The objective of the present study was to determine if patients with COPD who were taking Theo-Dur bid or tid (total dose 400 to 900 mg per day) could be safely switched to Uni-Dur, 800 mg given qd at bedtime. Twenty-eight patients were enrolled in the study, and 23 completed the study. The mean daily dose of theophylline prior to the study was 828 mg, while the mean dose after three weeks of Uni-Dur therapy was 783 mg. The mean serum theophylline level 10.5 +/- 3.6h after the last Theo-Dur dose was 10.5 mg/L. After three weeks of Uni-Dur therapy, the mean theophylline level at 8:00 AM was 14.6 mg/L, while the mean theophylline level at 8:00 PM was 9.9 mg/L. This latter level did not differ significantly from that obtained at the start of the study 10.5 +/- 3.6 h after the last dose of Theo-Dur. After three weeks of Uni-Dur therapy, the peak expiratory flow rate, the FEV1, and the FVC were not significantly changed from those at the initial evaluation. Twenty-one of the 23 patients ended up receiving 800 mg Uni-Dur qd. From this study, we conclude that once daily theophylline dosing with Uni-Dur compared with bid or tid dosing with Theo-Dur produces similar theophylline levels and pulmonary function, and most COPD patients who are taking 400 to 900 mg Theo-Dur daily can be managed with 800 mg Uni-Dur once daily at bedtime.

Previous studies have reported that the inhalation of the alpha 2-agonist clonidine decreases airways reactivity. Other studies have shown that oral doses of clonidine acutely increase airways reactivity to histamine, but not to methacholine. Recently, a transdermal clonidine delivery system (TTS) has been approved for use, and there is an increasing interest in using this system for management of postmenopausal and smoking cessation symptoms. To our knowledge, the effects of TTS on airways function in asthmatics have not been reported. The purpose of this study was to determine if use of TTS would alter airways reactivity. Six asymptomatic asthmatic subjects underwent a baseline methacholine challenge (M). In a double-blinded randomized crossover fashion, either a placebo or a TTS patch (TTS-1, 0.1 mg/day), was applied to the arm. Four days later, the challenge was repeated. After two to three days of washout, the alternate patch was applied, and a second challenge was performed. Several days later, a second baseline challenge was repeated. This sequence was then repeated using histamine (H). The patch was well tolerated by all subjects. There was no significant change in resting pulse or blood pressure, and for the group no change in airways reactivity to either M or H was noted. In conclusion, while use of TTS-1 does not improve airways function, its short-term use in asthmatics is not associated with an increase in airways reactivity.

The purpose of this study was to compare the effects of isocaloric liquid meals with high fat (55 percent) and low carbohydrate (28 percent) content (Pulmocare) to meals with low fat (30 percent) and high carbohydrate (53 percent) content (Ensureplus) on exercise performance in subjects with chronic airflow obstruction (CAO). Twelve stable subjects with CAO (FEV1 = 1.30 +/- 0.47 L) underwent incremental symptom-limited exercise tests 90 minutes following the ingestion of 920 calories of EnsurePlus HN (E), 920 calories of Pulmocare (P), or a noncaloric placebo (C). Tests were performed on three days, in a double-blind randomized fashion. Expired gases were collected continuously and analyzed every 30 seconds. The mean maximal work load after E (81 +/- 24 W) was significantly less than that after P (88 +/- 21 W) or C (88 +/- 24 W). The mean ventilation at exhaustion was similar after E (48 +/- 13 L/min), P (51 +/- 11 L/min), and C (49 +/- 10 L/min). In comparison to C, six of the 12 individuals had a decreased work load following E, while only one had a decreased maximal tolerated work load following P. The results of this study suggest that meals with a higher fat and lower carbohydrate content may be less likely to impair work performance of patients with CAO in the absorptive phase than meals with a lower fat and higher carbohydrate content. These findings may have clinical significance to patients with CAO who complain of postprandial exertional dyspnea.

The objective of this study was to assess the effect of a novel regimen of antibiotic prophylaxis on the incidence of lower respiratory tract infection in patients requiring prolonged (at least five days) mechanical ventilation. The design was a controlled, prospective, randomized trial, with blinded comparison of the groups regarding the incidence of respiratory tract infection in an intensive care unit of a university hospital. After determination of the APACHE II score for severity of disease, 88 patients were randomly divided in three groups. Twenty-four of these patients did not complete five days of mechanical ventilation, and eight were withdrawn for other reasons. Fifty-six patients (18 in group 1, 21 in group 2, 17 in group 3) completed the study. Patients in both control groups 1 and 2 did not receive antibiotic prophylaxis, but the two groups differed in the antibiotic policy in case of infection. Patients in group 3 received antibiotic prophylaxis consisting of norfloxacin, polymyxin E, and amphotericin B, applied topically in oropharynx and stomach from time of ICU admission until extubation, and intravenous cefotaxime 500 mg three times a day during the first five days of admission. In both control groups, about 90 percent of the patients acquired microbial colonization of oropharynx or stomach. In group 3, only 12 percent and 24 percent of the patients acquired colonization of oropharynx and stomach, respectively (p less than 0.001). This resulted in a reduction of the incidence of lower respiratory tract infection (78 percent in group 1, 62 percent in group 2, 6 percent in group 3 [p = 0.0001]). The regimen of antibiotic prophylaxis studied prevented respiratory tract infection in mechanically ventilated patients. Antibiotic prophylaxis should be considered in all patients expected to require prolonged mechanical ventilation.

We have investigated the effects of inhaled budesonide on the bronchial responsiveness to both directly and indirectly acting spasmogens in man. Following treatment with budesonide or placebo for three weeks in a double-blind, crossover trial with a three-week washout, the response to histamine and bradykinin was determined in ten patients with mild asthma. After treatment with budesonide, the response to both inhaled histamine and bradykinin was decreased when compared with placebo. The PD35 histamine was increased by 1.95 doubling doses and PD35 bradykinin by 2.1 doubling doses. Daily (PEF) recordings were significantly increased during budesonide therapy, the morning PEF by 34.8 +/- 14.1 L/min and evening by 50.3 +/- 23.1 L/min. Baseline laboratory lung function on the study days was not altered by budesonide nor were symptom records altered significantly. Inhaled budesonide therefore inhibits to the same extent the exaggerated response to both directly acting histamine and bradykinin which acts through airway nerves.

Alveolar macrophages (AMs) may play a key role in human respiratory immune defenses, partially by synthesizing and releasing interleukin 1 (IL = 1). D53 (Ribomunyl), a composite bacterial ribosomal immunostimulant, has been recognized as an efficient prevention of respiratory tract infections. In vitro, D53 enhances the IL-1 production by mouse spleen adherent cells. A thymocyte proliferative response assay was used to evaluate the in vitro IL-1 production by AMs in healthy subjects who received D53 immunostimulant. Twelve nonsmoking healthy subjects took part in a prospective double-blind placebo control study. On day 1, a first bronchoalveolar lavage (BAL) was performed to assess IL-1 production by unstimulated and lipopolysaccharide (LPS) stimulated AM. Then, subjects were randomized to receive D53 (n = 6) or its placebo (n = 6) by both oral and subcutaneous injection routes from day 1 to day 15. On day 15, a second BAL was done and AM IL-1 production was again tested. IL-1 production on day 15 did not significantly differ from day 1 in both D53-treated and placebo groups either when AMs were unstimulated or were stimulated with concentrations of LPS resulting in maximal IL-1 production. However, in the D53-treated group, but not in the placebo group, IL-1 production induced by low LPS concentration (5 mg/L) was significantly higher (mean +/- SEM: 1,238 +/- 287 U/10(6) AM) on day 15 in comparison with day 1 (577 +/- 113 U/10(6) AM; p less than 0.05, Wilcoxon W test) and in comparison with the control group (day 15 IL-1 production induced by 5 mg/L LPS, 758 +/- 175 U/10(6) AM; p less than 0.05, Mann-Whitney U test). Moreover, in the D53-treated group, the optimal LPS concentration (ie, LPS concentration that induced maximal IL-1 production) was significantly lower on day 15 (mean +/- SD: 11 +/- 7 mg/L) than on day 1 (16 +/- 7 mg/L; p less than 0.05 Wilcoxon W test). We conclude that D53 immunostimulant in vivo primes AM to produce IL-1 following low LPS concentration stimulation. This may partially explain the protective effect of D53 immunostimulant against respiratory tract infection.

We studied high intensity, symptom-limited, endurance exercise training in 52 patients with COPD participating in a pulmonary rehabilitation program. The patients had moderate to severe airway obstruction and reduced exercise tolerance with ventilatory limitation. The target workload for endurance exercise testing was 95 percent of the baseline maximum treadmill work load. At training weeks 1, 4 and 8, they were training at 85, 84, and 86 percent respectively, of baseline maximum. After rehabilitation, there was an increase in maximal treadmill work load, VO2max, and endurance exercise time, and a decrease in perceived symptoms. Patients who did not reach anaerobic threshold (group 2) were able to train at a higher percentage of maximum exercise tolerance than patients who reached anaerobic threshold (group 1). The increase in exercise performance of both groups, however, was similar. We conclude that patients with moderate to severe COPD can perform exercise training successfully at intensity targets which represent higher percentages of maximum than typically recommended in normal individuals or other patients.

To describe the frequency of aerosol pentamidine-induced bronchoconstriction, its relationship to non-specific airway responsiveness, and its response to preventive therapy using salbutamol, ipratropium bromide, or sodium cromoglycate.

Protripyline is the pharmacologic agent most commonly used to treat obstructive sleep apnea (OSA); however, its anticholinergic side effects make it intolerable to many patients. Because serotonin may be a central respiratory stimulant and because the serotonin-uptake inhibitor, fluoxetine, is usually well tolerated, we wanted to try fluoxetine in the treatment of OSA. Therefore, we compared the effect of fluoxetine to that of protriptyline in 12 patients with OSA. Both drugs significantly decreased the proportion of REM sleep time and decreased the number of apneas or hypopneas in NREM sleep. The response to fluoxetine was equivalent to that of protriptyline; however, for the group as a whole, there was no significant improvement in the number of arterial oxygen desaturation events, the level of arterial oxygen desaturation, or the number of arousals with either agent. Although there was wide variability in the response to each medication, six of the 12 patients had good responses, including improvement in oxygenation, to either fluoxetine or protriptyline. Three patients could not complete the trial of protriptyline. We conclude that fluoxetine is beneficial to some, but not all, patients with OSA. Fluoxetine was better tolerated than protriptyline.

The effect of two different circuit leaks on the measurement of maximal static inspiratory and expiratory pressures at the mouth (Pimax, Pemax) was assessed in 70 patients with respiratory disease. Patients were divided into three groups with similar anthropometric and spirometric characteristics. The first group (30 patients) had their Pmax measured with a leak of 2.0 mm internal diameter (ID) and 37 mm length (as proposed by T. Ringqvist) and repeated with a second leak of 1.0 mm ID and 15 mm length (as recommended by J. L. Clausen). The two measurements were done in random order. Measurements for the other two groups (20 patients each) were taken with one or another, the two leaks randomly alternated with no leak. Pimax measurements obtained with Ringqvist's leak were 17 percent (p less than 0.005) lower than those with Clausen's leak and 22 percent (p less than 0.005) lower than those with no leak. Pemax measurements performed with Ringqvist's leak in place were 11 percent (p less than 0.005) lower than those with Clausen's leak and 11 percent (p less than 0.005) lower than those obtained with no leak. The comparison between Clausen's leak and no leak showed no statistically significant difference. We conclude that whenever the effect of pressure generated in the mouth is to be avoided in the measurement of respiratory Pmax, a leak of the size proposed by Ringqvist is to be preferred.

The influence of positive expiratory pressure (PEP) applied during inhalation of a beta 2-agonist in treatment of bronchial asthma was investigated in a randomized crossover study with two-week treatment periods. In one period, two puffs (0.5 mg) of terbutaline was given from a metered dose inhaler and inhaled through a device consisting of a conespacer connected to a facemask giving PEP (10 to 15 cm H2O). In a second period, terbutaline 0.5 mg was inhaled similarly but without PEP, and in a third period placebo spray was inhaled with PEP. Treatments were given three times daily. Peak expiratory flow (PEF) was measured before and after each inhalation and symptom scores for dyspnea, cough, and mucus production were noted in a diary. All treatments increased PEF significantly (p less than 0.0001). The mean increase was 32 L/min during treatment with terbutaline and PEP. This was greater than the increase of 25 L/min during terbutaline treatment (p = 0.005). The increase in PEF during terbutaline treatment was significantly higher than the achieved 18 L/min during PEP (p = 0.026). The study showed improved bronchodilation when PEP was combined with inhalation of beta 2-agonist compared with beta 2-agonist alone.

Methacholine challenges were performed in ten subjects with mild asthma at 2 h before and 20 min after placebo or 5, 10, 20, 40, 80, and 160 mg of inhaled verapamil given in a single-blind randomized crossover manner on different days. While verapamil did not have a bronchodilator effect, the 10-mg dose modestly increased the concentration of methacholine required to decrease FEV1 by 20 percent (PC20). The mean (+/- SEM) increase in PC20 from baseline was 2.1 +/- 0.2 times baseline after 10 mg of verapamil, compared to 1.1 +/- 0.1 times baseline after placebo (p less than 0.001). Unexpectedly, bronchoconstriction (greater than 10 percent decrease in FEV1) associated with cough or wheezing was observed in seven of ten subjects at doses of 20 mg or more. This adverse effect was not related to the osmolarity of the nebulized solutions. Thirty minutes before a standardized exercise challenge, 13 subjects inhaled placebo, 10 mg, or the highest dose of verapamil tolerated during the methacholine study (20 to 160 mg) in a double-blind randomized crossover manner. The exercise challenge was aborted in three subjects because of bronchospasm that occurred after administration of the higher dose. The mean (+/- SEM) maximum change in FEV1 after exercise in the ten subjects completing all three regimens of treatment was -17.1 +/- 4.0 percent after placebo, -12.7 +/- 4.3 percent after 10 mg (p less than 0.05), and -6.4 +/- 3.6 percent after the highest dose (p less than 0.05). We conclude that increasing the dose of verapamil above 10 mg did not provide greater benefit but, paradoxically, induced bronchoconstriction in most of the subjects. Because of this potential bronchoconstrictor effect, high doses of oral or intravenous verapamil should be used with caution in asthmatic subjects.

Adequate humidification of inspired gases with HMEs during long-term MV remains controversial. In this study, a comparison is made between tracheal secretions during long-term MV either with HME or conventional HH. Both the HME and HH groups were similar with respect to age, sex, diagnosis, duration of MV, SAPS and mortality. Temperature of gases in the tracheal tube was lower and the amount of tracheal instillations was greater in the HME group than in the HH group. Tracheal secretions became thicker between day 1 (control) and day 5, in the HME group than in the HH group. Four and two tube occlusions occurred in HME and HH groups, respectively. Tracheal bacterial colonization was similar in the two groups. Given the advantages of HME (reduced nurses' work and financial cost), HME could be routinely used under cautious surveillance and replaced by HH if difficulty in suctioning occurs.

We have shown that in patients with COPD, myocardial efficiency during exercise is enhanced following acute elevations of plasma phosphate (Pi). A decrease in Hb-O2 affinity (increase in P50) was not responsible for the improvement. We postulated that the physiologic benefit was due to the acute reversal of a subclinical myocardial Pi depletion. To further test this hypothesis in a chronic state, we studied nine stable hypoxemic (PaO2 = 64 +/- 2 mm Hg [+/- SEM]) patients with COPD over five weeks: two weeks at normal plasma Pi; and three weeks at elevated plasma Pi, induced by etidronate disodium (Didronel; 750 mg orally daily). Administration of etidronate disodium increased (p less than 0.05) plasma level of Pi (4.4 +/- 0.2 to 5.8 +/- 0.1 mg/dl), RBC level of Pi (3.1 +/- 0.2 to 4.1 +/- 0.2 mg/dl), RBC level of 2,3-DPG (16.2 +/- 1.1 to 21.3 g+/- 1.3 mumol/g of Hb) and P50 (23.7 +/- 0.5 to 26.0 +/- 0.8 mm Hg). At the end of the treatment, the widening of the C(a-v)O2 with exercise (7.1 +/- 0.8 to 8.9 +/- 0.6 ml/dl) was less pronounced than under control conditions (6.9 +/- 0.4 to 10.1 +/- 0.6 ml/dl; p less than 0.02); concomitantly, the crossover point (COP; the PaO2 below which a rightward-shifted Hb-O2 curve causes the C(a-v)O2 to become narrower rather than wider) increased (37 +/- 2 to 49 +/- 1 mm Hg). Indicators of myocardial work efficiency were not affected by etidronate disodium at rest or during exercise. We postulate that during exercise the potential beneficial effect of the rightward shift of the Hb-O2 curve upon cardiac function was negated by the fall of PaO2 to or below the COP level, a situation which would limit increases in tissue O2 extraction.

To examine the differential effect of drugs used for stress ulcer prophylaxis on nosocomial pneumonia in critically ill patients.

To determine whether caffeine consumption affects bronchoprovocation challenge (BPC).

In a randomized, double-blind, crossover cumulative study, the individual maximal bronchodilator dosages for formoterol (F) and salbutamol (S) were assessed for their respective influence on ECG, pulse rate, and serum potassium levels in 13 patients with stable and reversible asthma. The following dosages were administered with an interval of 1 h: 12-24-48-(48)-(48) micrograms for F and 100-200-400-400-(400)-(400) micrograms for S. The study day was discontinued if pulse rate was above 140 beats min-1, a flattening of T wave on the ECG was recorded, or a maximal bronchodilation in FEV1 was observed (above 110 percent of the predicted value or an increase in FEV1 in the last two measurements below 5 percent). The maximal individual dose of F administered was 84 micrograms in six patients, 132 micrograms in three patients, 180 micrograms in three patients, and 228 micrograms in one patient. For S, the maximal individual dose was 400 micrograms in three patients, 2,200 micrograms in eight patients, 3,000 micrograms in one patient, and 3,800 micrograms in one patient. The mean maximal increase in FEV1 was 36.0 percent after F and 35.1 percent after S. Pulse rate increased from 73 to S3 beats.min-1 after F and from 75 to 84 beats.min-1 after S (both statistically significant). No pulse rate above 140 beats.min-1 was observed. In the high-therapeutic range (up to 36 micrograms of F and 6,090 micrograms of S), no changes in potassium level were observed. In still higher dosages, mean potassium level decreased from 4.16 to 3.78 mmol.L-1 after F and from 4.02 to 3.88 mmol.L-1 after S (not clinically relevant). The lowest individual potassium level recorded was 3.1 mmol.L-1. No clinically important changes in ECG were observed. In conclusion, very high doses of F and S administered from a metered dose inhaler proved to be safe for patients.

Patients with artificial airways frequently need aerosol or humidity therapy. For this study, we used aerosols generated from a heated Puritan all-purpose nebulizer and humidity generated from a heated Bennett cascade humidifier to determine the effects of these therapies in spontaneously breathing neurosurgical patients with nasal endotracheal tubes and normal lungs. Crossover comparison of oxygenation status before and after aerosol or humidity therapy was done by analyzing P(A-a)O2 in these patients. We found that aerosols have a detrimental effect on the patient's oxygenation status, suggesting that humidity is preferable in maintaining adequate oxygenation in a patient with a normal lung plus artificial airway. The arterial pH and PaCO2 were not affected by aerosol therapy. Care should be exercised with regard to the adverse hypoxemic effect of bland aerosols when a large-reservoir jet nebulizer is used in an intubated patient who already has impaired cardiopulmonary function or borderline PaO2.

Patients presenting to a chest clinic because of adult-onset wheezing with no history of allergy had a 90 percent prevalence of gastroesophageal reflux, even though reflux symptoms were mild or absent. Ninety patients were randomly assigned to receive cimetidine or an identical placebo or to undergo antireflux surgery. During a six-month period, all groups improved clinically; the cimetidine and surgical groups improved more than the placebo group. The intake of pulmonary medication decreased significantly in both cimetidine and surgical groups. Pulmonary function test results improved in the cimetidine- and surgically treated patients; improvement was not statistically significant. At long-term follow-up, the surgical group maintained clinical improvement and decreased pulmonary medication intake, whereas the placebo group worsened. We conclude that gastroesophageal reflux can play a significant role in some patients with nonallergic pulmonary disease and that its treatment can improve pulmonary symptoms and objective measurements of pulmonary function.