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.

This study of guanfacine in 27 patients suffering from moderate-to-severe hypertension showed a satisfactory blood pressure control in 26 patients. Twenty-one of the 27 patients completed a one-year clinical trial with good blood pressure response. The new drugs, acting through the stimulation of the central alpha-adrenoceptors, are useful in patients suffering from moderate-to-severe hypertension. They are a good alternative to adrenergic neuron-blocking drugs, methyldopa, or beta-blockers, and useful in patients with refractory hypertension where conventional therapy has failed.

The bronchodilator effect of ipratropium bromide (IB) (Atrovent-Sch 1000), 40 micrograms inhaled, and metaproterenol (Met), 1.25 mg in various combinations, was compared in ten allergic asthmatic patients, aged 23 to 63 years. Six combinations were used at random in a double blind study. The following ventilatory functions-FVC, TGV, SGAW, FEV1, FEF 25-75, VEmax, VE50, VE25, were measured at 30 min. intervals for the first two hours and at 60 minute intervals for the additional three hours. Inhalation of IB followed by Met resulted in additive bronchodilator effect that was significantly greater and longer than IB alone (p less than 0.05), Met alone (p less than 0.05), two consecutive inhalations of Met (p less than 0.05), or Met followed by IB (p less than 0.05). The bronchodilating effect of IB and Met after five hours was the same as IB after one hour.

CP-804-S is a substituted phenylbutylamine, known to lower arterial pressure in hypertensive animal models. In a double-blind, crossover study, 12 patients with essential hypertension receiving a constant sodium intake received placebo and CP-804-S, 150 mg daily. Standing (-5.5/-6.0 mm Hg) and supine (-8.5/-7.5 mm Hg) blood pressures and standing (-7.0 beats/min) and supine (-7.5 beats/min) pulse rates were significantly reduced by CP-804-S. Plasma renin activity (-0.41 ng/ml/hr) and plasma angiotensin I (-47 pg/ml) and angiotensin II (-3.0 pg/ml) levels decreased significantly. No significant changes were observed in plasma aldosterone or in the urinary excretion of aldosterone, kallikrein, and prostaglandin E2, F2 alpha, and F alpha metabolite.

To determine the amount of sympathetic outflow suppression due to the alpha 2-adrenergic receptor stimulating agent clonidine, its effect on heart rate, blood pressure, and on circulating plasma catecholamines was assessed in ten healthy subjects at rest and during submaximal ergometric exercise. Similar exercise studies were performed in eight healthy normotensive persons after beta-blockade using propanolol. In nine healthy subjects the effect of an acute intravenous (IV) intervention of clonidine on plasma catecholamines was compared with the results obtained after IV administration of the cardioselective beta-blocker metoprolol or of both drugs. Clonidine taken orally produced significantly reduced plasma levels of epinephrine and norepinephrine (p less than 0.01). During submaximal ergometric exercise, the sympatholytic effect of clonidine was relatively less marked than at rest (p less than 0.05). After beta-blockade, either orally with propanolol or IV with metoprolol, plasma catecholamines at rest did not change significantly; their plasma levels during exercise, however, exceeded those obtained after administration of placebo (p less than 0.05). Giving IV clonidine and metoprolol combined revealed no significant changes of plasma catecholamines at rest and during exercise; heart rate and blood pressure decreased significantly (p less than 0.001). Clonidine on the one hand and the beta-blocking agents on the other exhibit oppositely directed effects on plasma levels of catecholamines.

To evaluate the hemodynamic effects of nifedipine on anginal patients during exercise in the upright position, a placebo (P) and 20 mg of nifedipine were administered in a double-blind random sequence to ten patients presenting with exertional angina and a healed myocardial infarction. All patients had previously undergone coronary angiography. The effects of nifedipine in the upright position at rest, at the anginal threshold, and at the maximal level of exercise were studied. Nifedipine decreased systemic vascular resistances in upright position and increased the cardiac index. It reduced the severity of angina and allowed a higher physical work capacity without anginal symptoms. The most important beneficial effect of nifedipine appears to be the reduction in afterload, but an improvement of left ventricular function cannot be ruled out.

The effect of chewable isosorbide dinitrate on submaximal bicycle exercise capacity was evaluated in a double-blind randomized study involving 13 patients with chronic heart failure. All patients had impaired maximal exercise capacity (VO2 max = 12.0 +/- 2.6 ml/kg/min) due to fatigue and dyspnea but not angina. The administration of isosorbide dinitrate lowered the resting mean blood pressure (82 +/- 9. mm Hg to 78 +/- 10 mm Hg, (p less than 0.03)) and the resulting pulmonary wedge pressure (26 +/- 5 mm Hg to 12 +/- 6 mm Hg, (p less than 0.01)). Isosorbide dinitrate acutely improved exercise duration during upright bicycle exercise at a workload fixed at 50 percent of the maximal workload (placebo): 21.8 +/- 14.1 min vs isosorbide dinitrate: 31.4 +/- 13.6 min, (p less than 0.003)) due to reduced exertional dyspnea. Administration of chewable isosorbide dinitrate acutely improved submaximal exercise tolerance in patients with chronic heart failure.

The efficacy of guaifenesin in reducing cough frequency in young adults with acute respiratory disease was evaluated by both an objective cough counting system and a questionnaire. A guaifenesin cough preparation and the syrup vehicle were administered in a double-blind manner. Coughs were recorded on tape over a 24-hour baseline evaluation period and a 36-hour treatment period for 42 patients. A pronounced diurnal variation in cough frequency was observed. The evaluation of efficacy was based upon comparisons between equivalent six-hour time periods of successive days. No antitussive effect of guaifenesin was demonstrated. The questionnaire was administered to 65 patients, including the 42 whose coughs were recorded. Of 26 patients with productive cough receiving guaifenesin, 25 (96 percent) reported a decrease in sputum thickness compared to 13 (54 percent) of 24 patients receiving the vehicle (p = 0.01, Fisher exact test). Twenty-three of 26 (88 percent) patients receiving guaifenesin also reported reduction in sputum quantity compared to 15 of 24 (62.5 percent) receiving the vehicle (p = 0.07, Fisher exact test). The diurnal variation in cough frequency measured by the tape recording was not apparent from the subjective cough frequency estimates obtained by the questionnaire.

The ability of digoxin to increase exercise capacity and stroke volume (SV) during exercise was evaluated in ten patients with cystic fibrosis (CF) ages 12 to 20 years with moderate to severe degrees of airway obstruction but no history of heart failure. A double-blind crossover trial of digoxin versus placebo was carried out. An evaluation of exercise performance was undertaken upon entry into the study, and after each of the one-week periods in which digoxin 0.25 mg/day or placebo was taken. Exercise testing consisted of a progressive exercise test on a cycle ergometer to measure maximum work capacity (Wmax) and a steady state test at 2/3 of the baseline Wmax. During the steady state test, the oxygen consumption and carbon dioxide production were measured and cardiac output (Q) was calculated by the indirect Fick (CO2) method. From Q and heart rate (HR), SV was derived. After digoxin, Wmax was unchanged. On steady state exercise HR was unchanged, but there was a slight but significant fall in Q due to a fall in SV. The decrease in SV was associated with exercising hypoxemia. We conclude that digoxin did not increase exercise capacity or improve exercising cardiac function in patients with moderate to severe airway obstruction due to CF.