Placebo Inhalation Research Articles

Neutrophil-derived S100A12 in acute lung injury and respiratory distress syndrome

Both persistent accumulation and activation of neutrophils may contribute to the most severe form of acute lung injury, acute respiratory distress syndrome. We analyzed the expression of neutrophil-derived S100A12 and the proinflammatory receptor for advanced glycation end products (RAGE) in patients with acute respiratory distress syndrome. Additional in vivo and in vitro experiments were performed to further analyze the contribution of S100A12 to pulmonary inflammation. We included 14 patients with acute respiratory distress syndrome and eight controls. In addition, 16 healthy subjects were included in an experimental lipopolysaccharide challenge model. Concentrations of S100A12 and soluble RAGE were analyzed in bronchoalveolar lavage fluid. The expression of S100A12 and RAGE in lung biopsies from patients was analyzed by immunohistochemistry. S100A12 was also analyzed in bronchoalveolar lavage fluid from eight healthy subjects after challenge with lipopolysaccharide and compared with eight controls who received placebo inhalation. Effects of S100A12 on endothelial cells were analyzed in vitro. Patients with acute respiratory distress syndrome had significantly enhanced pulmonary S100A12 expression and higher S100A12 protein concentrations in bronchoalveolar lavage fluid than controls. Levels of soluble RAGE were not significantly elevated in acute respiratory distress syndrome. S100A12 concentrations decreased with time from disease onset. In healthy volunteers, S100A12 was elevated in bronchoalveolar lavage fluid after lipopolysaccharide inhalation. In vitro experiments confirmed strong proinflammatory effects of human S100A12. S100A12 and its receptor RAGE are found at high concentrations in pulmonary tissue and bronchoalveolar lavage fluid in acute lung injury. S100A12 expression may reflect neutrophil activation during lung inflammation and contribute to pulmonary inflammation and endothelial activation via binding to RAGE.

Schulung des Inhalationsmanövers bei Kindern mit Asthma bronchiale mittels optischem Feedback

For inhalation as a mainstay of asthma therapy, the correct inhalation technique is of utmost importance. This comprises not only the correct handling of the device but also specific device-dependent requirements concerning the inhalation manoeuvre itself. We examined whether totally different inhalation manoeuvres can be educated in parallel in asthmatic children. As target manoeuvres we defined: 1) an inhalation as fast as possible (peak inspiratory flow >or= 60 l/min) with high acceleration in the starting phase as it is normally required for dry powder inhalers. 2) A constant inhalation at a flow between 40 and 90 l/min with a long duration as it is regarded to be optimal for propellant driven systems. As models for dry powder inhalers the Diskus (Accuhaler, a medium resistance device) and the Turbuhaler (high resistance) were chosen. As an example of a propellant-driven we used the Autohaler (breath-actuated MDI). A total of 52 outpatients (age 4 to 14 years) with asthma were educated two times. We measured peak inspiratory flow (PIF), duration of inspiration with inspiratory flow >or= 30 l/min (Ti30), inspiratory volume (Vol) and acceleration of inspiratory flow (mPIF) through the devices in random order before and after each training session. Measurements were performed using the inhalation manager, a computer based spirometry system, which allows recording of inspiratory manoeuvres through Placebo inhalers by means of a pneumotachometer. Results are immediately visualized (optical feedback) and evaluated. Training children simultaneously with different inhalation systems appeared to be difficult. Only for the DPIs a significant increase of children inhaling in the pre-given target area could be reached. With Diskus, the rate of correct manoeuvres increased from initially 57.7 % to 88.5 % after training and with Turbohaler from 32.7 % to 65.4 %, respectively. With MDI, this rate increased only from 32.7 % to 42.3 %. This indicates that a high inspiratory flow may be easier to be learned than a constant slow inhalation, at least when training is done simultaneously in children. Thus, training of the different inhalation manoeuvres for DPI and MDI should be performed separately. When prescribing inhaled drugs for reliever treatment and maintenance therapy for any individual patient, prescribers should select inhalation devices, which can be used in a similar way without clinical disadvantage.

Formoterol Turbuhaler Is As Effective As Salbutamol Diskus in Relieving Adenosine-Induced Bronchoconstriction in Children

Salbutamol diskus (SD) and formoterol turbuhaler (FT) are both fast-acting beta(2) agonists delivery systems used to relieve bronchoconstriction, such as that which accompanies acute exacerbations of asthma. Although SD (which is used only on an as-needed basis) is flow independent, the FT (currently recommended for regular therapy) requires a forceful deep inspiration. Thus, the efficacy of FT in children with bronchoconstriction may be inferior to that of SD. We have studied the bronchodilatation response induced by FT after a standard adenosine-5-monophosphate (AMP) bronchial challenge, and compared it to that induced by SD, and placebo. Seventeen children (mean age +/- SD 10.3 +/- 1.7 y) with asthma underwent three AMP challenges, each time followed by inhalation of either placebo, SD (200 mug) or FT (9 mug), in random order. Patterns of bronchodilatation (forced expiratory volume in 1 second recovery) to 90% of baseline levels were compared. Both SD and FT were significantly better than placebo. FT was slightly better than SD, but this difference was not statistically significant. FT and SD are both effective bronchodilators and may be of comparable efficiency during acute bronchoconstriction in young children with asthma.

Functional, inflammatory and morphological characterisation of a cat model of allergic airway inflammation

The aims of this study were to characterise a model of feline allergic airway inflammation and to test through a longitudinal investigation whether five repeated allergen exposures would lead to signs of airway remodelling that would be detectable in vivo. Eight healthy control cats and eight cats sensitised with Ascaris suum allergens were investigated. Barometric whole body plethysmography (BWBP) was used for the assessment of respiratory variables and airway responsiveness (AR). Bronchoalveolar lavage fluid (BALF) was sampled for cytology and determination of F2-isoprostane concentration and matrix metalloproteinase type 9 (MMP-9) activity. Thoracic radiography and bronchoscopy scores were also established. Cats were investigated prior to sensitisation and after inhalation of placebo or allergen challenge 1.BWBP measurements revealed a significant increase of enhanced pause (Penh), an index of bronchoconstriction, and AR in sensitised cats in response to allergen challenge 1. A significant increase in BALF neutrophil and eosinophil %, F2-isoprostane concentration and MMP-9 activity, and increased radiography and bronchoscopy scores were recorded. After a recovery period of 6weeks, all variables except BALF MMP-9 returned to baseline values. Four further allergen challenges induced similar changes to those seen in challenge 1 and no signs of persistent changes suggestive of bronchial remodelling were detectable. The model provides an in vivo approach to functional, inflammatory and morphological changes occurring in response to single and repeated allergen exposure.

The effect of tiotropium on the pulmonary diffusing capacity

To our knowledge, there is no data on the effect of tiotropium on pulmonary gas exchange in healthy subjects. The aim of this study was to assess the effects of tiotropium on pulmonary diffusing capacity. Twenty-one healthy volunteers were enrolled for a prospective, randomized, double-blind, placebo-controlled study. Spirometric measurements, including pulmonary-diffusing capacity, were obtained before and after inhalation of drug or placebo. There was a significant decrease in forced vital capacity (FVC) and, consequently, an increase in the forced expiratory volume in one second (FEV1) to FVC ratio after placebo inhalation (p < 0.05), but no changes were found for percent-predicted FVC, FEV1, percent-predicted FEV1, percent-predicted forced expiratory flow (FEF25%-75%), percent-predicted peak expiratory flow (PEF), diffusing capacity of the lung for carbon monoxide (DLCO), single-breath alveolar volume (VA) and DLCO/VA ratio when compared with the baseline. Tiotropium inhalation caused a significant increase in FVC, percent-predicted FEV1, FEV1/FVC and percent-predicted FEF25%-75%, although the decrease in DLCO was insignificant (12.4 +/- 0.9 to 11.4 +/- 0.9). In conclusion, tiotropium does not change the pulmonary-diffusing capacity in healthy volunteers.

CO2 challenge induced HPA axis activation in panic

The hypothalamic-pituitary-adrenal axis (HPA axis) plays a critical role in stress management. Involvement of this physiological axis in the underlying mechanisms of panic disorder (PD) has been suggested. Studies using 35% CO(2) inhalation to provoke panic found no evidence for robust increases in cortisol levels in PD. However, cortisol levels alone may not be conclusive, as this hormone is merely the end product of a complex physiological axis. Sixteen PD patients and 16 healthy control subjects underwent a 35% CO(2) inhalation and a placebo inhalation on separate days according to a fixed order, double-blind design. Both serum and salivary cortisol, as well as adrenocorticotropic hormone (ACTH) were measured at regular time intervals. Cortisol and ACTH levels increased in the patient and control groups following 35% CO(2) inhalation. The magnitude of the increase was similar in patients and controls despite marked differences in anxiety. This study is the first to document a clear HPA response following 35% CO(2) inhalation in both PD patients and controls. This effect occurs independently of the specific panicogenic properties of the CO(2) challenge. It remains to be clarified whether panic is initially accompanied by major HPA axis activation or whether other stress-responsive systems underlie panic.

Sources de partialite chez les auteurs de guides de pratique clinique

BACKGROUND: Cessation of regular therapy with inhaled beta 2 agonists in patients with asthma may lead to a temporary deterioration of lung function and airway responsiveness. Few such studies have been reported in patients with chronic obstructive pulmonary disease (COPD), so an investigation was carried out to determine whether rebound airway responsiveness and rebound bronchoconstriction also occurs in COPD and if there is any relationship with the dose of beta 2 agonist being used. METHODS: Lung function (forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF)), airway responsiveness (PC20 methacholine (PC20)) and symptoms were assessed in a double blind, placebo controlled crossover study during and after cessation of two weeks regular treatment with placebo, and low dose (250 micrograms) and high dose (1000 micrograms) inhaled terbutaline via a dry powder inhaler (Turbohaler) all given three times a day. Sixteen non-allergic patients with COPD of mean (SD) age 58.7 (6.5) years, FEV1 57.1 (12.8)% of predicted, and reversibility on 1000 micrograms terbutaline of 4.5 (3.5)% predicted were studied. PC20 and FEV1 were measured 10, 14, 34 and 82 hours after the last inhalation of terbutaline or placebo. Measurements performed at 10, 14, and 34 hours were expressed relative to 82 hour values in each period, transformed into an area under the curve (AUC) value and analysed by ANOVA. RESULTS: Mean morning and evening PEF increased during terbutaline treatment. PC20 and FEV1 did not change after cessation of terbutaline treatment. CONCLUSIONS: Cessation of regular treatment with both low and high dose inhaled terbutaline does not result in a rebound bronchoconstriction and rebound airway responsiveness in patients with COPD.

Efficacy of the nicotine inhaler in smoking reduction: A double-blind, randomized trial

Many smokers are not ready to quit but are interested in changing their smoking behavior, particularly if such a change is associated with a reduction in health risk. The present study evaluated the efficacy of the nicotine inhaler in reducing smoking. Exploratory studies assessed whether reduction in smoking was associated with reduction in markers of disease risk. A total of 429 healthy smokers (smoking at least 20 cigarettes/day) were randomly assigned to either nicotine-containing or placebo inhalers, which subjects were allowed to use ad libitum for up to 1 year. The nicotine inhaler was significantly superior to placebo in achieving reduction in daily cigarette consumption by at least 50% after 4 months, compared with baseline (18% vs. 8%, p = .004). Active treatment promoted smoking cessation: 8% of subjects in the nicotine group and 1% in the placebo group were abstinent at month 15. Throughout the study, smoking reduction, per se, independent of treatment group, was associated with a statistically significant decrease in exhaled carbon monoxide and serum cotinine and thiocyanate. Smoking reduction also improved established risk markers for cardiovascular disease over 4 months. The incidence of adverse events did not differ significantly between the active and placebo groups. The most common treatment-related adverse events were throat irritation and cough. In conclusion, the nicotine inhaler can help smokers who are unable or unwilling to quit to reduce daily cigarette consumption, which may be a health benefit on its own and may further promote quitting.

Inhibition of mast cell PGD2release protects against mannitol-induced airway narrowing

Mannitol inhalation increases urinary excretion of 9alpha,11beta-prostaglandin F2 (a metabolite of prostaglandin D2 and marker of mast cell activation) and leukotriene E4. The present study tested the hypothesis that beta2-adrenoreceptor agonists and disodium cromoglycate (SCG) protect against mannitol-induced bronchoconstriction by inhibition of mast cell mediator release. Fourteen asthmatic subjects inhaled mannitol (mean dose 252+/-213 mg) in order to induce a fall in forced expiratory volume in one second (FEV1) of > or = 25%. The same dose was given 15 min after inhalation of formoterol fumarate (24 microg), SCG (40 mg) or placebo. Pre- and post-challenge urine samples were analysed by enzyme immunoassay for 9alpha,11beta-prostaglandin F2 and leukotriene E4. The maximum fall in FEV1 of 32+/-10% on placebo was reduced by 95% following formoterol and 63% following SCG. Following placebo, there was an increase in median urinary 9alpha,11beta-prostaglandin F2 concentration from 61 to 92 ng.mmol creatinine(-1), but no significant increase in 9alpha,11beta-prostaglandin F2 concentration in the presence of either formoterol (69 versus 67 ng.mmol creatinine(-1)) or SCG (66 versus 60 ng.mmol creatinine(-1)). The increase in urinary leukotriene E4 following placebo (from 19 to 31 ng.mmol creatinine(-1)) was unaffected by the drugs. These results support the hypothesis that the drug effect on airway response to mannitol is due to inhibition of mast cell prostaglandin D2 release.

Responses to inhaled bronchodilators in infancy are not linked with asthma in later childhood

Many doctors consider wheezing infants and young children who respond to beta-adrenergic agents to be asthmatics, or at least at risk for later asthma. The aim of this study was to compare responses to inhaled albuterol and racemic epinephrine in infancy between children with and without asthma later in childhood. In a crossover study setting, 100 acutely wheezing infants aged less than 24 months were randomized to receive inhalations of either racemic epinephrine and placebo, or albuterol and placebo. Clinical evaluation consisted of measurements of respiratory rate, heart rate, and oxygen saturation, and clinical assessment of the respiratory distress assessment instrument (RDAI) score, consisting of wheezing and chest indrawings. The asthma status of the children was evaluated at three clinical follow-up visits, at 4.0, 7.2, and 12.3 (median) years of age. Responses to bronchodilating agents, when respiratory rates and RDAI scores were used as outcome measures, were not different in future asthmatics compared to nonasthmatics. However, oxygen saturation was significantly higher after albuterol inhalation in children who had asthma at all three visits (92.67% confidence interval (CI), 91.39-93.96) than in those without asthma at these visits (92.52% CI, 91.79-93.25), but lower, correspondingly, after racemic epinephrine (91.97% CI, 90.74-93.19 vs. 93.04% CI, 92.29-93.79) and placebo (91.38% CI, 90.49-92.28 vs. 93.12% CI, 92.60-93.65) inhalations (P = 0.04). In conclusion, we were not able to confirm that future asthmatics respond better than future nonasthmatics to bronchodilating agents during wheezing in infancy. More studies are needed to characterize the subset of infants who benefit from bronchodilating treatment in infancy.

Non-invasive assessment of airway responsiveness in healthy and allergen-sensitised cats by use of barometric whole body plethysmography

This study aimed at determining whether airway responsiveness (AR) tests performed by use of barometric whole body plethysmography (BWBP) were repeatable in cats and to what extent AR was affected by the nebulization protocol used, the age of the animals, the inflammatory status of the airways and prior bronchodilator treatment. Repeatability of AR was tested on two occasions in 30 healthy cats. The concentration of carbachol inducing a 300% increase of the enhanced pause (Penh) – an estimator of airflow limitation – was calculated (C-Penh300) and did not differ significantly between the two tests (0.035 ± 0.017% compared to 0.034 ± 0.016%) and was significantly and positively correlated. The comparison between rapidly and slowly increasing carbachol concentrations was performed in ten healthy cats and showed a significantly lower C-Penh300 (%) when slowly increasing concentrations were used (0.037 ± 0.013% compared to 0.039 ± 0.015%, P < 0.05). A significant age-related increase of C-Penh300 was evidenced by performing AR tests in 15 healthy cats at 12, 18, 24 and 30 months (12 months: 0.026 ± 0.008%, 18 months: 0.031 ± 0.009%, 24 months: 0.038 ± 0.01%, 30 months: 0.043 ± 0.014%, P < 0.05). C-Penh300 significantly decreased in 12 Ascaris suum-sensitised cats after allergen exposure (0.026 ± 0.016% compared to 0.033 ± 0.016%, P < 0.05) and was negatively correlated with the granulocyte percentage of bronchoalveolar lavage fluid ( r = −0.36, P < 0.01). Compared with a placebo inhalation, pre-treatment with inhaled salbutamol significantly increased C-Penh300 in four healthy cats (0.093 ± 0.021% compared to 0.036 ± 0.004%, P < 0.05). This study provides evidence that AR determination by use of BWBP is promising as non-invasive indicator of lower airway inflammation or for monitoring response to bronchodilator treatment.

The effects of Aspergillus fumigatus challenge on exhaled and nasal NO levels

Several studies have previously shown that exposure to indoor air microbes from moisture-damaged buildings can cause adverse health effects. Aspergillus fumigatus is one of the best-documented moulds causing health problems to those exposed. In this study, inhalation of a commercial A. fumigatus solution was assessed, to establish if it would have effects on fractional exhaled (FeNO) and nasal (FnNO) nitric oxide levels and on lung function. The results were compared with placebo challenge. A total of 28 subjects were divided into three study groups: group 1 had been exposed to occupational mould; group 2 consisted of atopic subjects; and group 3 was a control group. Some 3 h after A. fumigatus challenge, there was a considerable increase in FeNO, and a significant difference was observed between the A. fumigatus and placebo inhalations. The difference was seen in all study groups. No such differences were found in the levels of FnNO or nitrite in nasal lavage fluid. Subjects reported significantly more frequent respiratory tract symptoms after the A. fumigatus inhalation compared with placebo challenge. In conclusion, it was shown here that inhalation challenge of Aspergillus fumigatus elevated fractional exhaled nitric oxide levels. An increase in fractional exhaled nitric oxide may serve as an indicator of respiratory inflammation of acute mould exposure.

Inhaled hyaluronic acid against exercise-induced bronchoconstriction in asthma

Hyaluronic acid (HA) is a polysaccharide that is present in human tissues and body fluids. HA has various functions, including a barrier effect, water homeostasis, stabilizing the extracellular matrix, increased mucociliary clearance and elastin injury prevention. It may therefore exert prophylactic activity in the treatment of asthma. We tested the hypothesis that HA inhalation will prevent exercise-induced bronchoconstriction (EIB) in a randomised double-blinded placebo-controlled crossover study. Sixteen asthmatic patients with EIB were included in the study (mean (SD)) (age 24.5 (7.3) yr, FEV 1 88.6 (11.3) %predicted, PC 20 methacholine (g-mean (SD in DD)) 0.4 (1.5) mg/ml). On two separate visits an exercise challenge was performed 15 min post-inhalation of either HA (3 ml 0.1% in PBS) or placebo (3 ml PBS). The maximum fall in FEV 1 and the AUC 30 min post-exercise were used as outcomes. After inhalation of both HA and placebo, baseline FEV 1 decreased significantly (HA 4.1 (3.1)%, placebo 2.9 (4.1)%, P<0.017). The maximum fall in FEV 1 following exercise challenge was not significantly different between HA versus placebo (median HA 22.50%, placebo 27.20%, P=0.379), as was the AUC (median HA 379.3 min*%fall, placebo 498.9 min*%fall, P=0.501). We conclude that at the current dose, inhaled HA does not significantly protect against EIB. This suggests that HA is not effective as a prophylaxis for EIB in patients with asthma.

Effects of long‐term treatment with oxytocin in chronic constipation; a double blind, placebo‐controlled pilot trial

Oxytocin and its receptor have been found throughout the gastrointestinal (GI) tract, where it affects gut function. Clinically, we have noticed an improvement of bowel habits during lactation in constipated women. The aim of this study was to examine whether oxytocin has an effect on bowel symptoms and psychological well being in women with refractory constipation. Fifty-nine women with refractory constipation were included in a double blind, multicentre study. After a 2-week run-in period, they were randomly allocated to nasal inhalation of either placebo or oxytocin treatment twice daily for 13 weeks, followed by a 2 weeks, posttreatment period. The patients completed a questionnaire every day concerning bowel habits, abdominal pain and discomfort, and Gastrointestinal Symptoms Rating Scale (GSRS) and Psychological General Well-being (PGWB) twice during the study; namely, during the baseline period and at the end of the treatment period. Both oxytocin and placebo led to improvement of the constipation according to the GSRS and led to improvement in the sensation of incomplete evacuation and anorectal obstruction, without significant differences between the groups. Abdominal pain and discomfort responded weakly to oxytocin, with no effect of the placebo. In a subgroup of patients with IBS and concomitant depression, a weak improvement in depressed mood was observed after oxytocin administartion. Nasal administration of oxytocin had no significant advantage over placebo concerning an effect on constipation. However, it seems to have a positive effect on abdominal pain and discomfort and depressed mood. These findings should be further explored.

The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality

Randomized clinical trials have not yet demonstrated the mortality benefit of smoking cessation. To assess the long-term effect on mortality of a randomly applied smoking cessation program. The Lung Health Study was a randomized clinical trial of smoking cessation. Special intervention participants received the smoking intervention program and were compared with usual care participants. Vital status was followed up to 14.5 years. 10 clinical centers in the United States and Canada. 5887 middle-aged volunteers with asymptomatic airway obstruction. All-cause mortality and mortality due to cardiovascular disease, lung cancer, and other respiratory disease. The intervention was a 10-week smoking cessation program that included a strong physician message and 12 group sessions using behavior modification and nicotine gum, plus either ipratropium or a placebo inhaler. At 5 years, 21.7% of special intervention participants had stopped smoking since study entry compared with 5.4% of usual care participants. After up to 14.5 years of follow-up, 731 patients died: 33% of lung cancer, 22% of cardiovascular disease, 7.8% of respiratory disease other than cancer, and 2.3% of unknown causes. All-cause mortality was significantly lower in the special intervention group than in the usual care group (8.83 per 1000 person-years vs. 10.38 per 1000 person-years; P = 0.03). The hazard ratio for mortality in the usual care group compared with the special intervention group was 1.18 (95% CI, 1.02 to 1.37). Differences in death rates for both lung cancer and cardiovascular disease were greater when death rates were analyzed by smoking habit. Results apply only to individuals with airway obstruction. Smoking cessation intervention programs can have a substantial effect on subsequent mortality, even when successful in a minority of participants.

Evaluation of the Magnitude of the Bronchodilator Response in Children and Adolescents With Asthma

Bronchodilator response criteria have been determined in adults; however, data applicable to children and adolescents are scarce. We measured pulmonary function in asthmatic patients to determine the bronchodilator response. A blind study. Outpatient clinic of Pneumology Unit, Instituto da Crianca and Center of Asthma Care and Research, University Hospital, University of Sao Paulo Medical School. Sixty patients aged 6 to 20 years (median, 12 years). Spirometry and plethysmography were performed before and after blind placebo and bronchodilator inhalation (400 mug salbutamol by metered-dose inhaler). Approximately 90% of the patients had mild-to-moderate persistent asthma. The mean FEV(1) at baseline was 79.6% of the predicted value. Distribution of variations of the different pulmonary function parameters was analyzed after placebo inhalation. The 95th percentile was adopted as a criterion for a significant bronchodilator response. After the bronchodilator test, the patients were classified based on criteria derived from the placebo inhalation and the American Thoracic Society guidelines. Parameters established as cutoff values were 265 mL, 14.2% and 10% FEV(1) expressed as absolute volume, percentage compared with that at baseline and percentage of the predicted value, respectively, and 55% specific airway conductance (sGaw) expressed as a percentage compared with that at baseline. Based on the spirometric data, 37 patients (61%) had reversibility of obstruction, while 48 patients (80%) were classified as responders based on the analysis of variations in sGaw. The classifications based on variations in FEV(1) expressed as absolute volume and percentage of the predicted value showed a substantial correlation with the international classification. The cutoff values established for the assessment of the bronchodilator response in the present population agree with those reported in the literature. sGaw was the most sensitive parameter for the identification of changes in airway caliber.

Short-Term Safety and Tolerability of??Double-Dose Salmeterol/Fluticasone??Propionate in Adult??Asthmatic Patients

The incidence of asthma exacerbations in patients receiving salmeterol/fluticasone propionate (Seretidetrade mark or Advair((R))) is low. However, when asthma control deteriorates, clinicians may instruct patients to double the dose of their inhaled corticosteroid medication for a short period. The purpose of this study was to demonstrate that doubling the dose of Seretidetrade mark for a period of 2 weeks in subjects with persistent asthma is safe and well tolerated. This randomised, double-blind, parallel-group study was conducted in primary-care centres. Adults with a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of >/=70% predicted were stratified to receive a single dose of Seretidetrade mark 50mug/100mug, 50mug/250mug or 50mug/500mug twice daily from a Diskustrade mark inhaler for a 4-week run-in period, dependent on the dose of inhaled corticosteroid on entry. Subjects were then randomised to receive either an extra inhalation of the same dose of Seretidetrade mark received during the run-in (double dose) or an inhalation of matching placebo (single dose) for 14 days in a 2 : 1 ratio. Subjects were asked to record any adverse events, morning and evening heart rate (HR), peak flow and relief medication use in daily record cards. The primary endpoint was tremor as perceived by the subject. Clinic evaluations included HR, 12-lead ECG, and potassium and glucose levels. 110 and 208 subjects received single- and double-dose Seretidetrade mark, respectively. Only one subject experienced tremor. This was classified as mild and occurred in a subject receiving double-dose Seretidetrade mark (50mug/100mug). There was no difference between the treatment groups in the incidence of tremor (difference <1%; 95% CI -6, 8). Other salmeterol-related adverse events (palpitations, muscle cramps and headache) and fluticasone propionate-related events (oral candidiasis and hoarseness) occurred in a similar percentage of subjects in each treatment group. The treatment differences for morning and evening HR measurements showed small differences between the two groups (<2 beats/min). The adjusted mean treatment difference (double dose - single dose) in morning HR was 1.1 beats/min (95% CI 0.2, 2.0) and evening HR was 0.9 beats/min (95% CI 0.1, 1.7). Seven percent of subjects receiving single-dose Seretidetrade mark and 8% receiving double-dose Seretidetrade mark had a QTc change from baseline in the interval 30-59 msec. No increases above 59 msec were seen in either group. There were no clinically significant changes from baseline for potassium levels. Two percent of subjects in the single dose and <1% in the double-dose group had a change from a non-clinically significant baseline blood glucose assessment to a clinically significant abnormality at the end of treatment. In circumstances in which a physician may be considering doubling the dose of Seretidetrade mark for a short period of time in adult asthmatics, this study demonstrates that doubling the dose for a period of 2 weeks is safe and well tolerated.

Comparison of the effects of ipratropium bromide and salbutamol on autonomic heart rate control

B2-agonists and anticholinergic drugs may alter cardiac autonomic modulation. The aim of this study was to investigate the effects of inhaled salbutamol and ipratropium bromide on heart rate variability (HRV). A randomized, double-blind, crossover design study was conducted on 13 healthy volunteers. Salbutamol, ipratropium or placebo was administered in three different testing sessions. Time domain parameters; mean R-R interval (mean-RR), the standard deviation of R-R interval (SDNN) and the root mean square of successive R-R interval differences (RMSSD) and power spectral analysis of HRV were assessed in the supine position and during handgrip exercise before and after taking each drug. In time domain analyses, ipratropium administration resulted in a reduced mean-RR, SDNN and RMSSD during handgrip exercise compared with baseline values (775 +/- 30 ms vs. 748 +/- 21 ms, P < 0.05; 57 +/- 5 ms vs. 50 +/- 5 ms, P < 0.05; 30 +/- 2 ms vs. 26 +/- 2 ms, P < 0.01, respectively). This effect was not detected with salbutamol or placebo administration. In frequency domain analyses, salbutamol but not ipratropium and placebo inhalation increased high frequency power/total power during handgrip exercise compared with baseline (0.09 +/- 0.02 vs. 0.12 +/- 0.02, P < 0.05). Ipratropium inhalation may alter autonomic control of the heart rate in therapeutic doses during mild sympathetic stimulation in healthy subjects, while salbutamol does not show these effects.

Negative affectivity and the influence of suggestion on asthma symptoms

Objective To investigate the effect of suggestion on subjective and objective asthma symptoms as a function of negative affectivity of the patients. Methods Asthmatics ( n=32) took puffs from three separate placebo inhalers, being described as an inert (practice) substance, a bronchoconstrictor, and a bronchodilator. Negative affectivity, social desirability, probability of medication-intake, intensity of asthma symptoms and total respiratory resistance were measured at onset. The latter three measures were repeated after each trial. Heart rate, end tidal PCO 2, and breathing behaviour were measured during each trial. Results Asthmatics with high negative affectivity had overall more intense asthma symptoms. They also reported more airway obstruction after suggested bronchoconstriction and less after suggested bronchodilation, whereas persons with low negative affectivity did not show such variation. These effects were unrelated to social desirability. Respiratory symptoms correlated with the odds of medication intake. Neither negative affectivity nor suggestion influenced lung function and only breathing parameters under voluntary control changed as a function of suggestion. Conclusion Self-reported symptoms of asthmatics with high negative affectivity are more influenced by suggestion than those of patients with low negative affectivity.

Measurement of Forced Expiratory Flows and Lung Volumes

After completing this article, readers should be able to: 1. Describe the information that measurements of forced expiratory flow can provide in spontaneously breathing and mechanically ventilated infants. 2. Delineate how lung volume can be measured. The measurements of forced expiratory flows and lung volumes are important to the evaluation of patients who have respiratory symptoms. Until recently, measurements have been restricted to adults and children old enough to cooperate with testing maneuvers. Newer techniques have enabled such measurements to be made in infants and led to improved understanding of normal lung and airway growth during infancy and early childhood, when dramatic changes occur. The measurements have had important clinical uses in the evaluation and treatment of infants who have respiratory disease, but their use has been limited because they require specialized equipment and expertise as well as sedation of the infant. In this article, we discuss the techniques required for measurement of forced expiratory flows and lung volumes, their limitations, and applications in clinical practice. Detection of airflow obstruction, by physical examination or by quantitative measurement techniques, is facilitated by increasing expiratory flow rates. Measurement of forced expiratory flows is useful because flow rates are inversely proportional to the fourth power of the radius of the airway and, therefore, are indicative of airway size when flow is limited. Disease states affecting the airways, including asthma, bronchopulmonary dysplasia (BPD), or congenital lesions such as pulmonary hypoplasia or vascular airway compression, are expected to decrease expiratory flow. Infants typically are sedated for testing to maintain relaxed breathing with a face mask placed over the mouth and nose. This sedation often is perceived by parents and physicians as one of the barriers to such testing. (1) However, sedation can be achieved safely using oral chloral hydrate at a dose of 80 to 100 mg/kg. …