We have studied the antitussive effects of two anticholinergic agents, oxitropium bromide (200 micrograms) and ipratropium bromide (80 micrograms), and a combined beta-agonist and anticholinergic preparation containing fenoterol hydrobromide (200 micrograms) and ipratropium bromide (80 micrograms), in 16 normal and ten asthmatic volunteers in a double-blind, randomized, placebo-controlled crossover trial. Cough was induced by inhalation of ultrasonically nebulized distilled water and hypotonic saline solution. All treatments significantly reduced the cough response to inhaled distilled water aerosol when compared with placebo (p less than 0.001). There was no difference between oxitropium bromide and ipratropium bromide (p greater than 0.05), but the combination preparation displayed a greater antitussive effect than either oxitropium bromide (p less than 0.05) or ipratropium bromide (p less than 0.025). Cough frequencies in response to hypotonic 0.18 and 0.32 percent saline aerosol were lower than those obtained with distilled water (p less than 0.005) for all treatments. Asthmatic patients coughed less frequently than normal volunteers in response to all solutions when placebo was given (p less than 0.05), but there is no evidence to suggest that the response to treatment was different in the two groups. Our results suggest that inhaled anticholinergic bronchodilators alone or in combination with beta 2-adrenergic agonists might be effective in the treatment of pathologic cough.

Twenty seven healthy individuals were divided randomly into three groups. The first group of nine subjects received only a routine bronchoscopic examination. The second group of nine subjects was examined with the bronchoscope followed by bronchoalveolar lavage (BAL) with 200 ml of 25 degrees C normal saline solution. The third group of nine subjects received a bronchoscopic examination followed by BAL, but with 200 ml of 37 degrees C normal saline solution. Examination in all groups included arterial blood gas (ABG) analysis and pulmonary function test (PFT), both pre- and post-procedure. In group 1 there was no statistical difference in the pulmonary function test result after routine bronchoscopic examination except for decrease in PaO2. The results in group 2 showed a statistical difference in both ABG and PFT data, especially PaO2, FEF 200-1200, FEF25%-75%, FEF25%, FEF50%, and FEF75%. In group 3, there was a significant decrease of PaO2 and no significant difference in PFT before and after BAL. From these data we conclude that BAL is a safe examination. However, the administration BAL fluid (BALF) with 25 degrees C normal saline solution can affect the results of the PFT significantly. Much of this adverse reaction can be minimized by using body temperature (37 degrees C) saline solution. At 37 degrees C, the ABG data showed a decrease in PaO2, but pulmonary function was not affected significantly.

A six-month double-blind controlled trial compared a 2,000 microgram per day dose of beclomethasone dipropionate aerosol (BDP), with current upper level doses of 800 micrograms per day of the standard BDP, in asthmatics requiring oral corticosteroids in addition to BDP and bronchodilators. Both groups showed a significant reduction in their oral steroid requirements during the study, with a 34 percent reduction in the lower dose group and a 57 percent reduction in the high dose BDP group while maintaining good symptomatic control of asthma; there was an associated improvement in baseline serum cortisol levels. Over the same period, the pulmonary function of the lower dose group showed significant worsening relative to that of the group receiving the high dose BDP which improved. There was no increase in dysphonia or oropharyngeal candidiasis among those using the concentrated BDP. We conclude that high dose concentrated BDP appears to be a safe medication in long-term steroid-dependent asthma, and is effective in reducing dependence on the use of oral corticosteroid with associated improvement both in pulmonary and adrenal function.

We studied the effects of oral nutritional supplementation on respiratory muscle (RM) performance in 25 ambulatory patients with severe chronic obstructive pulmonary disease (COPD). There was a relationship between body weight and anthropometric parameters of nutritional status (triceps skinfold thickness [r = 0.67; p less than 0.005], midarm muscle circumference (r = 0.53; p less than 0.005), but body weight did not correlate with daily caloric intake, serum albumin, transferrin, or blood lymphocyte count. None of these measurements of nutritional status correlated with any measure of RM strength or endurance. In a randomized observer-blinded crossover trial, patients were allocated to one of two groups. In the first eight weeks of the study, group A received nutritional supplementation, and patients in group B were control subjects. In the second eight weeks, patients in group A were control subjects, and group B received supplement. Mean daily caloric intake and body weight increased in both groups while receiving supplement (both p less than 0.05). Calories provided by the supplement were frequently substituted for normal dietary calories. Any increases in RM performance in the group receiving supplement were matched by increases (due to learning) in controls. We conclude that oral dietary supplements have no important effects on RM performance in ambulatory patients with COPD.

We evaluated the safety and efficacy of transdermal clonidine (TC) in 23 patients with essential hypertension over a two-year period. Fourteen patients achieved control of blood pressure using TC alone. Six patients achieved control with a combination of TC and the diuretic chlorthalidone (CH). Three patients had control with CH alone or did not achieve control with either TC alone or TC plus CH and were dropped from the study. Of the 20 patients remaining in the study, six patients remained on TC or TC plus CH for the two-year study. Ten of the 20 patients quit the study because of skin reactions and four because of other side effects. No clinically significant changes were noted in serum or urinary laboratory parameters. Finally, TC was effective as long-term monotherapy for essential hypertension in only four of our patients. The major limitation is skin-related side effects.

A cooperative, prospective, randomized study to evaluate the effectiveness of preoperative irradiation in curatively resected esophageal carcinoma was performed in 364 cases in eight institutions from August 1982 to November, 1983. Based on the survival curves, postoperative irradiation alone was superior to preoperative plus postoperative irradiation. Because of the progression of the disease and complications after operation, there were many inevaluable cases in this study. However, analysis revealed there was no bias caused by a greater number of unfavorable patients being selectively included in inevaluable cases in the postoperative irradiation only group. Our data question the value of preoperative irradiation being performed in addition to resection plus postoperative irradiation.

In the absence of clinical trials, positive end-expired pressure (PEEP) has been accepted as efficacious for treatment of postoperative decreases in arterial oxygen tension (PaO2) from a variety of causes including adult respiratory distress syndrome (ARDS). PEEP is thought to increase PaO2 by alveolar recruitment, which in turn, has been hypothesized to play a decisive role in pulmonary recovery. One hundred and eighteen patients were followed prospectively, and after development of decreased PaO2, randomized to receive recruitive PEEP (determined by blood gas criteria) or supportive PEEP (the minimal PEEP required to maintain PaO2 above 60 mm Hg on .5 inspired O2 fraction (FIO2). No prognostic factors were significantly different between the two groups. Recruitive PEEP application in 22 patients yielded a significantly increased incidence of hypotension (55 percent), pneumothorax (20 percent), and death during treatment (27 percent) when compared to the 28 supportive PEEP patients who had no hypotension or pneumothorax and only one death during treatment (4 percent). After PEEP treatment, deaths in each group were similar (19 percent and 15 percent, respectively). We find no evidence that PEEP treatment promotes beneficial outcomes and conclude that recruitment attempts may be harmful.

In ten young asthmatic subjects, we studied the effect of a single oral dose of 4.4 mg of azelastine hydrochloride on exercise-induced bronchoconstriction during the breathing of cold air. Exercise challenges were performed on two different days before and four hours after azelastine and placebo given in a randomized double-blind crossover fashion. Placebo had no effect on baseline pulmonary function and postexertional obstruction of the airways, in contrast to azelastine, which exerted a small but significant (p less than 0.05) bronchodilation and a significant attenuation (p less than 0.01) of exercise-induced bronchoconstriction as compared to data from before treatment and after placebo.

This study evaluated educational effectiveness of preclinical training of residents in diagnostic bronchoscopic techniques which used videotaped programs. Sixty-five residents in eleven medical centers were randomized. Experimental subjects viewed five videotaped programs dealing with bronchoscopic anatomy and pathology. Following their tenth clinical experience in bronchoscopic diagnosis, performance of both experimental and control subjects was objectively evaluated using a Visual Discrimination Test (VDT) that contained six videotaped sequences in suspected cancer patients. Clinical performance was subjectively evaluated by teachers who used a list of Minimum Competency Requirements (MCRs). Experimental subjects provided a significantly greater number of correct answers in the VDT and achieved higher scores for the MCRs that were specifically related to recognition of bronchoscopic anatomy and pathology. This study demonstrated that preclinical training using videotaped programs could improve visual perception and discrimination skills of residents in their bronchoscopic examination of patients with suspected cases of cancer.

A new bronchoscopic-protected catheter brush (BPCB), designed to obtain uncontaminated bronchial secretions, was studied in vitro and in vivo. The device was composed of a standard biopsy brush, protected by a single catheter and occluded with an agar plug. Ejection of the plug was obtained neither by advancing the brush nor by advancing an inner cannula (as in a telescoping catheter brush), but instead, by an air flux, provided by a syringe which was connected to the proximal tip. In the first part of the study the ability of the BPCB to obtain uncontaminated specimens was tested in comparison with the reference telescoping catheter brush (BFW brush 10/70/90, Medi-Tech Corp Watertown, MA). Catheters of each type were successively passed through the inner channel of a bronchofiberscope which was contaminated with Klebsiella pneumonia. After ejection of the distal plug, sampling of bronchial secretions infected with a marker organism (Pseudomonas aeruginosa), was performed with the brush. Culture of brush specimens of each type of catheter grew the marker organism in pure culture and obtained the same amount of bronchial secretions (0.001 ml). The manual vortexing of the brush in the transport medium (Ringer's solution) proved to be as effective as the mechanical vortexing so that transecting of the brush was no longer mandatory. In the second part of this study, paired bronchial samplings from 27 patients were performed using both types of catheters and similar results for both were obtained. In these in vitro studies, completed by a clinical trial, our single-sheathed, plugged catheter brush proved to be as reliable as the double telescoping catheter brush. However, because of its relatively simple conception, making it easier to use and lower in cost than the double catheter brush, routine use of this sampling device should be considered.

Many patients with chronic obstructive pulmonary disease (COPD) report greater limitation for activities involving the upper extremities than the lower extremities. Exercise training has generally emphasized lower-extremity exercise. We designed and evaluated two simple, practical, and widely applicable upper-extremity training programs in 45 patients with COPD participating concurrently in a comprehensive, multidisciplinary pulmonary rehabilitation program. Patients were randomly assigned to one of the following three groups: (1) gravity-resistance (GR) upper-extremity training; (2) modified proprioceptive neuromuscular facilitation (PNF) upper-extremity training; or (3) no upper-extremity training (control). Patients were evaluated before and after at least six weeks of uninterrupted training. Twenty-eight patients completed the study. Compared to controls, both GR and PNF patients demonstrated improved performance on tests specific to the training performed (upper-extremity performance test, maximal level and endurance on isokinetic arm cycle). There were no significant changes on isotonic arm cycle, ventilatory muscle endurance, or simulated activities of daily-living tests. Ratings of perceived breathlessness and fatigue decreased significantly in all groups for several tests. We conclude that specific upper-extremity training may be beneficial in the rehabilitation of patients with COPD and warrants further investigation.

A prospective randomized study was conducted in 200 patients undergoing coronary artery bypass surgery. All patients received intravenous (IV) cephalothin prophylaxis for 48 hours beginning with anesthetic induction. Group A (99 eligible patients) received cephalexin 500 mg po, qid for three extra days. Group B (94 eligible patients) received no oral therapy. The overall infection rate was 9.3 percent (18 patients). Six patients had multiple sites of involvement. There was no difference between group A (9.0 percent, nine patients) vs B (9.5 percent, nine patients) (p greater than 0.5). The median sternotomy infection rate, superficial or deep, was 2.6% (five patients). The surgical wound infection rate was 4.7 percent (nine patients). The overall infection rate compares favorably with that of high risk groups for clean surgical procedures defined in SENIC study. There was no advantage to prolonged oral cephalexin prophylaxis following coronary artery bypass (CAB) surgery.

A controlled double-blind crossover study of ocular complications associated with nebulized ipratropium bromide and salbutamol therapy for respiratory distress was undertaken in 46 chronic bronchitis patients. There was no significant rise in intraocular pressure or change in anterior chamber angle in patients with open-angle glaucoma, narrow-angle glaucoma or control subjects following treatment with either drug. However, when the two drugs were used in combination, intraocular pressure rose in patients with narrow-angle glaucoma but not in patients with open-angle glaucoma or in control subjects. Transient angle closure was seen in five of these patients. Intraocular pressures did not rise when swimming goggles were used to protect the eyes or when antiglaucoma treatment was continued. Nebulized bronchodilator therapy is safe in nonglaucomatous patients and those with open-angle glaucoma. Ocular complications can follow combined ipratropium bromide and salbutamol nebulization in patients with narrow-angle glaucoma, but can be prevented by using the drugs separately, protecting the eyes and ensuring continued antiglaucoma measures.

To assess the safety of combined intervention in acute myocardial infarction, a pilot study of thrombolysis and beta-adrenergic blockade was performed. Twenty-five subjects were randomized to therapy with intravenous (IV) metoprolol and IV streptokinase (group 1) or to IV metoprolol (group 2) alone. Two-dimensional echocardiography was performed before intervention and five days later. The mean time from onset of symptoms to intervention was 1.92 hours. No major adverse reactions related to the intervention were observed in either group. Significant improvement from baseline was observed with combined therapy on both the biplane mean ejection fraction (p less than .02) and a calculated wall motion index of regional wall motion abnormalities (p less than .002). The presumed reperfusion rate was significantly higher in group 1 (p less than .03). Intravenous metoprolol and IV streptokinase in combination was found to be safe in the acute phase of acute myocardial infarction when administered to appropriate patients without contra-indications and deserves further study.

Esmolol, an intravenous, ultrashort-acting beta-blocker, was studied for its ability to safely control supraventricular arrhythmias up to 24 hours in 15 postoperative cardiothoracic surgery patients with atrial fibrillation or flutter and rapid ventricular response. Esmolol obtained an initial therapeutic response in nine (60 percent) patients. Mean heart rate for the 15 patients was reduced from 139 +/- 12 beats/min before therapy to 106 +/- 21 beats/min during esmolol infusion (p less than 0.01). The mean time to a therapeutic response after initiation of therapy, using a multistep titration regimen (500 micrograms/kg/min loading infusions over one minute, prior to incremental titration steps from 50 to 300 micrograms/kg/min over 4 to 14 minutes), was 22 +/- 9 minutes, and therapy was continued for 17 +/- 9 hours in responders. Esmolol significantly lowered blood pressure in the group studied and resulted in mild supine or orthostatic hypotension in ten (67 percent) patients. Side effects, including hypotension (10/15 patients), gastrointestinal disturbances (2/15), and weakness or somnolence (6/15), were transient and were not associated with serious clinical sequelae. We conclude that esmolol is effective for rate control in a majority of postoperative cardiothoracic surgery patients with atrial fibrillation or flutter. Side effects, although mild, occur relatively frequently, limiting prolonged infusions and warranting close surveillance of patients.

Traditionally, patients with acute airflow obstruction are treated with bronchodilator aerosols delivered by continuous flow nebulizers. While bronchodilator administration with the metered dose inhaler (MDI) and reservoir or spacer attachment is as effective as administration with the nebulizer in most settings, the former has not been widely accepted for treatment of acute airway obstruction in the emergency room. We compared the efficacy of the continuous flow nebulizer to that of the MDI with InspirEase (reservoir spacer) in 75 patients (45 men and 30 women), ages 18-73 (chi 44 years) who presented to the emergency room with acute asthma and COPD. Subjects in each group (22 COPD and 53 asthma) were randomly assigned to treatment with three puffs of metaproterenol (0.65 mg/puff) via the MDI with InspirEase plus nebulizer with placebo, or placebo MDI with InspirEase plus nebulizer with 15 mg metaproterenol in double blind fashion. Either treatment was given three times at 30 min intervals. The FEV1 and dyspnea scores according to the Borg scale were measured at baseline, 30 min after the first treatment, and 30 min after the third. There was no significant outcome difference between the two treatments in either diagnostic group. There also was no significant outcome difference for patients with baseline FEV1 less than 0.9L. Serum theophylline levels, the need for concomitant therapy with corticosteroids, or additional emergency room therapy after the study, hospitalizations and treatment side effects did not differ between treatment groups. We conclude that there is no demonstrable advantage of a continuous flow nebulizer over an MDI with InspirEase for the treatment of acute airflow obstruction.

To establish a dose-response curve for the effects of isocapnic hypoxemia on cardiac output (CO), we studied 20 healthy men, aged 20 to 34 years, using a tight-fitting face mask and an isocapnic partial rebreathing system (a modified anesthesia machine). We blended oxygen and hypoxic gas to achieve arterial oxygen saturations (SaO2) of 80, 85, and 90 percent; subjects also breathed 100 percent oxygen and room air (RA). Target SaO2 and end-tidal carbon dioxide were continuously monitored using an ear oximeter and CO2 gas analyzer. Subjects experienced the five SaO2 measurements in random order. CO was measured noninvasively at approximately two-minute intervals, using continuous-wave Doppler echocardiography. Mean cardiac output increased with increasing hypoxemia from 6.84 L/min at FIo2 1.0 to 8.44 L/min at SaO2 80 percent (p less than 0.0005); the increase was entirely due to increased heart rate. We concluded that cardiac output increases significantly in a dose-response manner in response to acute isocapnic hypoxemia in normal persons.

We compared the bronchodilating effects of intravenously administered enprofylline (2 mg/kg) with nebulized terbutaline (10 mg) in patients presenting to hospital with acute asthma in a multicenter double-blind parallel study. One hundred twenty three patients were randomized into the study, and 69 of these fulfilled the inclusion criteria and a retrospective time to study entry criterion; 34 received enprofylline and 35 received terbutaline. There was no significant difference in maximum increase in forced expired volume in 1 second (FEV1) between the enprofylline group (0.24 +/- 0.33 L) and the terbutaline group (0.25 +/- 0.28 L) (p greater than 0.05), nor for the increase in FEV1 over the 1-hour study period. Tremor was reported more in the group receiving terbutaline, and nausea was reported more in the group receiving enprofylline. Two patients experienced hypotension and one patient had a vasovagal episode with enprofylline treatment. Both agents acted as bronchodilators with similar efficacy in patients with acute asthma in this study.

Changes induced by nifedipine (10 mg sublingually) in the residual luminal diameter of significant (greater than 50 percent) coronary lesions were assessed angiographically in 69 patients with effort-induced angina (group 1), in 22 patients with mixed angina (group 2), and in 14 patients with Prinzmetal's angina (group 3). These changes were related to the clinical response to treatment with the same drug, as evaluated through diary records and Holter monitoring in the mixed (spontaneous component) and Prinzmetal forms and through exercise testing in effort-induced and mixed (effort-associated component) angina. In groups 1 and 2, segments of stenotic vessels showed either an increase or decrease or no change in diameter with the calcium antagonist; in group 3, the majority of the lesions had compliant portions which invariably responded with dilatation. Nifedipine failed to improve cases with exertional (20 percent [14/69] unchanged; 19 percent [13/69] worsened) and mixed (41 percent [9/22] exacerbated) forms; 100 percent of the 14 patients with the Prinzmetal form had relief of the anginal episodes. In group 1, the response to exercise tests was dissociated from the short-term vasomotor pattern, and the pressure-rate product failed to explain the clinical results. Forty-five percent (ten) of the patients in group 2 showed significant short-term widening of critical stenoses, as well as obvious improvement; patients who did worse with treatment in this group had reacted to nifedipine with narrowing of critical stenoses. These data suggest that the response to nifedipine of classic effort-induced angina is probably the net result of an interaction of changes in myocardial oxygen consumption and supply; coronary vasomotion has a role in mixed angina, and influences of nifedipine may be either favorable or unfavorable; stenotic lesions in the Prinzmetal form are quite sensitive to the relaxant action of calcium blockade, and this probably represents a background to the highly positive clinical response to treatment.

Adenosine has been found to contract human bronchial smooth muscle in vitro and to induce bronchoconstriction in asthmatic patients when administered by inhalation. The aim of the present study was to investigate if elevation of circulating levels of adenosine influence bronchial tone or bronchial reactivity. Seven patients with bronchial asthma in whom bronchial hyperreactivity had been confirmed in a pretrial bronchial histamine challenge (PC20 FEV1 0.064 to 2.45 mg/ml) received intravenous infusions of adenosine in increasing doses (10, 30 and 50 micrograms/kg/min, 6 min on each dose step) or placebo (saline solution) on two different days in a randomized, single-blind manner. Heart rate, blood pressure and lung function (lung volumes, flow-volume loops and airway conductance) were measured on each dose step. Infusion rate was held constant (at 50 micrograms/kg/min) throughout the trial and a bronchial methacholine challenge was performed during the infusion of adenosine or placebo. Infusions of adenosine and placebo did not influence heart rate, blood pressure or bronchial tone on either day and bronchial reactivity was similar on both days. We conclude that bronchial tone and bronchial reactivity in asthmatic patients are not increased by intravenously administered adenosine at a dose level which, in other studies, has been shown to induce regional effects in the systemic arterial circulation.