (p < 0.001). Analysis of deposition in the whole right lung was performed by separating the SPECT lung data into a series of thin concentric shells centred on the entry of the right main bronchus. Measures were defined for describing the variation of deposition density and cumulative total deposition with distance from the lung centre. These showed significant correlation with planar CP ratio (p < 0.001). SPECT analysis using CT is consistent with planar measures of aerosol deposition but offers a more complete quantification of aerosol penetration and absolute deposited activity within the whole lung. It is a valuable new tool for aerosol analysis.

Pulmonary alveolar proteinosis in association with Fanconi's anemia and psoriasis. A possible common pathogenetic mechanism.

We report a case of PAP which proved to be fatal despite whole lung lavage. The need for early BAL and transbronchial biopsies in diffuse infiltrative lung disorders of unknown etiology is highlighted. The occurrence of PAP in association with Fanconi's anemia and psoriasis raises the possibility of a common pathogenetic defect which may be related to abnormal cytokine metabolism. Investigation of cytokine metabolism in PAP is warranted.

Attenuation of exercise induced asthma by local hyperthermia.

BACKGROUND: Prior treatment with local hyperthermia has been shown to prevent mast cell degranulation and leucocyte histamine release, and to reduce mortality and cellular infiltrates in a model of acute lung injury. Local hyperthermia is effective in reducing the symptoms of the common cold and perennial and seasonal allergic rhinitis, nasal patency also being improved in rhinitis. It is possible that these effects are mediated by common anti-inflammatory mechanisms, and that this treatment may be effective in the treatment of asthma. The effect of prior local hyperthermia on the response to exercise challenge and histamine bronchoprovocation was therefore examined. METHODS: In a randomised, double blind, placebo controlled, crossover study, 10 asthmatic subjects with exercise induced asthma used machines delivering 40 1/minute of fully humidified air at either 42 degrees C (active treatment) or 31 degrees C (placebo treatment) for 30 minutes' tidal breathing. For each pretreatment, at two week intervals they underwent exercise challenges starting one and 24 hours after starting the inhalations. After a further two weeks the protocol was repeated with histamine substituted for the exercise challenges. RESULTS: The mean (SE) maximum percentage fall in forced expiratory volume in one second (FEV1) was significantly lower one hour after treatment with air at 42 degrees C (30.8% (3.1%)) than after treatment with air at 31 degrees C (22.3% (2.9%)). There was no significant effect on exercise challenge at 24 hours, or on histamine challenge at either time point, though there were nonsignificant trends towards protection with exercise at 24 hours and with histamine at one hour. CONCLUSION: In asthmatic subjects the response to exercise challenge is significantly attenuated one hour after treatment with local hyperthermia. This treatment warrants further investigation in the treatment of clinical asthma and other inflammatory disorders.

The effect of respiratory manoeuvres and pharmacological agents on the pharmacokinetics of nedocromil sodium after inhalation.

1. Eight healthy subjects inhaled nedocromil sodium from a metered-dose inhaler using a standardised inspiratory technique. Blood samples were taken for up to 270 min after inhalation for radioimmunoassay of plasma nedocromil sodium concentrations. 2. To investigate the possibility that respiratory manoeuvres can alter the absorption of the drug from the lungs, on the first (control) study day at 70 min after dosing, subjects performed nine forced expiratory manoeuvres over a 3 min period. At 110 min after dosing, subjects took a slow, full inspiration with a 30 s breath-hold, and at 150 min after dosing the subjects performed one single forced expiration. 3. On the second study day, subjects inhaled methoxamine, 0.15 mg kg-1 of a 20 mg ml-1 solution at 60 min after dosing, and the study continued as above. On the third day, subjects repeated the sequence of respiratory manoeuvres, after having taken phenoxymethyl penicillin and probenecid by mouth for 48 h. 4. Both multiple forced expirations and the deep inspiration with breath-hold produced significant increases in the absorption of nedocromil sodium. Inhaled methoxamine did not alter airway calibre or the response to the respiratory manoeuvres. Probenecid, but not penicillin, was detected in the subjects' plasma, and had the effect of increasing the rise in plasma nedocromil sodium concentrations after the multiple forced expirations when compared with the control day. 5. These data suggest that disruption of epithelial tight junctions induced by the respiratory manoeuvres leads to enhanced paracellular transport of nedocromil sodium into the draining circulation of the airways and alveoli.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchial reactivity to histamine and bradykinin is unchanged after rhinovirus infection in normal subjects.

We investigated the effects of rhinovirus (RV) infection on airways reactivity. Twenty seven normal volunteers (11 atopic) were inoculated with RV 2 or RV EL. The provocative concentrations of histamine and bradykinin required to produce a 15% fall in the forced expiratory volume in one second (FEV1) (PC15FEV1) were measured before, 7 and 21 days after inoculation. Infection was determined by a fourfold rise in anti-viral antibody titre and by viral culture from nasal washings. Peak expiratory flow rate (PEF) was recorded three days before and for 21 days after inoculation. All subjects underwent the first two bronchial challenges, and 22 the third challenge. For the whole group and for atopic subjects, there were significant correlations between the PC15 values for bradykinin and histamine (r = 0.82 and r = 0.85, respectively). Twenty subjects were infected; six had clinical colds. For the 16 infected subjects who had all three challenges, the median (range) PC15FEV1 for the histamine challenges was 36 (0.89-64), 62 (1.5-64) and 34 (0.94-64) mg.ml-1, respectively, and 32 mg.ml-1 for each bradykinin challenge (range: 0.015-32, 0.088-32 and 0.033-32). There were no significant differences between study days for PC15FEV1 histamine or bradykinin for the whole group, the infected subjects, those with clinical colds or for those infected with either RV subtype. There was no significant change in mean daily PEF after viral infection. We conclude that airways reactivity to histamine and bradykinin is unchanged after experimental RV infection in normal volunteers.

A non-bronchoconstrictor, bacteriostatic preservative for nebuliser solutions.

We have studied the bacteriostatic and airways effects of the preservatives chlorocresol and chlorbutol, to assess if they may be safely used in nebuliser solutions. The bacteriostatic study was carried out according to standard techniques, and the preservatives were able to inhibit the growth of a range of bacteria and yeasts for a period of 28 days. The airways effects were studied in eight asthmatic subjects, who were challenged with either the preservatives or saline (as placebo). Pulmonary function was followed as FEV1 for 60 min after inhalation, and there was no change in FEV1 following inhalation. We conclude that these preservatives may be used safely in nebuliser solutions.

Multiple pneumatocoeles and bilateral tension pneumothoraces complicating pneumocystis pneumonia in AIDS.

Pneumatocoele and pneumothorax are uncommon complications of Pneumocystis carinii pneumonia. We report a patient with the Acquired Immune Deficiency Syndrome who developed multiple bilateral pneumatocoeles which we demonstrate to have ruptured leading to the subsequent bilateral tension pneumothoraces and to death. The computerised tomographic appearances, and histopathology of these unusual complications are presented. The literature on these manifestations is reviewed and management discussed.

Nebulized ipratropium in the treatment of acute asthma.

The efficacy of ipratropium and salbutamol was determined in 117 patients with acute asthma who presented to an emergency department to determine whether the order of administration of the two agents affects the improvement in peak flow rates. Patients were given two nebulized treatments at an interval of one hour in a randomized, double-blind design. They received either 5 mg nebulized salbutamol followed by 0.5 mg ipratropium, ipratropium followed by salbutamol, or both drugs administered together followed by nebulized saline. Ipratropium was an effective bronchodilator when given as the first agent. Simultaneous administration with salbutamol was as effective as sequential administration. At one hour after treatment, there was no difference in peak flow between the combination of drugs and either drug given alone. Ipratropium given after salbutamol was not superior to saline solution given after the combination of drugs. Our data do not suggest a substantial therapeutic effect from addition of ipratropium to salbutamol in the immediate treatment of acute asthma.

The protective efficacy of inhaled, oral and intravenous nedocromil sodium against adenosine-5'-monophosphate-induced bronchoconstriction in asthmatic volunteers.

We have investigated the pharmacokinetics and pharmacodynamics of nedocromil sodium administered by inhalation (4 mg), by mouth (80 mg) and by intravenous infusion (6 micrograms/kg) against adenosine-5'-monophosphate (AMP) induced bronchoconstriction in 9 mildly asthmatic subjects. Their mean baseline FEV1 was 83.8% of the predicted value, geometric mean (GM) PC20 FEV1 histamine 0.33 mg/ml (range 0.03-4.0), and GM PC50 baseline sGaw AMP 4.37 mg/ml (range 0.158-26.38). Blood collected at intervals for up to 4 h after drug administration was assayed for nedocromil sodium by radioimmunoassay, to derive the maximal drug concentration (Cmax), concentration at time of AMP challenge (Cchall), area under the plasma concentration-time curve (AUC), and the mean residence time (MRT). Airways responsiveness to inhaled AMP was assessed before and after administration of nedocromil sodium by each of the three routes of administration, and the protective efficacy was expressed as the concentration ratio (CR). AMP challenge was carried out 60 min after inhaled nedocromil sodium, 120 min after drug ingestion and 75 min after the start of the intravenous infusion. The GM PC50 sGaw AMP determined after inhaled, oral and intravenous nedocromil sodium was 28.84, 7.24 and 7.94 mg/ml respectively. For the group as a whole, nedocromil sodium by the oral or intravenous routes produced little overall protection against AMP (CR increasing by 0.75 and 0.88 doubling dilutions respectively). However, with inhaled drug, the concentration response curve with AMP was displaced to the right achieving an increased CR of 2.71 doubling dilutions. No relationship could be established between baseline FEV1, and AUC, Cmax or Cchall, or between these indices and the protective efficacy for the drug.(ABSTRACT TRUNCATED AT 250 WORDS)