The results of previous studies comparing bronchodilatation from beta agonists administered by metered-dose inhaler (MDI) and nebulizer solution have been conflicting. We therefore evaluated a range of albuterol doses administered by these two methods, using histamine bronchoprovocation as a bioassay for the amount of drug reaching the beta 2 receptors in the lung. Twelve stable asthmatic volunteers received, in a double-blind, randomized, crossover design on different days, placebo or one, two, four, or six puffs from an MDI attached to an InspirEase device (90 micrograms per puff) or 0.625, 1.25, 2.5, or 5.0 mg of solution delivered in 2 ml of buffered saline through a Hudson Updraft II nebulizer. The histamine concentration required to decrease FEV1 by 20 percent (PC20) was measured 1 h before and 30 min after administration of each treatment and expressed as the increase in PC20 from baseline. The dose-response curves for change in PC20 indicated that the higher doses of the nebulizer solution delivered more drug to beta 2 receptors in the lung than the lower doses from the MDI. For example, the geometric mean increase in PC20 was 1.1 +/- 1.6 (SD) after placebo, 7.5 +/- 2.7 after two puffs from the MDI, and 20.0 +/- 2.1 after 2.5 mg of nebulizer solution (p less than 0.05). Using this bioassay method and administration technique, we estimated that ten puffs from the MDI (0.9 mg) would deliver approximately the same amount of albuterol to lung receptors as 2.5 mg of the nebulizer solution. Taking into account previously published reports and the results of the present study, we conclude that differences in dose, administration technique, nebulizer system efficiency, and severity of airway obstruction can alter the amount of drug reaching the beta 2 receptors in the lungs and, thus, the clinical response.

To contrast the effect of increasing blood calcium concentrations on the cardiovascular actions of intravenous beta-adrenergic agonists and phosphodiesterase inhibitors, 46 patients recovering from aortocoronary bypass surgery received either dobutamine or amrinone both in the presence and absence of a calcium infusion. Cardiac output, systemic arterial pressure, pulmonary arterial pressure, central venous pressure, pulmonary artery occlusion pressure, heart rate, and blood ionized calcium concentration were measured before and during infusions of dobutamine (2.5 and 5.0 micrograms/kg/min) and amrinone (0.75 mg/kg bolus + 10 micrograms/kg/min or 2.25 mg/kg bolus + 20 micrograms/kg/min). After the initial dobutamine infusion period, patients were randomly and blindly assigned to receive either a calcium or placebo infusion, and the dobutamine infusions were repeated. Because of the long duration of amrinone's actions, the amrinone maintenance infusion was continued while randomized, blinded infusion of either calcium or placebo was added. Dobutamine (5 micrograms/kg/min) increased cardiac output from 7.1 +/- 0.3 L/min to 9.1 +/- 0.4 L/min, and increased heart rate from 93 +/- 4 beats/min to 107 +/- 4 beats/min. Systemic vascular resistance decreased and stroke volume increased. Dobutamine had no significant effects on other hemodynamic values. Amrinone (2.25 mg/kg bolus + 20 micrograms/kg/min) increased cardiac output from 5.6 +/- 0.4 L/min to 6.9 +/- 0.5 L/min, and increased heart rate from 87 +/- 3 beats/min to 98 +/- 3 beats/min. Amrinone decreased mean arterial pressure, systemic vascular resistance, pulmonary artery occlusion pressure, central venous pressure, and pulmonary artery pressure. Calcium infusion increased arterial pressure (8 to 13 percent) but had no significant effects on any other hemodynamic parameters. Calcium reduced the increase in cardiac output produced by dobutamine by 30 percent, but it did not alter the cardiotonic actions of amrinone. Thus, calcium inhibits the cardiotonic actions of certain beta-adrenergic agonists, most likely by interfering with signal transduction through the beta-adrenergic receptor complex.

In this study, 322 patients were evaluated with two aims: determination of identifiable factors at the time of admission to an ICU that predict short-term survival. Application of the SAPS to this population. Characteristics of patients were as follows: age, 65.5 +/- 14.5 years; COLD, 45 percent; restrictive, 13.4 percent; obstructive and restrictive CRI, 13 percent; asthma progressing to CRI, 11.2 percent; diffuse bronchiectasis, 7.2 percent; neuromuscular diseases, 2.2 percent; others, 8 percent. Cachectic patients, those confined to home, those with initial coma or those who required MV had a higher percentage of M. The SAPS at admission was higher in those patients who died; however, there was no link between the SAPS and M. Prognostic factors in ARF complicating CRI and identifiable at the time of admission to an ICU are few and reflect severity of chronic respiratory disease; SAPS appears to be less useful in ARF complicating CRI.

To investigate the efficacy of bronchodilators in patients with irreversible chronic obstructive pulmonary disease (COPD), we conducted a double-blind, randomized, four-phase, crossover comparison between placebo, oral theophylline, inhaled salbutamol, and a combination of both drugs in 12 patients with stable COPD (mean age, 63 years) whose increase in forced expiratory volume in 1 s (FEV1) was less than or equal to 15 percent following 200 micrograms of inhaled salbutamol. Patients received two weeks of therapy with each of the test regimens. Both theophylline and salbutamol resulted in statistically significant improvement in FEV1, forced vital capacity (FVC), slow vital capacity (SVC), residual volume (RV), airway resistance (Raw), and maximum expiratory flow rate at 50 percent of vital capacity (V50). In most instances, there were no significant differences between theophylline and salbutamol. Combination therapy produced significantly greater improvement in FEV1, FVC, V50, Raw, and RV than either agent alone. The two drugs interacted in an additive fashion. Neither of the drugs, used singly, significantly reduced the severity or incidence of symptoms. The reduction in dyspnea and wheeze during combination therapy approached statistical significance (p = 0.06) and patient preference was significantly in favor of the combination regimen. None of the active treatments produced significantly more side effects than placebo. We conclude that theophylline and inhaled salbutamol produce significant, and approximately equal, improvement in pulmonary function in patients traditionally classified as suffering from "irreversible" COPD. The combination of theophylline and inhaled salbutamol generally results in additional improvement over that obtained with either drug used alone and this improvement is reflected by reduced symptomatology and treatment preference.

Investigators have validated an abbreviated protocol for testing nonspecific bronchial reactivity with methacholine. We performed a similar validation study with histamine, another bronchoprovocative agent known to induce airflow obstruction. Histamine is pharmacologically distinct from methacholine and, under some circumstances, may provide specific clinical and investigative advantages to methacholine. Twenty-four patients with a clinical history of asthma underwent bronchoprovocative testing using the standard histamine airway protocol recommended by the American Academy of Allergy, Committee on Standardization of Bronchoprovocation. In addition, two abbreviated histamine challenge protocols were tested using the same administration and testing equipment. The abbreviated protocols involved fewer dilutions and dosages of histamine than the standard histamine protocol but covered the same range of cumulative doses. The two abbreviated protocols differed only in the intervals for determination of FEV1 between doses of histamine (30 s vs 3 min). The sequence of these three protocols was randomized for each study subject and each airway challenge was separated by one week. The two abbreviated protocols took significantly less time to administer than the standard protocol--18 min vs 30 min vs 44 min. Both the provocative dose to cause a 20 percent decline in the FEV1 (PD20 FEV1) and the slope of the dose-response curve were not significantly different between the standard protocol and either of the two abbreviated protocols. Moreover, a high degree of agreement was observed between the two abbreviated protocols and the standard histamine protocol for both the PD20 FEV1 and the slope of the dose-response curve. These findings indicate that similar estimates of bronchial reactivity are obtained from either of the abbreviated protocols when compared with the standard histamine protocol.

The effects of three different regimens of inhaled bronchodilators on spirometry and respiratory impedance as measured with the technique of forced oscillations were compared in a double-blind crossover study in 22 patients with stable chronic obstructive pulmonary disease (FEV1 less than 70 percent predicted). On three trial days, patients inhaled, in random order, 40 micrograms ipratropium bromide, 200 micrograms fenoterol hydrobromide, or a combination of 40 micrograms ipratropium and 100 micrograms fenoterol from a powder inhaler, followed by a second dose of the same drug after 60 min. The effects were measured at baseline and 20, 40, 60, and 120 min after the first inhalation. No significant decrease in total respiratory resistance at 8 Hz (Rrs [8]) was observed after ipratropium, whereas Rrs (8) decreased significantly 20 min after fenoterol and 40 min after the combination regimen (p less than 0.05). All three studied drugs resulted in a significant increase in the reactance (p less than 0.01) and decrease in resonant frequency. Both fenoterol (delta FEV1 34 percent, p less than 0.0001) and the combination regimen (delta FEV1 38 percent, p less than 0.0001) resulted in a significantly larger increase in FEV1 than ipratropium alone (delta FEV1 17 percent, p less than 0.0001). A second dose of fenoterol and of the combination regimen resulted in a further significant increase in FEV1 after 120 min (p less than 0.05). A second dose of ipratropium did not result in a further significant increase in FEV1. The changes in respiratory impedance were qualitatively similar for all three drug regimens, but larger in absolute terms after fenoterol and the combination regimen than after ipratropium. The similar effect of these drugs on the reactance can be explained by an increase in the capacitance of the respiratory system, and in combination with a decrease in frequency dependence of resistance, by assuming a decrease in peripheral airway resistance.

The effect of broxaterol, a new beta 2-agonist, on respiratory muscle endurance and strength was studied in a double-blind, placebo-controlled, randomized crossover clinical trial in 16 patients with chronic obstructive pulmonary disease (COPD) with irreversible airway obstruction (FEV1 = 57.1 percent of predicted). One patient withdrew from the study because of acute respiratory exacerbation. Inspiratory muscle strength was assessed by maximal inspiratory pressure (MIP) and endurance time was determined as the length of time a subject could breathe against inspiratory resistance (target mouth pressure = 70 percent of MIP, Ti/Ttot = 0.4). Broxaterol (B) or placebo (P) was given orally for seven days at the dose of 0.5 mg three times a day with a washout period of 72 h between study treatments. Measurements were performed before administration of B or P and 2 h (six patients) or 8 h (nine patients) after the end of each treatment. No significant changes in FEV1 or FRC were observed after B or P suggesting that diaphragmatic length was maintained constant with each treatment. The MIP did not significantly change, while endurance time increased after B in the patients tested at 2 h (from 234.8 +/- 48.1 s to 284.0 +/- 48.0 s, p less than 0.05) and at 8 h (from 187.2 +/- 31.1 s to 258.2 +/- 40.4 s, p less than 0.005). No changes were observed after P. Minute ventilation, airway occlusion pressure (P0.1), integrated electromyographic activities of the diaphragm (Edi), and intercostal parasternals (Eic) (normalized to the value obtained during MIP) showed no change during the endurance run with different treatments. We conclude that in a group of COPD patients with irreversible airway obstruction, B significantly improves respiratory muscle endurance, and that this does not arise as a result of an effect on neuromuscular drive or pulmonary mechanics, but may be mediated by peripheral factors.

Clarithromycin, a new macrolide antibiotic, is at least four times more active in vitro than erythromycin against Legionella pneumophila. In this study the safety and efficacy of orally administered clarithromycin (500 to 1,000 mg bid) in the treatment of Legionella pneumonia were evaluated. Forty-six patients were enrolled in the study, 15 of whom had not responded to previous routine anti-Legionella therapy (erythromycin, ofloxacin, rifampin [rifampicin], or tetracycline). Twelve patients prematurely discontinued the study (nine by the patient's request while feeling well; one because of cancer diagnosis; and two because of adverse events). The response rates after treatment were as follows: clinical cure rate, 98 percent (43/44); clinical success (cure or improved), 100 percent (44/44); radiographic success (cure and improved), 93 percent (28/30); direct antigen fluorescence resolution, 100 percent (40/40); and bacteriologic cure, 100 percent (13/13). Ten patients reported 13 adverse events (seven mild, four moderate, and two severe). Clarithromycin is a safe effective treatment for patients with severe chest infections due to Legionella pneumophila.

Because T-piece breathing may impair oxygenation, the best airway pressure from which to extubate ventilated patients is controversial. We compared the effects of extubation after 1 h of either CPAP 5 and T-piece/ZEEP. Once weaned from mechanical ventilation and breathing spontaneously, 106 patients were randomized to 1 h CPAP or 1 h T-piece/ZEEP, following which patients were extubated and mask O2 administered. No significant difference existed between groups in age, sex, HR, BP, FIO2, PaCO2 or PaO2. However, P(A-a)O2 was significantly greater at 120 min in the CPAP group. Within the CPAP group, P(A-a)O2 was also significantly worse at 120 vs 0 min. Nineteen T-piece patients showed improved P(A-a)O2 at 120 min compared with only ten CPAP patients. Three CPAP and two T-piece patients subsequently required reintubation. This study demonstrates that use of a T-piece dose not impair arterial oxygenation and may in fact be superior to direct extubation from CPAP 5.

We compared the effectiveness of albuterol with isoproterenol as a bronchodilator for use in pulmonary function testing. A total of 180 patients presenting for routine pulmonary function testing were randomly assigned to receive 5 mg of either albuterol or isoproterenol by compressed air nebulizer. Forced expiratory maneuvers were performed before, 5 min after, and 10 min after bronchodilator administration. The average increase in FEV1 and FVC did not differ between drugs. Also, the fraction of patients achieving a clinically significant bronchodilator response did not differ between drugs. Importantly, there was no significant difference between average 5 and 10 min postbronchodilator values for FEV1 or FVC for either bronchodilator, suggesting that a peak response was reached by 5 min. These results show no advantage of isoproterenol over albuterol in terms of potency or speed of action. Given the well-known cardiovascular side effects of isoproterenol, albuterol is the preferable agent for use in pulmonary function testing.

To determine the effects of intermittent hypoxemia on daytime sleepiness in the clinical setting of obstructive sleep apnea syndrome, we enrolled seven patients in a prospective, randomized, crossover study. We had two experimental conditions with NCPAP treatment as follow: (1) to correct apneas, sleep fragmentation, and hypoxemia; and (2) to correct apneas and sleep fragmentation and at the same time, induce intermittent hypoxemia. The outcome variable, daytime sleepiness, was measured objectively with the multiple sleep latency test following completion of baseline and each treatment condition. Compared with sleep latencies in the untreated condition, both experimental treatment arms prolonged sleep latencies (p less than 0.05). We found no statistically significant differences between mean MSLT scores obtained after NCPAP treatment under hypoxemic and nonhypoxemic conditions. In summary, two nights of intermittent nocturnal hypoxemia during NCPAP treatment for OSAS did not diminish the objective improvement in daytime somnolence seen with NCPAP treatment in the absence of nocturnal hypoxemia. Results lend further support to the hypothesis relating excessive daytime sleepiness to sleep fragmentation.

Between December 1985 and August 1988, there were 115 patients at 13 centers who were entered on a randomized comparison of tetracycline and bleomycin for treatment of malignant pleural effusions. Fifteen patients were not treated, primarily due to rapid progression of systemic cancer. Fifteen patients entered on a high-dose regimen of bleomycin (120 units) were excluded from this analysis (following early closure of that arm), leaving 85 patients randomized to low-dose bleomycin (60 units; 44 patients) or tetracycline (1 g; 41 patients). Patients were required to have a cytologically positive pleural effusion, good performance status (0, 1, or 2), lung reexpansion following tube thoracostomy with drainage rates of 100 ml/24 or less, no prior intrapleural therapy, no prior systemic bleomycin therapy, no chest irradiation, and no recent (four weeks) change in systemic therapy. A total of 11 patients (five with bleomycin and six with tetracycline) were not evaluable due to technical problems with tube drainage (one), loss to follow-up (two), sudden death due to pulmonary embolus (one), and rapid progression of systemic disease (seven). There were no clinically significant differences in demographic factors, primary site, performance status, or presence of metastases other than pleural effusion. Overall survival did not differ between the two groups. Median time to recurrence or progression of the effusion was 32 days for tetracycline-treated patients and at least 46 days for bleomycin-treated patients (p = 0.037). The recurrence rate within 30 days of instillation was 36 percent (10/28) with bleomycin and 67 percent (18/27) with tetracycline (p = 0.023) (not all patients were restudied in the first 30 days). By 90 days the corresponding recurrence rates were 30 percent (11/37) for bleomycin and 53 percent (19/36) for tetracycline (p = 0.047). Toxicity was similar between groups.

The efficacy and safety of oral temafloxacin (600 mg) and ciprofloxacin (500 mg) twice daily for seven days were compared in patients with mild to moderate lower respiratory tract infections. Fifty-eight of 64 (91 percent) patients who received temafloxacin and 63 of 67 (94 percent) patients who received ciprofloxacin had clinical cure or improvement; bacteriologic cure occurred in 61 (95 percent) and 63 (94 percent), respectively. All 14 patients with pneumonia were clinically cured or improved and bacteriologically cured; 11 had complete resolution of roentgenographic evidence of pneumonia. Both quinolones eradicated most major respiratory pathogens. In the ciprofloxacin group, organisms persisted in three of seven Pseudomonas aeruginosa isolates and in one of eight Hemophilus parainfluenzae isolates; all these pathogens were eliminated with temafloxacin. Theophylline blood levels significantly increased by 25 percent in the ciprofloxacin group and decreased by 5 percent in the temafloxacin group. Adverse events, mostly dizziness, headache, and gastrointestinal effects, occurred in 43 percent of temafloxacin patients and in 31 percent of ciprofloxacin patients.

We studied the effects of two chest physiotherapy regimens on whole lung and regional tracheobronchial clearance (TBC) in ten patients with cystic fibrosis. The regimens were given on two separate days and consisted of 20 min of (1) postural drainage and the forced expiration technique (PD + FET), and (2) positive expiratory pressure (PEP-mask) and FET (PEP + FET). A third day served as control. The study days were randomized. Each day, the clearance of lung radioactivity was measured for 3 h by gamma camera. The number of spontaneous coughs was recorded and the sputum expectorated was sampled. We found that both PD + FET and PEP + FET improved whole lung TBC at 30 minutes and 1 h four or fivefold (p less than 0.01) compared with control, whereas at 2 h and 3 h only the improvement following PEP + FET (approximately 1.4 times) was significant (p less than 0.05). There was no significant difference in whole lung or regional TBC between the PD + FET and PEP + FET treatments. The correlations between TBC and the radioactivity content in sputum expectorated (rs2 = 0.76) and between TBC and numbers of coughs (rs2 = 0.65) were better than between TBC and the weight of sputum expectorated (Rs = 0.39). We conclude that PD or PEP when combined with FET have similar effects on short-term whole lung and regional TBC in patients with cystic fibrosis. Evaluation of TBC during chest physiotherapy when only based on the weight of sputum expectorated seems inadequate.

This study compared the effect of "standard" dose metaproterenol delivered by hand-held nebulizer (HHN) with two puffs of metaproterenol delivered by a metered dose inhaler (MDI) via a spacer (InspirEase) (MDI-spacer). Seventeen patients with an acute exacerbation of obstructive pulmonary disease were studied. Each patient received both MDI-spacer and HHN. Alternate patients were randomized to either MDI-spacer or HHN as initial treatment. Each subject was tested four different times: before and 30 minutes after the initial aerosol delivery technique, and before and 30 minutes after the alternate aerosol delivery technique. Testing consisted of spirometry, lung auscultation, and measurement of vital signs. The interval between treatments for all subjects was 2.96 +/- 0.27 hours (mean +/- SEM) and was not different for subjects who received therapy via MDI-spacer first or HHN first. The patient population studied demonstrated severe airways obstruction (baseline FEV1 33.3 percent predicted +/- 4.9 percent). There was a statistically significant improvement in FVC and FEV1 after metaproterenol delivered by HHN, but not after MDI-spacer. Metaproterenol treatment with HHN resulted in a greater improvement in FEV1 (p less than .05) than MDI-spacer when the data were reported as absolute improvement (0.19 +/- 0.05 L for HHN) vs (0.06 +/- 0.03 L for MDI-spacer) or reported as percent change (23.2 +/- 6.6 percent for HHN) vs (9.5 +/- 3.4 percent for MDI-spacer). Asthmatic patients exhibited a significantly greater (p less than 0.05) improvement in FEV1 after HHN (23.4 +/- 4.7 percent change) than after MDI-spacer (6.6 +/- 4.5 percent change). Patients with chronic obstructive pulmonary disease (COPD) exhibited a greater improvement in FVC (p less than 0.05) after HHN (25.2 +/- 6.7 percent change) than after MDI-spacer (5.8 +/- 4.7 percent change). We conclude that the "standard" dosage of metaproterenol delivered by HHN results in greater spirometric improvement in patients with acute obstructive pulmonary disease than the conventional dosage of metaproterenol delivered by MDI-spacer. It is likely that this reflects the fact that the recommended dose of metaproterenol delivered by MDI is too low and should be increased.

To evaluate renal and vasodilator effects of synthetic atrial natriuretic factor (ANF) in patients undergoing cardiopulmonary bypass (CPB) with special reference to the applicability of ANF as a diuretic and natriuretic.

Recertification for long-term oxygen therapy (LTOT) has been recommended for patients who are clinically unstable when home oxygen therapy is begun. Periods of observation for clinical stability have ranged from three weeks to three months in large multicenter clinical trials. There is concern, however, that an increase in arterial oxygen tension occurring after three months may be related to the beneficial effects of oxygen rather than to continued changes in clinical stability. In a review of 20 patients receiving transtracheal oxygen (TTO2) therapy, it was found that four (20 percent) did not qualify for oxygen therapy at the end of six months because the PaO2 breathing ambient air had increased to levels above 55 mm Hg. All patients were clinically stable at the time of insertion of the transtracheal catheter and all had been receiving nasal oxygen for at least seven months (mean, 25.8 months) before entering the study. A retrospective analysis of data published by Weitzenblum et al disclosed that four (25 percent) of 16 patients had a similar increase in PaO2 when reexamined after one year of oxygen therapy. All of the patients had been studied at least one year before oxygen therapy was initiated and each had three consecutive arterial blood gas measurements done monthly to ensure clinical stability. The increase in PaO2 to levels above 55 mm Hg observed in patients receiving TTO2 therapy was associated with a reduction in alveolar-arterial oxygen gradient; however, arterial oxygen desaturation with walking persisted. The specific mechanisms for improvement in PaO2 during oxygen therapy require further study. Any recommendation for recertification of LTOT must recognize that an increase in PaO2 after three months may be due to the beneficial effects of the oxygen therapy and does not provide prima facie justification for termination of therapy.

We have investigated the protective effect of oral terfenadine, a H1 antagonist, on the dermal and pulmonary response, and changes of circulating WBCs to injected and inhaled platelet activating factor. Nine men with mild asthma participated in a double-blind, crossover study using terfenadine, 120 mg, or placebo. Three hours after administration of study drug, pulmonary function was measured, and a PAF challenge was performed. Skin test to histamine and PAF was performed prior to study drug, and 2.5 hours after drug. Circulating WBC count was determined prior to PAF inhalation and during the PAF challenge. There was a significant improvement in pulmonary function on terfenadine. Terfenadine significantly inhibited the wheal and flare response to histamine and the flare response to injected PAF. Terfenadine did not have an effect on the change in circulating WBC count or the change in pulmonary function to inhaled PAF. These results suggest a limited role for endogenous histamine for the effects of PAF.

This study was designed to assess the risk of colonization and biofilm formation of central venous catheters left in situ for seven days vs those changed over a guidewire at three days and removed at seven days. Colonization was determined using scanning and transmission electron microscopy and compared to a special scraping/sonication culture method. Thirty-one catheters were examined, and no difference was found between catheters left in situ (9 of 16 colonized) and those changed over a guidewire (11 of 15 colonized). Colonization rates rose significantly from 4 of 15 catheters at the time of guidewire change to 11 of 15 at 7 days (p less than 0.001). Of the catheters defined as colonized by SEM, the special culture technique showed bacterial growth in only 35 percent, making a negative culture result of dubious value in ruling out catheter colonization. No beneficial effect of guidewire changes in reducing colonization could be demonstrated.

To evaluate the importance of fluid balance and changes in extravascular lung water (EVLW) on survival in the ICU and short-term outcome in patients with pulmonary edema.