Energy expenditure was studied in ten patients with chronic obstructive pulmonary disease (COPD) and weight loss, and in five malnourished patients without clinical evidence of COPD (control group) prior to and after a two-week refeeding regimen. Patients received 5 percent dextrose solution (plus electrolytes) for 36 hours to establish standard baseline conditions and were then randomly assigned to either a carbohydrate-based (CB; 53 percent of calories) or fat-based (FB; 55 percent of calories) diet for the first week. The alternate diet was given the following week. Total calorie intake was set at 70 percent above the energy expenditure measured prior to institution of nutritional support. During energy repletion, energy expenditure was greater than predicted (116 percent) in patients with COPD and less than predicted (90 percent) in the control patients. Thermic effect of nutrients during administration of either regimen was significantly greater (p less than .05) in patients with COPD than in those without COPD during both diets. The difference between the two groups was enhanced during the CB regimen. These observations suggest that malnourished patients with COPD have an elevated resting energy expenditure, and an enhanced thermic response to nutrients as compared to malnourished patients without COPD. Increased diet-induced thermogenesis may contribute to weight loss in patients with COPD, in addition to factors previously described such as decreased caloric intake and increased resting energy expenditure.

We compared in a randomized fashion the hemodynamic effects of intravenous (IV) isosorbide dinitrate (ISDN) and nitroglycerine (NTG) in 45 patients with acute myocardial infarction and elevated pulmonary artery wedge pressure (Paw). Titration of ISDN dose to lower Paw greater than or equal to 25 percent resulted in a fall of this parameter from 32 +/- 8 to 24 +/- 5 mm Hg and was associated with a fall in mean blood pressure (96 +/- 15 to 90 +/- 14 mm Hg, p less than 0.05), systemic vascular resistance (1715 +/- 572 to 1548 +/- 414 dynes X s X cm-5, (p less than 0.05), pulmonary vascular resistance (182 +/- 106 to 154 +/- 78 dynes X s X cm-5, p less than 0.05) and mean right atrial pressure (11 +/- 4 to 7 +/- 4 mm Hg, p less than 0.05). In addition, ISDN significantly (p less than 0.05) increased cardiac index from 2.37 +/- 0.54 to 2.54 +/- 0.59 L/min/m2, stroke volume index from 28 +/- 8 to 31 +/- 8 ml/m2, and stroke work index from 28 +/- 11 to 31 +/- 12 g X m/m2. The ISDN dose ranged from 50 to 533 micrograms/min (mean +/- SD 326 +/- 176 micrograms/min) and could not be predicted from baseline hemodynamic values. A comparison between the effect of ISDN and NTG in doses producing comparable reduction in Paw showed similar hemodynamic changes. It was concluded that IV ISDN in patients with elevated mean pulmonary artery wedge pressure due to acute myocardial infarction results in a decrease in right and left ventricular preload and afterload and improvement of cardiac output and cardiac work. The effective dose ranges from 50 to 533 micrograms/min and cannot be predicted from baseline hemodynamic values. In doses producing comparable reduction in Paw, ISDN and NTG had similar hemodynamic effects.

Alcohol and benzodiazepines may increase sleep-disordered breathing by decreasing activity of pharyngeal dilating muscles, favoring the development of obstructive apneas and hypopneas. Narcotics cause greater depression of wakeful respiration than the previously mentioned drugs; however, the influence of narcotics on the upper airway and breathing during sleep has not been studied. We, therefore, examined, in 12 healthy adults, the effects of oral hydromorphone hydrochloride (2 and 4 mg) on breathing during sleep and on a variety of awake respiratory variables (minute ventilation, gas exchange, and chemoresponsiveness). In addition, awake pharyngeal inspiratory airflow resistance was determined before and after narcotic administration to assess the drug's influence on patency of the upper airway. Following both doses, minute ventilation decreased, and carbon dioxide pressure increased. The 4-mg dose of hydromorphone hydrochloride also produced a significant decrement in the hypoxic ventilatory response, whereas hypercapnic responsiveness and pharyngeal resistance did not change following either dose of the drug. Despite the respiratory depression during wakefulness described previously, no significant change was observed in any measure of sleep-disordered breathing after either dose of narcotic. We conclude that in healthy individuals without suspected sleep apnea, oral hydromorphone in standard dosages does not significantly increase sleep-disordered breathing. This result may be due to a lack of selective depression of upper-airway muscular function by the doses of narcotic used.

Glycopyrrolate, a quaternary ammonium anticholinergic compound is a potentially useful bronchodilator. To determine the efficacy, optimal dose, and duration of action of inhaled glycopyrrolate, we gave the drug to 11 asthmatic patients. Each subject received placebo or glycopyrrolate (100, 200, 600, or 1,200 micrograms) by inhalation in a double-blind, randomized, crossover design. Measurements included FEV1, FVC, heart rate, and blood pressure before administration of the drug and periodically for 12 hours. For eight hours following all doses of glycopyrrolate, both FEV1 and FVC (both as percent of predicted) were significantly greater for drug than for placebo. Glycopyrrolate may be a useful long-acting drug for the treatment of asthma.

We have previously shown that one night of sleep deprivation results in significant deterioration of spirometric performance and ventilatory responsiveness to inhaled carbon dioxide in normal people. Since even a small decrease in pulmonary function may be clinically important in patients with chronic limitation of airflow, we undertook the present study to assess the effects of sleep loss on breathing in patients with chronic obstructive pulmonary disease (COPD). Criteria for inclusion in this study were a ratio of the forced expiratory volume in one second over the forced vital capacity (FEV1/FVC) of less than 60 percent, no hospital admission for pulmonary disease within two weeks of testing, stable (less than 30 percent variation) in tests of pulmonary function on two occasions within three months of testing, and no history of asthma. We studied 15 men (mean age, 57 +/- 3 years) on two consecutive mornings. Patients were studied with and without sleep deprivation in a randomized fashion. Patients were hospitalized for the study so that sleep deprivation, medications, smoking, and diet could be monitored and enforced. We found small but statistically significant falls in FEV1 (1.06 +/- 0.11 to 1.00 +/- 0.09 L; p less than 0.05) and in FVC (2.56 +/- 0.20 to 2.43 +/- 0.17 L; p less than 0.05) following sleep deprivation. Changes of similar magnitude which were not statistically significant occurred in maximal voluntary ventilation (MVV) and response to carbon dioxide. The arterial oxygen (PaO2) and carbon dioxide (PaCO2) tensions were not affected. Maximal expiratory pressure at the mouth increased slightly, but there was a fall in maximal inspiratory pressure (MIP) at the mouth. We conclude that sleep loss is associated with small but significant falls in FEV1 and FVC, as well as changes of similar magnitude in MVV, minute ventilation, and MIP in patients with severe COPD. Although the sleep loss which frequently accompanies exacerbations of COPD may be a slight additional stress of pulmonary reserve, a single night's loss of sleep in the patient with stable chronic airflow obstruction does not have major clinical consequences.

To assess the effectiveness and site of action of bronchodilatation with an inhaled anticholinergic bronchodilator, ipratropium bromide, and a beta adrenergic agonist, fenoterol, we measured the density dependence of maximal flow and the density dependence of pulmonary resistance using a digital computerized averaging circuit. Eight normal subjects were studied on two separate days, before and after the bronchodilators were administered in a double blind manner. Both drugs resulted in significant and equivalent bronchodilatation. However, there were no significant changes in the density dependence of maximal flow or pulmonary resistance with either agent. These results in normal subjects, therefore, do not support the hypothesis of a preferential site of action of inhaled anticholinergic agents and beta-adrenergic agents.

Twenty-four patients (five women) aged 53-72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline (600 mg daily), enprofylline (600 mg daily) or placebo. The study was double-blind, randomized, triple-crossover with each regimen given for two weeks. Holter monitoring was used during 48 consecutive hours in each period. Compared with placebo, addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm (p less than 0.001). A small, but statistically significant (p less than 0.05) increase in mean hourly frequency of premature ventricular beats (PVBs) occurred with enprofylline as compared with placebo. However, in only two patients with enprofylline (and one patient with theophylline) the increase in PVBs was such that a clinically relevant proarrhythmic effect seems possible. Furthermore, ventricular tachycardia was not more frequently observed with any xanthine than with placebo. Thus, combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease. Holter monitoring is recommended to assess the individual patient's response to such therapy.

To evaluate the efficacy of a mild anxiolytic, alprazolam, in relieving dyspnea, we conducted a randomized, placebo-controlled double-blind study on patients with chronic obstructive lung disease. Twenty-four patients had alprazolam (0.5 mg bid) or placebo administered for one week, followed by placebo for one week, then either placebo or alprazolam for the third week. Assessment tests were performed at the outset, end of the first and second weeks, and finally end of the third week. The parameters measured were: pulmonary function, exercise testing on a bicycle ergometer, and the distance covered in a 12 minute walk. Subjective sensations of dyspnea at rest and during guarded exercise, as well as subjective feelings of calmness or anxiety were also recorded. There was no difference in mechanical lung function, but the PO2 tended to decrease and PCO2 to increase after alprazolam administration. The maximum exercise level attained and the distance covered in the 12 minute walk was unchanged. The subjective perception of dyspnea was the same before and after alprazolam, at rest and during exercise. We conclude that alprazolam is not effective in relieving exercise dyspnea in patients with obstructive lung disease.

Benign thymic hyperplasia (BTH) is a known feature of hyperthyroidism, but is infrequently appreciated by clinicians. In most cases thymic enlargement is minimal; however, it may occasionally present as an appreciable anterior mediastinal mass. While surgical resection is a common approach to such a mass, recognition of the benign nature of BTH and its regression following treatment of hyperthyroidism would prevent a major surgical procedure. We present three cases of BTH associated with hyperthyroidism and describe our approach to this syndrome.

Magnetic resonance imaging (MRI) was used for postoperative evaluation of spiral vein grafts in three patients with fibrosing mediastinitis who had undergone bypass of the superior vena cava (SVC) for SVC syndrome. The MRI images, obtained without ECG triggering, were compared retrospectively with postoperative bilateral arm venograms. Patent grafts were identified by MRI in all patients. Significant stenoses at innominate vein-spiral vein graft anastomoses in two patients were better demonstrated by venography than by MRI. MRI shows promise as a non-invasive technique for postoperative evaluation of spiral vein bypass grafts.

To compare the acute bronchodilator effect of increasing doses of intravenous theophylline and inhaled beta adrenergic agonists, we administered intravenous theophylline dissolved in ethylenediamine or proxyphylline and diprophylline or placebo in a double blind fashion to nine asthmatics on three different days. At each session, 100 mg theophylline or placebo were given during each of five subsequent periods of 30 minutes' duration and followed by inhalation of 0.4 mg fenoterol. In contrast to placebo, 500 mg theophylline in ethylenediamine or proxyphylline and diprophylline significantly decreased mean specific airway resistance (SRaw in cmH2O.s) from 31.2 to 23.6 or 34.2 to 23.5 at theophylline serum concentrations of 14.4 or 16.6 mg/L, respectively. Fenoterol lowered SRaw to about 40 percent of the respective baseline values independent of theophylline or placebo pretreatment. We conclude that the acute bronchodilator effect of theophylline is weak in comparison to inhaled beta agonists. Furthermore, proxyphylline and diprophylline cause a weak but not significant bronchodilation when compared to ethylenediamine.

Propafenone is a new membrane-stabilizing antiarrhythmic agent that structurally resembles the beta-adrenergic receptor antagonist, propranolol. To determine the potential asthmogenicity of this new drug, pulmonary function, airway reactivity to methacholine, blood pressure, the electrocardiogram, and plasma concentrations were measured in 12 patients with mild intermittent asthma after 48 to 72 hours of treatment with placebo and with oral propafenone in low dosage (150 mg every eight hours) and high dosage (300 mg every eight hours) in a double-blind crossover manner. The forced vital capacity (FVC), forced expiratory volume in one second (FEV1), forced expiratory flow over the middle half of the FVC (FEF25-75%), heart rate, and blood pressure during the three regimens of treatment were not significantly different; however, the QRS interval on the ECG was significantly widened with both dosages of active drug, and the mean provocative dose of methacholine (+/- SE) required to reduce FEV1 by 20 percent (PD20) decreased from 3.0 +/- 0.6 mg/ml with placebo to 2.1 +/- 0.7 mg/ml with the high dosage of propafenone (p less than 0.01). The mean PD20 on the low-dose regimen was not significantly different from placebo or high-dose therapy. A potentially relevant increase in airway reactivity, as measured by a ratio of less than 0.5 for PD20 after treatment to PD20 after placebo, occurred in seven subjects with high-dose and in one subject during low-dose treatment (p less than 0.01). These data suggest that propafenone should be used with caution in patients with asthma and that bronchial provocation will provide a more sensitive measure of the asthmogenicity of a drug with beta-adrenergic receptor antagonist activity than pulmonary function tests. Moreover, use of bronchial provocation allows the selection of subjects with mild disease, thus reducing the risk of potentially severe bronchospasm.

A placebo-controlled single-blind study on acute effects of captopril on hypoxic pulmonary hypertension was performed in 15 patients with severe chronic obstructive lung disease recovering from right heart failure. Ten patients received active drug (25 mg captopril orally), five patients received placebo and served as control subjects. Before drug administration, there was no difference in lung function data and pulmonary hemodynamics between patients in both groups. Captopril produced highly significant fall in systemic arterial pressure. No change in breathing frequency, minute ventilation, and pulmonary gas exchange was observed. There was no significant change in studied variables after placebo. The presented data suggest that captopril does not decrease pulmonary vascular resistance in patients with hypoxic pulmonary hypertension. A fall in pulmonary wedge pressure reflects a decrease in left ventricular afterload.

Pulmonary dysfunction commonly follows open heart surgery. To evaluate the effects of positive end-expiratory pressure (PEEP) upon the course and severity of impaired oxygen transfer and roentgenographic evidence of atelectasis after coronary artery bypass grafting (CABG), we randomly assigned 44 patients to positive pressure ventilation and 0, 5, or 10 cm H2O PEEP. Study groups did not differ with respect to preoperative P(A-a)O2 or time on cardiopulmonary bypass. We observed a significant reduction of P(A-a)O2 during positive pressure ventilation with 10 cm H2O PEEP and FIO2 = 0.6 (182 +/- 6 vs 135 +/- 7 mm Hg, p less than .005). Following extubation, P(A-a)O2 measurements of the three groups did not differ when compared 24, 48, 72, 96, or 120 hours after surgery. Roentgenographic atelectasis scores did not differ on the fifth postoperative day. Five days after CABG, P(A-a)O2 exceeded preoperative P(A-a)O2 (29 +/- 1 vs 18 +/- 1 mm Hg, p less than .001), although the roentgenographic distances from hemidiaphragm to lung apex were unchanged (21.2 +/- 0.9 vs 22.0 +/- 0.9 cm). We conclude that routine PEEP improves pulmonary oxygen transfer but, once discontinued, PEEP offers no sustained beneficial effect upon impaired oxygen transfer or roentgenographic evidence of atelectasis following CABG.

We randomized patients with severe hypertension in the Medical Intensive Care Unit to a treatment regimen of oral nifedipine or intravenous nitroprusside. Patients treated with nifedipine achieved a sustained reduction in diastolic blood pressure to less than or equal to 120 mm Hg in an average of less than five hours. Patients treated with nitroprusside achieved a similar reduction in 14 hours (p less than 0.05). Treatment with nifedipine was less expensive and required less time in the ICU than treatment with nitroprusside and was accompanied by no associated increase in morbidity or mortality. Oral nifedipine can be used as an alternative to intravenous nitroprusside in severe uncomplicated hypertension.

The effects of five bronchodilator drugs and two methods of delivery (nebulizer vs metered-dose inhalers) on pulmonary function were studied in ten subjects with stable asthma. All subjects demonstrated statistically significant improvements (p less than 0.05) in pulmonary function relative to baseline and placebo effects after each medication, regardless of method of delivery; however, there was no statistically significant difference between the changes in pulmonary function caused by medication, method, or medication-method combination (p greater than 0.05). The choice of medication and device for delivery would appear to depend on the budget and time available in the laboratory.

Although the mechanisms of nocturnal asthma are still uncertain, increased vagal cholinergic tone may be contributory factor. To examine this hypothesis, we have studied the effect of an anticholinergic drug, oxitropium bromide, on the early morning fall in peak expiratory flow (PEF) in patients with nocturnal asthma. Eighteen patients (aged 18 to 76 years; seven men) with documented nocturnal asthma were studied in a double-blind randomized cross-over study in which they received either oxitropium bromide (200 micrograms or 400 micrograms) or placebo in a single dose at night for two-week periods. With placebo the mean (+/- SE) fall in PEF (expressed as percentage of evening PEF) was 17.3 +/- 2.0 percent, which was significantly reduced to 10.3 +/- 3.3 percent after oxitropium (400 micrograms) (p less than 0.05; ANOVA). Closer analysis revealed that nine of the 18 patients had responded in a dose-dependent manner, with the mean percentage decreases with placebo, 200 micrograms, and 400 micrograms of oxitropium being 19.1 +/- 3.2, 11.5 +/- 4.4, and 5.0 +/- 4.5 percent, respectively (p less than 0.01 between each treatment). The remaining patients were unaffected by therapy. There were no differences between "responders" and "non-responders" in terms of age, atopic status, duration of asthma, severity of asthma, or bronchodilator response to albuterol (salbutamol). There were no differences in nocturnal symptoms between periods of treatment, and no side effects were recorded. We conclude that anticholinergic drugs may protect against nocturnal asthma in some patients, indicating the involvement of vagal cholinergic mechanisms.

Nineteen outpatients with stable obstructive pulmonary disease (mean forced expiratory volume in one second [FEV1], 1.00 + 0.10 L) were evaluated for airway response to albuterol (salbutamol) administered by metered-dose inhaler and Bosch ultrasonic nebulizer (BUSN). Albuterol administered by metered-dose inhaler but not by nebulizer caused a significant increase in FEV1 and the mean forced expiratory flow over the middle half of the forced vital capacity (FEF25-75%) (p less than 0.02). Absolute increase from baseline of FEV1 and FEF25-75% was significantly greater for metered-dose inhaler (0.21 +/- 0.05 L; 0.32 +/- 0.13 L/sec) compared to ultrasonic nebulizer (0.07 +/- 0.03 L; 0.03 +/- 0.04 L/sec) (p less than 0.02). In 11 subjects (mean FEV1, 1.08 + 0.14 L), the placebo effect of inhalation of the diluent from the metered-dose inhaler (Freon) and the ultrasonic nebulizer (isotonic saline solution) was determined. Freon produced the mean increase of 1.5 percent, whereas the ultrasonic aerosol of isotonic saline solution resulted in a mean decrease of 8 percent in FEV1. Therefore, the inferior response to albuterol administered by ultrasonic nebulizer was at least in part due to the superimposed broncho-constriction occurring with ultrasonically administered saline solution. The metered-dose inhaler was more effective than the ultrasonic nebulizer for administration of albuterol in stable obstructive pulmonary disease, and the latter device is not recommended. A specific ultrasonic nebulizer should be prescribed only if its superiority to a metered-dose inhaler can be objectively documented.