The literature is unclear as to whether theophylline loading doses should be based on total body weight (TBW) or ideal body weight (IBW). The objective of this study was to determine the most appropriate body weight for estimation of volume of distribution (Vd) in calculating theophylline loading dose in patients with acute bronchospasm. Fifty-four adult patients with acute bronchospasm requiring intravenous (IV) theophylline therapy were entered into the study. Patients were randomized into three theophylline loading dose groups based on (1) TBW, (2) IBW, and (3) adjusted body weight (ABW). Initial serum theophylline concentrations were used to determine an IV loading dose to reach a plasma concentration of 12 to 15 micrograms/ml. Percent prediction error was used to determine the appropriateness of each dosing group. Volumes of distribution were also determined for each group. There was a statistically significant difference at p less than 0.01 in the percent prediction error when patients in the TBW group were compared to the IBW and ABW groups. A statistically significant difference in the Vd was observed between the TBW and IBW group (p less than 0.01). We conclude that IBW is more appropriate than TBW or ABW for determining theophylline loading dose in patients with acute bronchospasm.

Recently, several transmembrane calcium-channel blockers have been used in experimental models to investigate the mechanisms through which Ca++ ions contribute to the regulation of the contractile response of airway smooth muscle and to determine the therapeutic use of these drugs in bronchial asthma. Since the data from these studies are inconsistent and inconclusive, we studied the effect of diltiazem, a calcium-channel blocker previously not examined to our knowledge, on histamine- and carbachol-induced bronchoconstriction in healthy and in asymptomatic allergic bronchial asthma. The study was performed in a double-blind, randomized, placebo-controlled fashion, using a single oral dose of 60 mg of diltiazem. Airway reactivity to histamine and carbachol expressed by PD35SGaw was significantly but weakly attenuated by diltiazem in the asthmatic, but not in the normal subjects. Baseline lung function was not significantly influenced by diltiazem. We concluded that the effect of diltiazem on unspecific airway hyperresponsiveness in asthmatic subjects is too weak to justify a recommendation as therapy.

Vigorous respiratory therapy can prevent the development of postoperative pulmonary complications which occur with increased frequency after upper abdominal surgery. Obesity poses an additional risk factor. To study the effects of postoperative chest percussion with postural drainage (CPT), 53 consecutive patients undergoing Roux-en-Y gastric stapling procedures for treatment of morbid obesity were randomized to two groups. Both received identical postoperative respiratory care, except the study group received additional CPT. It was concluded that the addition of CPT to patients without prior chronic lung disease undergoing upper abdominal surgery caused patient discomfort, increased hospital cost, and failed to affect the incidence of postoperative pulmonary complications.

The efficacy of a new antiarrhythmic agent, lorcainide, was compared with that of quinidine gluconate in a fixed-dose, randomized, crossover trial. Of 26 previously untreated patients with frequent ventricular ectopic beats documented by 24-hour ambulatory monitoring, 17 completed four weeks of therapy with quinidine and 12 with lorcainide. Of 22 patients receiving both drugs, early termination of therapy due to side effects occurred in ten (45 percent) patients receiving lorcainide and five (23 percent) receiving quinidine. Lorcainide (100 mg twice daily or three times daily, dependent on body weight) effectively suppressed ventricular arrhythmias in seven of 12 (58 percent) patients completing four weeks of therapy, and suppression by quinidine gluconate (324 mg three times daily) occurred in five of 12 (59 percent) patients. We conclude that in a dose of 100 mg twice or three times daily, lorcainide is as effective as quinidine gluconate, 324 mg three times daily, for the suppression of chronic ventricular arrhythmias. However, the high incidence of adverse reactions experienced with lorcainide make it an unacceptable agent for first-line antiarrhythmic therapy.

We compared the efficacy of corticosteroid therapy initiated as an alternate-day regimen to that of a four-times-daily regimen in patients with stable chronic obstructive pulmonary disease. In this double-blind study, 44 patients with moderate to severe COPD (mean FEV1 740 +/- 310 ml) were hospitalized and randomly allocated to receive methylprednisolone, 8 mg qid, 64 mg qod, or placebo for a ten-day period. The mean FEV1 and FVC improved significantly to a comparable degree in both steroid-treated groups, but not in the placebo-treated group. Eight of the 29 steroid-treated patients (28 percent) had improved FEV1 of more than 25 percent compared with only one of the 15 placebo-treated patients. Those in the qod group also had notable improvement in SaO2. Although the correlation between the improvement after the administration of nebulized bronchodilators and that after corticosteroid therapy was significant, some patients had more than a 25 percent improvement in their FEV1 with corticosteroids, but less than a 10 percent improvement after nebulized bronchodilators. We conclude that a substantial proportion of all patients with stable COPD will have a greater than 25 percent improvement in their flow rates with corticosteroid administration. Since the response to a qod regimen is comparable to that of a qid regimen, and since the qod regimen is associated with fewer side effects, we recommend that a qod regimen be tried initially.

Twenty-eight patients with advanced emphysema and/or chronic bronchitis and severe airflow obstruction were randomly assigned to receive either bitolterol or isoproterenol aerosol delivered by a metered dose device which was administered three times daily. Randomization resulted in similar patients with like degrees of airflow obstruction and responsiveness to a test dose of inhaled bronchodilator. Significantly greater improvement in airflow was achieved by administration of bitolterol compared to isoproterenol. Pharmacologic responses continued after 90 days of daily dosing. Both drugs were well tolerated and side effects included mild degrees of tachycardia for both drugs. Two patients assigned to isoproterenol stopped therapy during the study due to side effects. This study indicates that bitolterol is more effective than isoproterenol in degree and duration of bronchodilatation in patients with advanced chronic obstructive pulmonary disease.

Lorcainide, a new type I antiarrhythmic agent, was compared to quinidine in respect to antiarrhythmic efficacy and clinical safety. Thirteen subjects completed an open, randomized, crossover study with analysis of 24-hour ambulatory ECG monitoring and drug blood levels. The QRS and Q-T intervals increased with both lorcainide and quinidine. The mean reduction in total ventricular premature beats (VPBs) with quinidine was 16 percent compared to 68 percent with lorcainide (p less than .05). With lorcainide eight of 13 subjects had a significant (greater than 82 percent) reduction in VPBs compared to only three of 13 subjects taking quinidine (p less than .05). This same relationship was observed when mean VPB/1,000 heartbeats was analyzed. Ventricular tachycardia was no longer present in five of nine subjects taking lorcainide and in two of nine taking quinidine. No relationship could be established between drug level and arrhythmia suppression in this small population. Some CNS effects were reported in both groups, but no significant hematologic, chemical, or urinary adverse effects were seen with either drug. Thus, lorcainide compares favorably to quinidine in regard to arrhythmia suppression, but was limited in its clinical utility by CNS side effects.

The Memorial Sloan-Kettering lung cancer screening program was begun in 1974 to evaluate sputum cytology as a supplement to the annual chest x-ray examination for early detection and diagnosis. The 10,040 adult, male cigarette smokers who enrolled were randomly assigned to receive annual chest x-ray examinations only or a dual screen with annual chest x-ray examination and four monthly sputum cytology evaluation. Over 40 percent of the 288 who developed lung cancer were diagnosed in stage I, and their survival was 76 percent at five years; overall survival was 35 percent. Nearly one third of the lung cancers detected on first examination on the dual screen, and 14 percent of those on subsequent examinations were found by cytologic examination. The same number of cancers developed in the x-ray screen only group, and were diagnosed at a later date. Despite the delay, survival and mortality were the same, suggesting that the squamous carcinomas detected by cytologic examination alone are very slow growing and tend to remain localized until detectable by x-ray examination.

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.

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.

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.

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 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.

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.

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.