The effectiveness of inhaled fenoterol doses of 0.4 mg and 0.8 mg in preventing exercise-induced asthma was investigated in 12 patients. Exercise-induced asthma was prevented by both doses for two hours after administration, but the effect of neither dose was significantly different from that of placebo four hours after. There was no statistically significant difference between the effects of the two fenoterol doses; and only a few patients were protected for more than two hours by the higher dose.

Manual chest wall vibration is one physiotherapeutic technique frequently employed in the management of respiratory disease. A clinical study was undertaken to examine the effects of manual chest wall vibrations on pulmonary function and arterial oxygen saturation in patients with chronic bronchitis. Twelve patients participated in a three-day experimental design where the factors of three different days and three different treatments were randomized and balanced. On one day, deep-breathing exercises were given; on another, deep-breathing exercises with vibrations; and on the remaining day, no treatment was given. Lung volumes were measured before and after each maneuver, and arterial oxygen saturation was monitored continuously. There was a significant decrease in the expiratory reserve volume (ERV) immediately following the deep-breathing exercises alone, which remained constant after the 15-minute rest period (p = 0.032). The remaining outcome parameters do not appear to be significantly affected. Chest wall vibrations do not decrease the ERV in patients with chronic bronchitis.

We compared the effects of inhaled glycopyrrolate (G), 1.3 mg, and atropine (A), 2.6 mg, and placebo on FEV1 and specific conductance (sGaw) before and after exercise in six men with exercise-induced asthma. Subjects exercised with cold air (-2 degrees C) 30 and 120 minutes after each aerosol treatment. Spirometry was performed and sGaw determined before aerosol treatment (baseline) and before and after exercise. Decreased airway tone was noted before exercising with A and G but not with placebo. The decreases in FEV1 and sGaw resulting from exercise were not significantly different among the three treatment groups at either exercise session. Postexercise FEV1 and sGaw were significantly higher after A and G compared to P. Dry mouth, flushing, and resting tachycardia were prominent with group A. Symptoms in G did not differ from those in P. This study suggests that A and G do not prevent bronchoconstriction induced by exercise and cold air but improve postexercise pulmonary function by achieving preexercise bronchodilation. Systemic side effects were minimal with G compared to A.

Thirty patients undergoing elective cholecystectomy were randomly assigned to two groups. Fifteen patients received postoperative intermittent positive pressure breathing (IPPB) for four days together with physiotherapy while the other 15 had the same postoperative care but without IPPB. Vital capacity (VC), functional residual capacity (FRC) and PO2 were measured preoperatively and on days 0, 1, 3, and 5 postoperatively. The incidence of postoperative pulmonary complications utilizing chest x-ray films, sputum analysis, temperature, and clinical assessment was determined. Both groups had significant deterioration in pulmonary function but did not differ except for a greater depression in VC in the IPPB group (p less than .05). In patients receiving postoperative physiotherapy, the addition of IPPB did not usually result in improved pulmonary function.

We evaluated 12 patients with stable chronic airflow obstruction (CAO) and no clinical evidence of left ventricular disease to determine the effects of oral digoxin on exercise capacity (VO2 max) and on right ventricular pump function during exercise. In this randomized, double blind, placebo controlled, cross-over study, patients performed exercise tests and underwent measurement of ejection fractions after two weeks of therapy with oral digoxin (0.25 mg/day) and after two weeks of placebo. Incremental upright exercise testing to a symptom-limited maximum was performed on a cycle ergometer. Right and left ventricular ejection fractions (RVEF, LVEF) were obtained in the supine position at rest and at approximately 75 percent of the maximum workload by gated equilibrium radionuclide angiography. All patients had abnormal right ventricular function, manifested either by a low resting RVEF (less than 45 percent) or a subnormal response to exercise (less than 5 percent increase). The small increases in RVEF with digoxin (mean +/- SE) at rest (44 +/- 5 vs 41 +/- 4 percent) and during exercise (46 +/- 4 vs 44 +/- 3 percent) did not achieve statistical significance. With digoxin, small increases in exercise duration (10.0 +/- 1.5 vs 9.0 +/- 1.4 min), maximum workload achieved (48 +/- 6 vs 42 +/- 5 W), VO2 max (0.85 +/- 0.06 vs 0.81 +/- 0.06 L/min), and oxygen-pulse (O2-P) (6.6 +/- 0.5 vs 6.3 +/- 0.4 ml/beat) occurred. Only the increase in O2-P was significant (p less than 0.05). From this study we conclude that digoxin does not significantly improve exercise capacity in severe chronic airflow obstruction with impaired right ventricular function, nor does it improve RVEF either at rest or during supine submaximal exercise.

To assess whether verapamil taken orally twice daily (bd) was as effective as four times daily (qd) in patients with angina a placebo controlled double blind crossover trial was conducted in 12 patients. Each patient was randomized to verapamil, 160 mg bd, 80 mg qd, or corresponding placebo, each for three weeks. Patients were assessed subjectively and by treadmill exercise test. On both verapamil regimens, patients had less angina with delayed onset of ST segment depression during exercise compared to placebo, without any differences between the two regimens. On bd verapamil, patients could increase their exercise capacity as much as on qd without any increase in adverse effects. Angina threshold during exercise was increased by both regimens with a slightly higher threshold on qd verapamil compared to bd. Therefore, administration of verapamil twice daily is effective in patients with stable angina pectoris, with a similar efficacy to taking verapamil four times daily without any increase in adverse effects.

Controversy exists concerning possible tachyphylaxis of the acute bronchodilating effect of albuterol, especially with regard to the duration of its acute bronchodilating action. We evaluated 140 patients with bronchial asthma in a prospective double-blind controlled study of possible tachyphylaxis to albuterol aerosol as compared to isoproterenol aerosol. We demonstrated statistically significant tachyphylaxis with regard to duration of acute bronchodilating effect. We believe that this tachyphylaxis is not clinically significant because there was no tachyphylaxis with regard to peak bronchodilating effect and because the duration of bronchodilating effect remains significantly greater, both quantitatively and statistically, when compared to isoproterenol aerosol. Moreover, it appeared that most of the tachyphylaxis was present at four weeks of therapy. There was a small increment of tachyphylaxis after eight weeks of therapy, but no further increase in tachyphylaxis was demonstrated after 13 weeks of inhaled albuterol therapy. We therefore feel that clinically significant tachyphylaxis to inhaled albuterol aerosol must be quite unusual and that chronic therapy with inhaled albuterol aerosol is probably both safe and efficacious for bronchospastic disorders.

Nine men who were habitual snorers were studied during a control and a treatment night (in random order) to assess the effect of nasal continuous positive airway pressure (CPAP) on snoring, sleep-disordered breathing, and nocturnal oxygen desaturation. Four subjects had symptoms suggestive of the sleep apnea syndrome, but the other five were asymptomatic. Polysomnography and recordings of snores were obtained on both nights. On the treatment night, the subjects wore a customized infant anesthesia mask over their noses, and CPAP was applied and adjusted upward from 4 cm H2O to a level that obliterated snoring. Nasal CPAP (range 4 to 13 cm H2O) reduced the mean number of snores per night from 1,015 per subject to 23 per subject (p less than 0.01). Mean numbers of episodes of apnea, hypopnea, and desaturation were also significantly reduced. Analysis of sleep structure showed no significant differences in sleep period time, total sleep time, or the percentages of stages 3 and 4 sleep. The percentage of stages 1 and 2 was significantly greater on control nights, and the percentage of REM sleep was greater on treatment nights. On the control nights, snoring was common in stages 3 and 4 and least common during REM sleep.

At rest and during exercise, noninvasive studies of cardiopulmonary physiology in patients with chronic obstructive pulmonary disease (COPD) were carried out to determine the objective benefits of commonly used oral bronchodilator drugs in 15 stable patients without cardiovascular disease or reversible obstruction of airflow. Theophylline, terbutaline, a combination of theophylline and terbutaline, and placebo were given for ten days each in a randomly sequenced double-blind protocol for outpatients. Spirometric values, the ratio of physiologic dead space to tidal volume (VDp/VT), and the alveolar-arterial oxygen pressure difference (P[A-a]O2) were studied at rest on each regimen. During steady-state exercise the changes in VDp/VT and P(A-a)O2, as well as the ventilatory equivalent for oxygen and oxygen pulse, were measured. When compared with placebo, no significant change was noted in the previously mentioned measurements with any regimen, with the exception of a small improvement in the forced expiratory volume in one second, which was significant for all regimens. These findings suggest that commonly used oral bronchodilator drugs in usual doses may have small effects on airflow even in "irreversible" COPD but that the objective effect of these agents on gas exchange during rest and exercise is not significant.

Three hundred nine patients were randomly allocated to two ventilatory protocols; 157 patients were supported with a volume-cycled ventilator (VCV) (Bear Medical BEAR 1) and 152 with a high-frequency jet ventilatory (HFJV) developed at our institution. The two ventilators were compared for safety, reliability, ease of use, and efficacy in maintaining gas exchange. On VCV, end points of therapy were: fractional concentration of oxygen in the inspired gas (FIo2) less than or equal to 0.40; arterial oxygen pressure (PaO2) greater than or equal to 70 mm Hg; cardiac index (CI) greater than or equal to 3.5 L/min/sq m; and spontaneous respiratory rate less than or equal to eight breaths per minute. On HFJV, end points were: FIo2 less than or equal to 0.45; arterial oxygen saturation greater than or equal to 0.90; and CI greater than or equal to 3.5 L/min/sq m. Spontaneous ventilation and pulmonary venous admixture reduction were the goals on VCV, with oxygen transport the goal on HFJV, Total duration of use of the ventilators was approximately 800 days with both types of devices; there were no technical failures, and the incidence of barotrauma was less than 5 percent. The end point of mechanical ventilation was reached by a significantly higher percentage of the patients randomized to HFJV. Patients who failed to reach the therapeutic goal within 24 hours were crossed over to the other form of support. Those crossed from VCV to HFJV improved more rapidly and in greater number than those crossed from HFJV to VCV. When survival and total duration of stay in the intensive care unit were considered, there was no difference between VCV and HFJV. Considering data on gas exchange, VCV provided a higher PaO2 at equivalent positive end-respiratory pressure than HFJV. Alveolar ventilation was slightly better on HFJV. Differences were statistically but not clinically significant. On HFJV, oxygenation and ventilation were maintained with lower peak inspiratory pressures and smaller tidal volumes than those required for VCV. This investigation proves that HFJV is a safe and reliable method to provide mechanical support which does not, at this time, offer obvious benefits over VCV.

Previous reports have suggested that infusions of lidocaine (lignocaine) cause a high incidence of phlebitis. We investigated the possibility of reducing this high incidence by the addition of small amounts of heparin or hydrocortisone (or both) to the infusate of lidocaine. One hundred patients with acute myocardial infarction who were to receive a 48-hour prophylactic infusion of lidocaine (2.25 mg/min) were randomized to have one of the following added to their infusate in double-blind fashion: (1) placebo; (2) heparin (4,000 units/24 hr); (3) hydrocortisone (20 mg/24 hr); or (4) heparin and hydrocortisone. After 48 hours the incidence of phlebitis was 94 percent in the control group but only 41 percent in the group receiving heparin and hydrocortisone (p less than 0.005). Had the infusion been stopped after 24 hours, the incidence of phlebitis would have been 56 percent in the group receiving placebo, but only 19 percent in the drug-treated groups (p less than 0.01). We conclude that infusion of lidocaine causes a high incidence of phlebitis which can be markedly reduced by adding heparin or hydrocortisone (or both) to the infusate and limiting the duration of the infusion in a given vein to 24 hours.

The effects of oral medroxyprogesterone acetate (MPA) (20 mg three times daily) were assessed on sleep-disordered breathing and on arterial blood gas levels in awake patients with chronic obstructive pulmonary disease (COPD). Seventeen men and two women (mean baseline PaO2, 65 mm Hg; PaCO2, 41 mm Hg; and FEV1/FVC ratio, 48 percent) participated in a double-blind, placebo-controlled, randomized study. After an initial night of polysomnography and daytime arterial blood gas analysis, the patients were randomized to receive either MPA or an identical placebo for one month; the studies were then repeated. The alternate compound was given for an additional month, and the studies were performed a third time. MPA in awake patients was associated with an increased mean PaO2 value, reduced PaCO2, and increased pH. Although there was no significant change in the number of episodes of sleep apnea, hypopnea, desaturation, or the minimal saturation, MPA marginally decreased the number of minutes of total sleep time when oxygen saturation was less than 90 percent (p = .06). In conclusion, MPA improves oxygenation and CO2 elimination and increases the pH in awake patients with COPD, but during sleep, does not significantly affect disordered breathing and only marginally improves desaturation.

Fifteen patients suffering from asthma received inhalations of phentolamine, albuterol (salbutamol), a combination of phentolamine and albuterol, and placebo, in a single-blind fashion; the changes in the pulmonary function tests were recorded over a three-hour period. Three patients responded to phentolamine with marked bronchodilatation, whereas severe bronchoconstriction was induced by the drug in two patients. Five patients improved more with phentolamine than with placebo, while all patients improved more markedly with albuterol and still more following inhalation of the combination of both drugs. As a group, there were no statistically significant differences between the responses to phentolamine compared with placebo, or between albuterol alone compared with the combination of both drugs. We concluded that both alpha-antagonist and beta 2-agonist agents act in the same direction in most patients, the beta 2-agonist being the dominant. These results do not offer convincing proof that enhanced alpha-adrenergic activity is the main bronchoconstrictor mechanism even in those few with good response to phentolamine, who also showed very good responsiveness to albuterol. The mechanism of phentolamine-induced bronchoconstriction was discussed, but in the light of presently accepted theories, we were unable to evolve a reasonable explanation.

The antianginal efficacy of a single sustained-release buccal nitroglycerin (BNTG) tablet was assessed in 16 patients with known coronary artery disease. Patients were trained in bicycle ergometry to induce angina pectoris within three to five minutes. A hemodynamically effective dose of BNTG was identified. Patients were tested at baseline and given placebo and BNTG in a randomized, double-blind manner on consecutive days. They were tested at 0.5, 1, 3, and 5 hours after drug administration. The average increase in exercise duration with BNTG compared with placebo at 0.5 hours was 40 percent (p less than 0.01); at 1 hour was 31 percent (p less than 0.01); at 3 hours was 27 percent (p less than 0.01); at 5 hours was 15 percent (p = NS). In a subset of ten patients in whom the tablet was maintained in the buccal pouch for five or more hours before dissolving, increase in exercise duration was significant at all times tested (p less than 0.05). We conclude that BNTG is an effective modality of administering nitroglycerin for rapid and prolonged effect with reduction in angina pectoris and increase in exercise duration which may persist for at least five hours.

The efficacy and safety of oral verapamil, 240 mg, with or without digoxin were studied in 52 patients with chronic atrial fibrillation at rest, and during mild and maximal exercise. Twenty-four patients were studied during the following therapeutic modalities: no therapy; digoxin, 0.25 mg and 0.5 mg daily; digoxin, 0.25 mg and verapamil; and verapamil alone. Heart rate at rest and during all levels of exercise was decreased significantly (p less than 0.005), either by combining digoxin with verapamil or by verapamil therapy alone. In contrast, the excessive heart rate response to exercise was not prevented by digoxin even with good serum concentrations. The improved control of heart rate with verapamil was associated with a significantly improved exercise capacity. Verapamil is an important and safe modality of treatment, with or without digoxin, in the long-term control of heart rate in chronic atrial fibrillation. It is superior to digoxin in controlling the ventricular rate and in improving exercise capacity.

Labetalol is a new adrenergic antagonist with both alpha- and beta-blocking effects. To evaluate its usefulness in the treatment of hypertension in patients with coexisting chronic obstructive pulmonary disease (COPD), labetalol was administered in gradually increasing doses to a group of 11 patients with mild-to-moderate hypertension and COPD with a mild reversible component. Ten patients given hydrochlorothiazide served as control subjects. Blood pressure was controlled in seven of the 11 patients given labetalol and in six of the ten patients given hydrochlorothiazide in dosages up to 1,200 mg/day and 150 mg/day, respectively. No significant changes occurred in the FEV1 or FEF25-75% two hours after the administration of the maximum dose of either drug or after exercise on the same day. Labetalol was well tolerated in the doses given.

The effect of a centrally acting agent (clonidine) vs a diuretic as a single agent was studied in a group of hypertensive adolescents. Following placebo therapy, adolescents with blood pressure greater than 95th percentile were randomized to clonidine 0.1 mg or hydrochlorothiazide 25 mg, each given twice daily. Following 12 weeks' active treatment, those who had not achieved blood pressure goals proceeded to clonidine 0.2 mg or hydrochlorothiazide 50 mg twice daily. Blood pressure and clinical assessment was performed at two-week intervals. Cardiovascular response to mental stress and pre-post stress catecholamines were obtained prior to active therapy and during therapy. Clonidine therapy significantly lowered systolic and diastolic pressure and heart rate (p less than .01). Hydrochlorothiazide significantly lowered systolic pressure only. Mental stress testing resulted in a lower diastolic pressure and heart rate response (p less than .01), with lower norepinephrine in the clonidine-treated group. The diuretic group had higher plasma norepinephrine and no significant reduction in stress response. Hypertensive juveniles may be more sensitive to central control of blood pressure and more resistant to diuretics.

Ten men with stable angina not completely relieved by full doses of propranolol (mean, 218 mg daily) were given double-blind, on alternate mornings, a placebo or an oral dose (5 to 30 mg) of isosorbide dinitrate (ISDN) previously titrated to lower sitting systolic blood pressure by 20 mm Hg. Patients had been trained in a protocol which precipitated angina after three to six minutes of bicycle exercise. On test days, with propranolol continued, bicycle exercise was performed until the appearance of angina before ISDN or placebo administration, and hourly thereafter for eight hours. Mean exercise duration was greater one hour after ISDN than after placebo by 182 sec (423 +/- 39 vs 241 +/- 13, p less than 0.001), and a difference of 63 sec was still present at six hours (p less than 0.002). At one hour, ISDN lowered resting systolic blood pressure by 26 mm Hg (from 114 +/- 5 mm Hg to 88 +/- 4 mm Hg; p less than .001) without appreciably changing heart rate. We conclude that ISDN is a very effective and reasonably long-acting antianginal supplement to propranolol.

The effect of clonidine (average 0.24 mg/day) and propranolol (average 105 mg/day) on home blood pressure readings in 16 patients with borderline hypertension was investigated in a randomized, double-blind, placebo crossover design. Patients could detect small but significant decreases of blood pressure with both active compounds (-8/-5 with propranolol and -11/-7 with clonidine). The larger mean blood pressure decrease from clonidine vs propranolol was significant (p less than 0.015). Small doses of sympatholytic agents might control the blood pressure in patients with borderline hypertension, and the home blood pressure technique is a convenient tool to detect and monitor such changes. Biochemical predictors of the responsiveness to clonidine were investigated. There was no difference in placebo norepinephrine and renin values between better and lesser responders to clonidine. Plasma norepinephrine fell with clonidine treatment, but with no relationship to the blood pressure response. Plasma norepinephrine response to clonidine might reflect not only the central withdrawal of sympathetic tone, but also, in part, the effect of clonidine on peripheral presynaptic alpha 2-receptors.