[Clinical study of the month: the TORCH study (TOwards a Revolution in COPD Health)]. / L'étude clinique du mois. L'étude TORCH (TOwards a Revolution in COPD Health): vers une révolution de la santé des patients souffrant de BPCO.

The TORCH study (Towards a Revolution in COPD Health) was a double-blind, randomised, placebo-controlled clinical trial, investigating the combination of salmeterol/fluticasone propionate for 3 years in COPD. The primary end point was on all-cause mortality. Secondary end points included COPD exacerbation rate, lung function and health status. More than 6000 patients were randomised. In this article, we briefly report the most significant results of the study. The efficacy on mortality (reduction of the risk of death of 17.5%) was near the predetermined level of statistical significance (p = 0.052); the combination had a significant effect on the three pillars of COPD management, that is: improvement of quality of life and respiratory function, and reduction of the rate of exacerbations. In addition to being effective, the combination salmeterol/fluticasone (50/500 microg 2x/day) is well tolerated in COPD and had a favourable benefit/risk ratio.

Randomized controlled trial of salbutamol aerosol therapy via metered dose inhaler-spacer vs. jet nebulizer in young children with wheezing.

The jet nebulizer is a common device used for administering aerosol medication in young children. However, compared to a metered dose inhaler-spacer (MDI-spacer), it takes more time and personnel. This study aimed to compare the efficacy of salbutamol aerosol therapy given via these two devices in young wheezing children. A prospective randomized, double-blind, placebo-controlled trial was performed in children up to 5 years old who had acute wheezing and were admitted to the Department of Pediatrics, King Chulalongkorn Memorial Hospital. Patients were randomly divided into two groups. The first group received 2 puffs of placebo via MDI-spacer, followed by 0.15 mg/kg salbutamol respiratory solution via jet nebulizer. The second group received 2 puffs (100 microg/puff) of salbutamol via MDI-spacer, followed by placebo via jet nebulizer. Clinical scores and tidal breathing pulmonary function test were evaluated before and after treatment. Pulmonary function parameters included those derived from flow volume loops (volume to peak tidal expiratory flow over total expiratory volume, V(PTEF)/V(E); time to peak tidal expiratory flow over total expiratory time, T(PTEF)/T(E); and ratio of tidal expiratory flow at 25% remaining expiration to peak expiratory flow, 25/PF), compliance (Crs), and resistance (Rrs) of the respiratory system. The efficacy of both methods was compared by using analysis of covariance. Forty-seven wheezing children were studied (24 received salbutamol via MDI-spacer, and 23 received it via jet nebulizer). There was no statistical difference between the two groups regarding clinical scores and all pulmonary function parameters. However, heart rate was significantly increased after treatment in the jet nebulizer group when compared to those in the MDI-spacer group (P = 0.004). In conclusion, the efficacy of salbutamol aerosol therapy via MDI-spacer compared to jet nebulizer in young wheezing children was not different in terms of clinical score and postbronchodilator pulmonary function parameters. However, salbutamol aerosol therapy via jet nebulizer significantly increased the heart rate when compared to the MDI-spacer.

Can asthma treatment in sports be doping? The effect of the rapid onset, long-acting inhaled beta2-agonist formoterol upon endurance performance in healthy well-trained athletes.

Inhaled beta2-agonists have been subject to restrictions in relationship to sports due to fear of possible improvement in endurance performance. According to the international doping regulations only inhaled salbutamol, terbutaline and salmeterol are allowed for use in sports. Formoterol is a recently introduced rapid onset-long-acting inhaled beta2-agonist. The main aim of the present randomized, double-blind placebo-controlled study was to investigate possible improvement in endurance performance of inhaled formoterol in 24 healthy well-trained competitive male athletes, 21-29 years old. Lung function (flow-volume loops) was measured before, 15 min after each inhaled study drug and before and repeatedly after exercise. On day 1, maximum oxygen uptake (VO2max), peak ventilation (VEpeak) and running time till exhaustion were measured and used to determine the exercise load on days 2 and 3. On days 2 and 3 the subjects inhaled the study drugs, rested for 1 h, then exercised, and VO2max, VEpeak and running time until exhaustion were determined. Inhaled formoterol did not improve any parameter of endurance performance. On the other hand a statistically significant, although not clinically significant (0.05 ml(-1) min kg(-1)), change was found in estimated difference of VO2max between formoterol and placebo in favour of placebo. Lung function increased significantly after inhaled formoterol, and after exercise also for placebo, but without differences between the beta2-agonist and placebo after exercise. In conclusion, inhaled formoterol did not improve endurance performance compared to placebo.

Comparison of respiratory inductance plethysmography with thoracoabdominal compression in bronchial challenges in infants and young children.

Respiratory inductance plethysmography measuring thoracoabdominal asynchrony (TAA) has been claimed to be a useful tool for measuring changes in airway resistance in infants. In this study we evaluated the response to methacholine by thoracoabdominal compression and respiratory inductance plethysmography. Seventeen infants (mean age, 13.1 +/- 4.7 mo) with recurrent episodes of cough or wheeze underwent bronchial challenge with inhaled methacholine. Lung function was evaluated by measuring maximal expiratory flow at resting lung volume (VmaxFRC), and the degree of TAA was measured by phase angle (theta). Methacholine was inhaled for 1 min during tidal breathing using increasing doubling concentrations until a fall of at least 40% in VmaxFRC was achieved (final concentration). All infants responded to the final concentration of methacholine by a significant fall in VmaxFRC (from 31 +/- 10 to 12 +/- 5 ml/s/kg, p < 0.001). All but one infant responded to methacholine at the final concentration with a significant increase in phase angle (median theta increased from 11.7 to 31.7 degrees, p < 0.001). In two other infants there was an early response in theta compared with the response in VmaxFRC. Phase angle increase after methacholine was expressed as Z-scores (the difference between postmethacholine theta and postbuffer theta divided by the standard deviation of postbuffer theta). An increase of at least 2.0 Z-scores in theta was observed at the same concentration of methacholine when VmaxFRC fell by at least 40% in 15 of the 17 infants (88%). We conclude that respiratory inductance plethysmography is a sensitive method to measure bronchial reactivity to methacholine in most of the infants studied (14 of 17, 82%). A concentration of methacholine causing an increase in theta of at least 2.0 standard deviations above baseline is equivalent to the concentration causing a 40% fall in VmaxFRC.

Augmented hyperventilation via normoxic helium breathing does not prevent exercise-induced hypoxemia.

The purpose of this study was to determine if augmented hyperventilation produced via normoxic helium breathing would reduce exercise-induced hypoxemia (EIH). Seven highly trained endurance athletes with a mean maximum oxygen uptake of 65 ml.kg-1.min-1, performed two cycle ergometer tests to volitional exhaustion. During one of the tests the subjects breathed ambient air, while during the other they breathed normoxic helium (21% O2, 79% He). Mean maximum expired ventilation significantly (p < .05) increased from 139 L.min-1 during the ambient trial to 168 L.min-1 while breathing normoxic helium. Mean arterial oxygen saturation obtained at maximum exercise, however, was not significantly different for the two trials (ambient = 90%, helium = 89%). These results suggest that significantly augmenting exercise hyperventilation by 21% essentially had no effect on EIH in endurance athletes. Thus, the data do not support the hypothesis that inadequate hyperventilation is an important mechanism for arterial oxygen desaturation during graded exercise to exhaustion in highly trained individuals.

A prospective study of pulmonary function in patients receiving mitomycin.

Mitomycin is a chemotherapeutic agent that is used to treat a variety of solid tumors. Pulmonary toxic reactions from this agent can be life threatening. We prospectively investigated the utility of pulmonary function tests (PFTs) in monitoring for the occurrence of pulmonary toxicity due to mitomycin. PFTs were obtained at baseline and after three cycles of mitomycin therapy. We analyzed the clinical course, radiologic studies, and PFT results in 133 patients with metastatic squamous cell carcinoma of the lung randomized to treatment with either mitomycin, vinblastine, and cisplatin or mitomycin alone as part of a prospective treatment protocol of the North Central Cancer Treatment Group (NCCTG). The diffusing capacity (DCO) was available in only 40 patients after the third cycle due to a high rate of progression and death from their underlying disease. After three cycles of chemotherapy, there was an average decline in the DCO of 14% (p<0.0001) and no changes were observed in expiratory flows. No differences were noted between treatment arms. A significant decline in the DCO (defined as a >20% change after correcting for hemoglobin) was noted in 11 of 40 patients (28%). This decline in the DCO was not associated with a worse prognosis (p=0.77). Seven patients (5%) developed severe pulmonary toxic reactions attributed to chemotherapy, including noncardiogenic pulmonary edema, interstitial pneumonitis, and pleural effusions. Corticosteroid therapy resulted in temporary subjective improvement in three patients. The Dco did not correlate with the development of pulmonary toxic reactions in these seven patients. In conclusion, (1) the incidence of clinically significant pulmonary toxic reactions from mitomycin is relatively low (5%), (2) mitomycin therapy resulted in a greater than 20% decline in the DCO in approximately one-fourth of patients receiving three cycles of chemotherapy, and (3) the use of serial PFTs in patients receiving mitomycin was not shown to be predictive of pulmonary toxicity.

Sensitivity of FEV1 and indices of flow volume curve in the methacholine test.

Our aim was to asses the association between the decrease of FEV1 and the modifications of the indices (PEF, MEF25, MEF50 and MEF75% of FVC) during methacholine challenge. 105 patients of both sexes with mild bronchial asthma were included in this study and were subjected to methacholine test according to ATS standards. The results were analysed using analysis of variance (MANOVA), discriminant stepwise and multiple regression. The reduction of FEV1 induced by increasing dosage of methacholine was associated with a significant decrease of the other flow-volume curve indices but we can observe a different flow behaviour. The MEF50 was more significant during the first level of variations and the MEF75 and MEF25 being more significant during the subsequent phases. We conclude that the evaluation of the flow volume indices can be important for better study the site of action of methacholine.

[Bronchial hyperreactivity to the inhalation of hypo- and hyperosmolar aerosols and its correction by halotherapy]. / Giperreaktivnost' bronkhov na ingalatsii gipo- i giperosmoliarnykh aérozolei i ee korrektsiia metodom galoterapii.

18 bronchial asthma (BA) patients (12 with mild and 6 with moderate disease) were examined before and after halotherapy (HT) for airways reactivity using provocative tests with ultrasonic inhalations of purified water (UIPW) and hypertonic salt solution (HSS). Bronchial hyperreactivity (BHR) to UIPW and HSS before treatment occurred in 13 and 11 patients (72 and 69%, respectively). HT reduced BHR in 2/3 and 1/2 of the patients, respectively. In the rest patients BHR was unchanged or increased, being so to UIPW only in patients with atopic asthma in attenuating exacerbation. Clinical efficacy of HT and initial BHR to UIPW correlated (r = 0.56; p < 0.05). No correlation was found between HT efficacy and initial BHR to HSS.

[Effect of salbutamol inhalation on small airways function in patients with sarcoidosis]. / Wplyw inhalacji salbutamolu na stan czynnosciowy drobnych dróg oddechowych u chorych na sarkoidoze.

The effect of Salbutamol (Polfa) inhalation on small airway function was studied in 20 patients with stage II sarcoidosis and 8 healthy volunteers. MEFV values and dynamic compliance were assessed. A significant statistical increase of FEV1, MEF50, Cdyn20 and Cdyn60 were seen only in healthy volunteers. In patients with sarcoidosis the assessed parameters were not effected by the Salbutamol inhalation.

Inhaled platelet-activating factor increases airway sensitivity but not maximal airway narrowing to methacholine in normal subjects.

To examine the effect of inhaled platelet-activating factor (PAF) on airway sensitivity and on maximal airway narrowing, we measured airway response to doubling concentrations of methacholine (MCh) 48 h before and 48 h after inhalation of 10, 50 and 100 micrograms of PAF in six nonatopic, nonasthmatic subjects. The forced expiratory volume in one second (FEV1) and airflow at 30 percent of vital capacity (V30) from partial forced expiration were used to assess changes in airway calibre. Inhalation of PAF caused only minor changes in FEV1. In contrast, inhalation of 100 micrograms of PAF caused a significant fall in V30 from 2.64 +/- 0.35 to 1.35 +/- 0.43 l.min-1 (p < 0.05). Two days after PAF inhalation a leftward shift of the concentration-response curve to MCh was observed. The MCh concentration causing a 20% fall in FEV1 (PC20FEV1) was 11.25 +/- 1.78 and 2.38 +/- 1.29 mg.ml-1 (geometric mean +/- GSEM; p < 0.05) before and after PAF inhalation, respectively. PAF did not affect the maximal airway response to MCh. The maximum percentage fall in FEV1 was 36.2 +/- 1.9% at baseline and 37.6 +/- 1.8% after PAF inhalation. Likewise, maximum percentage change in V30 was 72.8 +/- 3.7% at baseline and 73.6 +/- 3.4% after PAF inhalation. The results of this study show that PAF inhalation increases airway sensitivity without altering the maximal bronchoconstrictive response to MCh in normal subjects.

Effect of salbutamol on gas compression in cystic fibrosis and asthma.

In cystic fibrosis (CF), it has been suggested that increases in FEV1 postbronchodilator (BD) can be accompanied by paradoxical decreases in isovolume maximal flow at 25% of vital capacity (V25iso) measured from maximum expiratory flow-volume curves (MEFVC), raising concerns about determining the benefits of BD in CF. MEFVC measured using expired volume has been shown to be subject to errors due to gas compression. In the present study, BD response was assessed in 91 patients with asthma and 78 with CF using the percentage of change in FEV1 and V25iso determined using MEFVC from both mouth (m) and plethysmograph (p) volumes. From the two curves, volume of compression (Vcomp) was measured. Baseline measurements were similar for both groups, except that the residual volume to total lung capacity ratio (RV/TLC) was higher and Vmax25 and FVC were lower in CF. Both groups showed significant (p < 0.05) increases in FVC, FEV1, and V25iso after BD. The percentage of change in FEV1 correlated with the percentage of change in V25iso (r = 0.53 for CF and 0.66 for asthma, p < 0.001). Baseline Vcomp25 was higher in asthma than in CF. The percentage of change in V25iso was not related to the change in Vcomp25iso for either group. Only four patients with CF showed a paradoxical decrease in V25iso, and the differences in flow were small. Two had an increase in Vcomp and two had a decrease. We conclude that paradoxical decreases in V25iso are rare, are associated with small changes in flow, and are not related to changes in Vcomp.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in pulmonary function and cross-sectional area of trachea and bronchi in asthmatics following inhalation of procaterol hydrochloride and ipratropium bromide.

To determine the sites of action of inhaled adrenergic and anticholinergic bronchodilators, we used the acoustic reflection technique to measure airway area before and after administration of beta 2-selective adrenoreceptor agonist (procaterol hydrochloride) and quaternary anticholinergic agent (ipratropium bromide). Eight stable individuals with asthma (five men and three women; mean age, 34 +/- 12.7 yr) were studied on 2 days in single-blind randomized crossover fashion when they self-administered (using metered-dose inhaler) two puffs of either procaterol hydrochloride hemihydrate (10 micrograms/puff) or ipratropium bromide (20 micrograms/puff). Maximal expiratory flow-volume curve, specific airway resistance, and cross-sectional areas of three airway segments (extrathoracic tracheal, intrathoracic tracheal, and bronchial) were recorded at baseline and 15, 30, 60, and 120 min after drug administration. Both agents produced significant improvements in FEV1, FVC and forced expiratory flow at 50% of vital capacity (V50), and specific airway resistance (SRaw) as early as 15 min after drug administration. These effects were sustained for the 120 min monitoring period. However, all improvements were significantly greater for procaterol than for ipratropium. By contrast, there was no significant difference between drugs in the increased production in the cross-sectional areas of the three airway segments although there was a nonsignificant trend toward greater increases in tracheal area produced by the anticholinergic agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of vagus nerves in resiniferatoxin-induced bronchoconstriction of guinea pigs.

To study the role of vagal afferent C-fibers in resiniferatoxin (RTX)-induced bronchoconstriction in vivo, 30 guinea pigs weighing 347 +/- 28 g were evenly and randomly divided into five groups: Group 1, control; 2, chronic vagotomy; 3, local capsaicin (acute); 4, local capsaicin (chronic); and 5, systemic capsaicin. Each animal was anesthetized with pentobarbital sodium, cannulated with a tracheal cannula and venous catheter, paralyzed with gallamine triethiodide, and artificially ventilated. All animals were pretreated with atropine and phenoxybenzamine. Immediately after RTX was intravenously injected, each animal in the control group exhibited profound decreases in maximal expiratory flow, dynamic respiratory compliance, and total lung capacity, as well as an increase in functional residual capacity, indicating severe airway constriction. Animals in Groups 2-4 exhibited partial abolishment, while those in Group 5 showed complete abolishment of the RTX-induced bronchoconstriction. In 12 additional animals (6 animals each in control and chronic vagotomy groups), chronic vagotomy caused also suppressive effects on capsaicin-induced airway constriction. At one min, our data demonstrate that 36-51% of noncholinergic bronchoconstriction is due to the vagal component while the remaining constriction is due to the nonvagal component. Thus, the nonvagal component plays a significant role in this type of tachykinin-mediated airway constriction.

Bronchial symptoms and respiratory function in workers exposed to methylmethacrylate.

This study aimed to investigate the pulmonary effects of methylmethacrylate (MMA) in a group of occupationally exposed workers. In the exposed group 20% had chronic cough compared with 1% in controls. Spirometric values at the beginning of the workshift were similar in both groups, but a mild airways obstruction appeared during the workshift. The maximum expiratory flow when 50% of the forced vital capacity remained to be exhaled (MEF50) and the ratio of MEF50 to maximal expiratory flow (MEF50/MEF) decreased significantly during the workshift among exposed workers v controls (p = 0.04 and 0.01 respectively). Results remained unaffected after adjustment for smoking. Exposure to MMA seems to be responsible for a mild airways obstruction but further study on a larger population would be useful.

Contaminación del aire en interiores: efecto del tabaquismo pasivo sobre la función pulmonar de niños y adultos asmáticos / Pulmonary functional response to passive smoking of a group of asthmatic, adults and children

Se estudió la respuesta funcional pulmonar inmediata de un grupo de adultos y niños asmáticos, después de la exposición pasiva la humo de cigarro. Se le practicó pletismografía corporal y curva flujo-volumen, para medir la capacidad vital forzada, el flujo espiratorio forzado en el 50 por ciento de la capacidad vital, el columen espiratorio del primer segundo y la resistencia específica de las vías aéreas, antes y después de exponerlos al tabaquismo pasivo. Se definió como broncoespasmo subclínico a la coexistencia de tres cambios funcionales: disminución igual o mayor al 20 por ciento del columen espiratorio forzado del primer segundo; disminución igual o mayor al 20 por ciento del flujo espiratorio forzado en el 50 por ciento de la capacidad vital, y aumento igual o superior al 40 por ciento de la resistencia específica de las vías aéreas. Diez por ciento de los adultos y 22 por ciento de los niños asmáticos presentaron broncoespasmo funcional subclínico, después de la exposición. ningún voluntario sano del grupo control, mostró cambio alguno significativo. La conclusión de este trabajo refuerza la recomendación de evitar el tabaquismo pasivo especialmente en el asmático

Nedocromil sodium inhibits the increase in airway reactivity induced by platelet activating factor in humans.

To investigate the effect of nedocromil sodium on changes in airway reactivity to methacholine induced by platelet activating factor, we studied 12 nonasthmatic, nonatopic subjects (24 to 41 years) in a double-blind trial. The FEV1 and airflow at 30 percent of vital capacity from a partial forced expiration (V30p) were used to assess changes in airway caliber. Two concentration-response curves to doubling concentrations of MCh (from 0.3 mg/ml) were performed 48 h apart. The concentrations of MCh causing a 20 percent fall in FEV1 (PC20FEV1) or a 40 percent fall in V30p (PC40V30p) were calculated. After the first MCh challenge, subjects were matched by airway reactivity and randomly assigned to nedocromil sodium (two puffs qid 2 mg/puff) or placebo treatment. Two days after the second MCh challenge, PAF was inhaled, and changes in airway caliber were recorded. Administration of either nedocromil sodium or placebo was ended at this time and airway response to MCh was assessed two days after PAF. The two concentration-response curves to MCh obtained before PAF exposure were superimposable. The PAF caused a dose-related bronchoconstriction in both groups; the maximal fall in V30p was 27.6 +/- 6.6 percent (mean +/- SE) in the nedocromil sodium group and 37.4 +/- 4.6 percent in the placebo group. Two days after PAF, the PC20FEV1 did not change in subjects who received nedocromil sodium (4.86 vs 4.32 mg/ml; geometric mean), but it fell from 6.59 to 1.12 mg/ml (p less than 0.05) in placebo-treated subjects. These results indicate that nedocromil sodium inhibits PAF-induced increase in airway reactivity.

[The effect of inhaled salbutamol on pulmonary gas exchange in patients with chronic obstructive bronchopneumopathy]. / Effet du salbutamol inhalé sur les échanges gazeux pulmonaires de patients atteints de BPCO.

The aim of this study is to establish whether or not the inhalation of a puff of salbutamol (Ventoline, 100 micrograms) could induce hypoxemia. Twenty-five chronic obstructive pulmonary disease (COPD) patients were investigated. In a first group of 20 patients arterial blood gases and related indices were measured before and 5, 10, 30, 60 and 90 minutes after inhalation of salbutamol. The oxyhemoglobin dissociation curve was traced before and 90 minutes after the drug intake. Except in two subjects in whom salbutamol dramatically improves arterial blood gases, the drug had no effect on the investigated parameters. It is concluded that salbutamol does not affect the blood gases in COPD patients. In this respect the behaviour of COPD patients differs from that of asthmatics in whom salbutamol generally induced hypoxemia.