The 12-week efficacy and safety of aerosolized recombinant human DNase (dornase alfa) were evaluated in previously untreated patients with cystic fibrosis (CF) with advanced lung disease.

We compared the effects of evening administration of sustained-release theophylline (Uniphyl) and qid inhaled beta 2-agonist (salbutamol, two 100-micrograms puffs) on sleep quality and nocturnal oxygen saturation in 20 patients with COPD. Patients with FEV1 less than 70% predicted and FEV1/FVC ratio less than 70% were eligible to participate in this double-blind, crossover study, with 2-week treatment arms. Patients recorded morning and evening peak flow and symptoms in a daily diary. On the last day of each treatment period, overnight polysomnography was done. Spirometric indexes were measured before retiring and on awakening. Patients spent less time at less than 90% oxygen saturation (51 +/- 92 min vs 72 +/- 105 min; p = 0.03) during theophylline treatments than during salbutamol treatment. There was a smaller overnight decrease in FEV1 (0.04 L vs 0.13 L; p = 0.04) after theophylline than after sallbutamol treatment. FEV1/FVC ratio and maximum expiratory flow at 50% of vital capacity (V50) increased overnight with theophylline and decreased with salbutamol (p = 0.014, 0.025). Morning peak expiratory flow rate was higher with theophylline (4.0 +/- 1.7 L/s) than with salbutamol (3.6 +/- 1.8 L/s; p = 0.004). The duration of patient-reported nocturnal wheezing was lower with theophylline than with salbutamol (p = 0.006). There were no differences between treatments in sleep quantity, efficiency, staging, or subjective quality. We conclude that, compared with salbutamol, evening administration of once-daily theophylline results in better nocturnal oxygen saturation and an improvement in the overnight change in pulmonary function, without affecting sleep architecture, in patients with COPD.

The time course of inspiration has been shown to have a significant influence on the subsequent maximal expiratory flows and timed forced expiratory volumes in healthy adults and those with COPD. The purpose of this study was to evaluate the effect of two different inspiratory maneuvers on the spirogram in 15 patients with cystic fibrosis, aged 13 to 35 years, who had mild to moderate airway obstruction. Patients performed a forced expiratory maneuver either after a rapid inspiration without an end-inspiratory pause or after a slow inspiration with a 4-s end-inspiratory pause. Flow-time and volume-time curves were measured by a pneumotachograph. The mean values of FVC, FEV1, and peak expiratory flow were significantly larger by 11%, 13%, and 26%, respectively, after the rapid inspiration without an end-inspiratory pause compared to the slow inspiration with the end-inspiratory pause. This discrepancy probably reflects differences in effective elastic recoil pressure between the two maneuvers. Although the nature of this phenomenon is not fully understood, our results show that for spirometry in patients with cystic fibrosis, the preceding inspiratory maneuver influences the results. An important corollary is that this inspiratory maneuver should be standardized.

In patients with COPD, a relationship between breathlessness and respiratory effort, assessed in terms of mouth occlusion pressure (P0.1), has been described. To evaluate the short-term effects of inhaled terbutaline on breathlessness, breathing pattern, and P0.1 in patients with nonreversible COPD, we designed a randomized, double-blind, parallel, placebo-controlled study. Twenty-five patients with stable nonreversible COPD, mean age 64 +/- 11 years, were enrolled in the study. Patients received 500 micrograms inhaled terbutaline or placebo. Breathlessness, using the Borg scale, breathing pattern, and P0.1 were measured at baseline and 30 min after inhalation. Terbutaline resulted in a significant decrease in Borg scale, while no differences were observed after placebo. No significant changes in breathing pattern were found. Nevertheless, a decrease in P0.1 (0.31 +/- 0.07 vs 0.21 +/- 0.05 kPa; p < 0.001) after terbutaline inhalation was observed. Borg score was correlated with P0.1 in all patients. Moreover, changes in Borg score after medication were directly proportional to P0.1 changes (r = 0.85; p < 0.01). We conclude that terbutaline decreases central inspiratory drive and improves breathlessness in patients with nonreversible COPD.

To evaluate the role of inhaled ipratropium bromide in acute asthma, a double-blind study of 384 emergency department patients compared the effect of the combination of ipratropium and albuterol with that of albuterol alone. Patients were randomized to receive nebulizer treatments with either 2.5 mg of albuterol or 2.5 mg of albuterol mixed with 0.5 mg of ipratropium bromide at entry and at 45 min. Spirometry, vital signs, and oxygen saturation were measured before and at 45 and 90 min following the nebulizer treatments. Serum potassium levels were obtained at entry and 90 min. The two groups did not differ significantly in age (mean +/- SD = 33.4 +/- 9.3 and 32.5 +/- 9.7 years for the albuterol and ipratropium group and the albuterol group, respectively), baseline FEV1 (mean +/- SD = 1.22 +/- 0.42 and 1.25 +/- 0.44 L respectively), or prior use of asthma medications. At 45 min, there were significantly more responders (15% increase in FEV1 over baseline) in the group receiving albuterol and ipratropium compared with albuterol and saline solution (85% and 78%, respectively; p = 0.045), but the median change in FEV1 from baseline did not differ (0.530 L for the albuterol and ipratropium group and 0.420 L for the albuterol and saline solution group; p = 0.347). By 90 min, the percentage of responders did not differ (88% and 89%, respectively), and the median change in FEV1 was 0.680 L for the group receiving albuterol and ipratropium and 0.650 L for the group receiving albuterol and saline solution (p = 0.693). There were no significant adverse events experienced by patients in either group. Furthermore, there were no significant differences in the number of patients requiring additional therapy in the emergency department or hospitalization. We conclude that in this population of inner city asthmatics, we were unable to demonstrate significant additive benefit of nebulized ipratropium bromide to nebulized albuterol.

It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma.

To compare the safety and efficacy of percutaneous dilational tracheostomy (PDT) with surgical tracheostomy (ST).

There is widespread interest in the evaluation of clinical strategies that safely reduce health-care costs. Elimination of inappropriate chest physiotherapy may represent one of those strategies.

Although several studies on tuberculous (TB) pleurisy suggest that the addition of corticosteroids to anti-TB therapy may have beneficial effects, these agents are not used routinely. To assess the effects of short-term oral prednisone therapy in TB pleurisy, 74 patients were randomly assigned in a double-blind fashion to treatment with either placebo or prednisone at a dose of 0.75 mg/kg/d for up to 4 weeks with gradual reduction over an additional 2 weeks. All subjects received a standard 3-drug anti-TB chemotherapy regimen for 6 months. TB pleurisy was diagnosed by histologic study and/or culture of pleural biopsy specimens obtained at thoracoscopy. Complete drainage of the effusion was performed simultaneously. Outcome measures were assessed periodically for 24 weeks, including indexes of morbidity and pleural thickening. After randomization, four patients were excluded from the final analysis. Of the 70 patients analyzed, 34 received prednisone and 36 received placebo. Demographic and clinical characteristics of the treatment groups were comparable at the time of hospital admission. Although a statistically significant improvement in symptoms occurred earlier in the prednisone group (8 weeks) than in the placebo group (12 weeks), between-group comparison showed no significant differences at any of the follow-up evaluations. The proportion of subjects in the prednisone group (53.1%) with residual pleural thickening at 6 months did not differ significantly from that of the placebo group (60%). Pleural effusions did not recur in any of the patients. Initial complete drainage of the effusion was associated with greater symptomatic improvement than any subsequent therapy. We conclude that standard anti-TB therapy and early complete drainage is adequate for the treatment of TB pleurisy. The addition of short-term oral prednisone therapy neither results in clinically relevant earlier symptom relief nor confers a beneficial effect on residual pleural thickening.

The effects of vasoactive drugs, including bronchodilators, on vascular and pulmonary dynamics are interrelated, complex and difficult to measure, but important because of potential deleterious effects on gas exchange.

An open, randomized, parallel-group study was conducted to investigate whether asthmatic patients, considered adequately treated with a corticosteroid and/or short-acting beta 2-agonist via pressurized metered-dose inhaler (pMDI), could be transferred to a corresponding nominal dose of budesonide and/or terbutaline via Turbuhaler, an inspiratory flow-driven multidose dry powder inhaler (Astra Draco; Lund, Sweden), without a decrease in the effect of treatment. One thousand four patients (555 women; mean age, 44 years; mean peak expiratory flow [PEF], 102% predicted normal value) were randomized and treated with either pMDI (current therapy) or Turbuhaler for 52 weeks. The variables studied were asthma-related events, morning PEF, and inhaler-induced clinical symptoms. Asthma-related events were defined in two ways: (1) sum of health-care contacts plus doublings or additions of steroids, and (2) number of 2 consecutive days with PEF less than 80% of baseline. Baseline was obtained from a 2-week run-in period while receiving previous therapy. No statistically significant difference was found in asthma-related events according to definition 1. According to definition 2, there was a statistically significant difference between the groups in favor of Turbuhaler (p = 0.008). The mean number of events was 1.7 with Turbuhaler and 2.2 with pMDI. The mean number of weeks per patient with a PEF less than 90% of baseline was 4.5 with Turbuhaler compared with 6.0 with pMDI (p = 0.002). The sum of inhaler-induced symptoms after 1 year of use was statistically significantly lower with Turbuhaler (0.40) than with pMDI (0.75) (p = 0.0001). In conclusion, budesonide and terbutaline in Turbuhaler offered a superior alternative to corticosteroids and bronchodilators delivered by pMDIs in the maintenance treatment of asthma.

Adult patients suffering from acute asthma presenting to the Emergency Department with an FEV1 of less than 40% of predicted were randomized into four treatment groups. They were treated with nebulized albuterol at a high (7.5 mg) or standard (2.5 mg) dose given either continuously through 1 h, or intermittently every hour, for 2 h. When the FEV1 improvements for the different groups at 2 h were compared, the groups treated with continuous nebulization had the greatest improvement. The improvements (1.07 L for the high-dose group, and 1.02 L for the standard-dose group) were significantly greater than the improvement seen with standard-dose intermittent treatment (0.72 L; p < 0.05). The improvement in FEV1 of the high-dose, hourly treated group was intermediate in magnitude between these (0.09 L). There was no difference in the improvement seen between the two groups treated with continuous nebulization. The potassium fall, present in all groups, was more pronounced in the groups treated with high doses of albuterol. Only one person (high dose, continuous treatment group) developed hypokalemia of less than 3.0 mmol/L. The high-dose hourly treated group had the highest incidence of side effects, and the standard-dose continuously treated group had the lowest. The standard-dose continuous-treatment regimen had the greatest improvement in FEV1 with the least number of side effects.

The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma. It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful. PHASE 1: In a previous study in patients with asthma and COPD, we found that 2.5 years of treatment with a beta 2-agonist plus inhaled corticosteroid (BA + CS) was more effective in improving the FEV1 and the provocative concentration of histamine causing a 20% reduction in FEV1 (PC20) than treatment with a beta 2-agonist plus anticholinergic (BA + AC) or placebo (BA + PL). PHASE 2: We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy (800 micrograms beclomethasone dipropionate) in the groups previously not treated with inhaled CS (BA +/- AC) could also improve FEV1 and PC20 to the same degree. A distinction was made between patients with predominantly asthma (high baseline reversibility, delta FEV1 > or = 9% of predicted), and predominantly COPD (low baseline reversibility, delta FEV1 < 9% of predicted).

To compare the physiologic and inflammatory response following inhalation of corn dust extract (CDE) and lipopolysaccharide (LPS) solutions in normal subjects.

To assess separately the effectiveness and safety of nasal-continuous positive airway pressure (N-CPAP) and that of surgery in comparison to conservative management in patients with obstructive sleep apnea syndrome (OSAS). DESIGN. A randomized study with 1-year follow-up.

STUDY OFJECTIVE: The purpose of this study was to test the effectiveness of oropharyngeal decontamination on nosocomial infections in a comparatively homogeneous population of patients undergoing heart surgery.

Endothelial metabolism of L-arginine to L-citrulline and the potent vasodilator, nitric oxide (NO), is important in the regulation of vascular tone and resting BP. L-arginine improves abnormal endothelium-dependent vasodilation in the setting of hypercholesterolemia and has a vasodilatory effect in normal vessels, effects presumed to be mediated through increased endogenous NO production, although this has not been established by direct measurement of NO. In a randomized, placebo-controlled, crossover trial, 10 healthy male subjects received a 30-min infusion of 0.5 g/kg L-arginine hydrochloride. Subjects underwent continuous monitoring of BP and heart rate (HR) as well as intermittent determination of mixed expired NO concentration and plasma L-arginine and L-citrulline levels. Infusion of L-arginine produced a significant fall in mean BP with a peak effect of -9.3 +/- 0.9% (p<0.005). The hemodynamic effects of L-arginine were associated with an increase in mixed expired NO concentration (FeNO) of 55 +/- 15% (p<0.005) from 15 +/- 2 to 21 +/- 3 parts per billion (ppb) and an increase in the rate of pulmonary NO excretion of 118 +/- 45% (p<0.005), as well as a rise in plasma L-citrulline from 25 +/- 4 to 46 +/- 5 micromol/l (p<0.005). There was a significant correlation between the hypotensive response to L-arginine and the increase in expired NO (r=-0.68, p<0.05). The hypotensive effect of L-arginine in humans appears to be mediated, at least in part, by NO synthase metabolism of L-arginine and increased endogenous NO production as indicated both by increased plasma L-citrulline and by increased expired NO.

We hypothesized that the increased arousal threshold to upper airway occlusion exhibited by patients with obstructive sleep apnea (OSA) is in part secondary to the disease process itself. To test this hypothesis, we studied the effects of withdrawal of three nights of nasal continuous positive airway pressure (CPAP) treatment on arousal in six male patients with severe OSA who were using nasal CPAP on a long-term basis. During the control week, patients slept with nasal CPAP at home and on the first of 2 nights in the sleep laboratory (night C1, CPAP; night C2, no CPAP). During the apnea week, patients slept without nasal CPAP for 2 nights at home and 2 nights in the sleep laboratory (AP1, AP2). The control and apnea weeks were consecutive and in random order. The mean (+/-SEM) apnea+hypopnea index was 76.9 +/- 7.1 on AP1 vs 3.1 +/- 1.0 events per hour on C1 (p<0.05). Thus, the laboratory night (and presumably the 2 nights at home) preceding AP2 had dramatic increases in apnea compared with the nights preceding C2. The apnea duration during nonrapid eye movement sleep on nights following apnea was greater (AP2: 28.7 +/- 1.5 vs C2: 25.5 +/- 1. 7 s; p<0/05) and the arousal threshold as reflected by the maximum esophageal pressure deflection preceding arousal was higher (DPmax) (AP2: 55.1 +/- 5.7 vs C2: 45.3 +/- 6.4 cm H2O; p<0.005). We conclude that prior sleep apnea increases the arousal threshold to upper airway occlusion on subsequent nights and prolongs the apneic events.

Induction (neoadjuvant) chemotherapy has become an accepted treatment for stage IIIA (T1-3N2M0) non-small cell lung cancer. In two recent randomized trials, neoadjuvant chemotherapy plus surgery gave an increase in median survival at least fivefold greater than surgery alone. The Spanish Lung Cancer Group trial of preoperative chemotherapy, in which the cisplatin dose was randomized to either 50 mg/m2 or 100 mg/m2 plus 3 g/m2 ifosfamide and 6 mg/m2 mitomycin, examines the effect of K-ras gene mutations on tumor response and survival. Patients whose tumors contain K-ras gene mutations are more likely to develop distant metastases and have lower median survival than patients without such mutations. Microsatellite instability seems to be a frequent mechanism of genetic aberrations. Knowledge about these genetic alterations could have prognostic importance and may identify the patients who should receive the most aggressive additional treatment.