Breathing patterns in six normal awake subjects were monitored noninvasively during progressive hypoxia accomplished with the administration of nitrogen at 2, 4, 6, and 8 L/min by nasal cannula. The lowest value of arterial oxygen saturation (SaO2) of 88 +/- 4 percent (mean +/- SD) was achieved with nitrogen at 8 L/min. At baseline, tidal volume (VT) and frequency were fairly regular; with nitrogen at 2 and 4 L/min, some subjects showed minor fluctuations of VT. At 6 and 8 L/min, periodic breathing with marked oscillations of VT, apneas, hypopneas, and intermittent large tidal breaths were consistently observed. Inspired oxygen concentration fluctuated because of the variations of tidal breaths provoked when periodic breathing took place and enhanced fluctuation in SaO2. A randomized, double-blind crossover design was used to assess the effect of pretreatment with naloxone on this periodicity. In contrast to the irregular breathing pattern observed with pretreatment with placebo, the breathing pattern after pretreatment with naloxone was regular during nasal administration of nitrogen except at 8 L/min, when minor fluctuations in VT with occasional hypopneas and large tidal breaths occurred. On another day, irregular and periodic breathing with apneas or hypopneas (or both) produced by nasal nitrogen at 8 L/min was eliminated or blunted by short-term intravenous administration of naloxone. On another day, electroencephalographic monitoring corroborated visual observations made in the previous studies that the hypoxic subjects were awake during the breathing alterations. Thus, awake adults develop irregular and periodic breathing during induction of mild hypoxia produced by nasal administration of nitrogen. The irregularity in breathing appears to be mediated through release of endorphins, since the effect is blunted or eliminated by pretreatment or short-term treatment with naloxone.

The aim of this study was to investigate the effects of nebulized ipratropium in patients with acute asthma in order to determine whether it augments the bronchodilator effect of a beta agonist drug. A total of 28 patients with acute asthma were randomly allocated to treatment every six hours with either 1 mg nebulized fenoterol (group A) or 1 mg fenoterol and 0.5 mg ipratropium (group B). There was no significant difference between the mean FEV1 of the two groups prior to treatment and increasing the dose of fenoterol from 1 mg to 2 mg did not increase the response. However the mean change in FEV1 after 48 hours (expressed as a percentage of the predicted maximal response) was 40.1 +/- 7.2 percent in group A and 54.3 +/- 9.2 percent in group B (p less than 0.005). It was concluded that the response of patients with acute asthma to fenoterol was significantly enhanced by the addition of the anticholinergic agent ipratropium bromide.

To assess the effect of conventional chest physiotherapy and mechanical chest vibration on arterial blood gas levels, spirometry, and sputum production, we studied 20 stable outpatients with chronic obstructive lung disease. All patients had severe obstructive ventilatory defects with a mean FEV1/FVC ratio of 30 percent and all produced moderate amounts of sputum. Patients were randomized and received chest physiotherapy or mechanical vibration for 20 minutes. Arterial blood gas levels and spirometry obtained 20 minutes and 40 minutes after completion of the treatment did not show any significant change compared to the baseline. We conclude that neither chest physiotherapy nor chest mechanical vibration improved gas exchange, flow rates, or clearance of secretions in stable outpatients with severe chronic obstructive lung disease.

The efficacy of propafenone hydrochloride, a new antiarrhythmic agent, was evaluated in the treatment of chronic stable ventricular arrhythmias. Twenty-five patients who had suffered a myocardial infarction three months or longer before the trial were studied. All exhibited a minimum mean frequency of 30 ventricular ectopic beats per hour over at least two 24-hour Holter monitoring periods with the last recorded tape serving as a control. The mean decrease in ventricular ectopic activity with propafenone was 65.62 percent (p = less than 0.001). Side effects were infrequent, minimal, and of no clinical consequence. Oral propafenone was found to be an effective drug for reducing the level of chronic ventricular ectopy, as reflected by a short-term trial.

Ninety patients with stage-3 non-small cell lung cancer were given vindesine (3 mg/sq m) plus mitomycin (10 mg/sq m). Data on response are available for 84 adequately treated individuals (93 percent). For patients who had received no prior chemotherapy, the rate of major objective response was 36 percent (20/55). For previously treated patients the rate of major response was 17 percent (5/29). The drugs were routinely administered in the outpatient department without difficulty. Moderate or severe myelosuppression, neurotoxic, nephrotoxic, or pulmonary toxic effects, nausea, and vomiting occurred in less than 15 percent of all studied patients. Three-drug extravasation ulcerations occurred in 1,129 administrations of chemotherapy (0.3 percent). There were two treatment-related deaths, one from sepsis and one from the combination of mitomycin-induced pulmonary and renal toxic effects. The combination of vindesine plus mitomycin is an active, well-tolerated outpatient regimen for patients with non-small cell lung cancer who have not previously received chemotherapy. Further trials are warranted to compare this regimen to other active combinations and to use it as a component of a program of treatment using alternating regimens of chemotherapy.

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.

Atopic asthma is associated with diminished cell-mediated immunity and elevated levels of IgE, both of which may be caused by imbalances of T-lymphocyte subsets. We analyzed the response of peripheral blood T-cell subsets to two commonly used corticosteroid preparations as a probe of T-cell subset regulation. We administered prednisone (P) 60 mg or 20 mg, beclomethasone dipropionate (BDP) aerosol, 336 micrograms, placebo, or BDP vehicle in a double-blind protocol to 15 atopic asthmatic patients and ten nonatopic subjects. No difference was found between the groups of the baseline number of T-cells with T4, T8, M1, and Ia antigens, nor the ratio of T4+ (helper) to T8+ (suppressor) cells. Five hours after administration of BDP aerosol, BDP vehicle, and oral placebo, there was no change of these values in either the atopic or in the nonatopic group. In contrast, P, 20 and 60 mg, caused a fall of T4/T8 ratio in the atopic, but not in the nonatopic population. Atopic asthma is not associated with baseline imbalances of peripheral blood T-cell subsets, but is associated with an abnormal response to systemic, but not inhaled corticosteroid.

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.

A metered-dose aerosol formulation of terbutaline sulfate (Brethaire), 0.400 mg four times daily, was compared with an identical formulation of isoproterenol sulfate, 0.150 mg four times daily, in a parallel, double-blind, clinical study completed by 40 adult patients with asthma. All patients had been stabilized on theophylline (serum levels of 10 to 20 micrograms/ml). The effectiveness of isoproterenol peaked between 5 and 15 minutes after administration. The effectiveness of terbutaline peaked between 5 and 120 minutes after administration. In each of five visits spaced over a three-month period, patients receiving terbutaline showed a longer duration of bronchodilatory effect than those receiving isoproterenol, with the greatest difference occurring at 60 and 120 minutes after drug administration.

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.

Autopsy findings and a morphometric study of the lungs were compared in 18 subjects receiving nocturnal oxygen and 15 receiving continuous oxygen in the National Heart, Lung, and Blood Institute Nocturnal Oxygen Therapy Trial (about half of those who died). The emphysema score, average interalveolar wall distance, central airway lesions, peripheral airway lesions, and the ratio of weights of left ventricle plus septum to right ventricle were similar in the two groups. The causes of death in the two groups were also similar. This evidence supports the hypothesis that the improved prognosis observed with continuous oxygen therapy nocturnal oxygen therapy in patients with severe chronic airflow obstruction and hypoxemia was due to treatment. There was a trend for there to be more interstitial fibrosis and type 2 alveolar epithelial cell hyperplasia in those treated with nocturnal oxygen; in the hands of one observer, the type 2 cell hyperplasia was significant.

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.

Twenty-one patients with stable chronic obstructive pulmonary disease (mean FEV1 = 0.98 L) and high-normal serum theophylline levels (15-20 micrograms/ml) were evaluated in a randomized, double-blind fashion for additional bronchodilator response to aerosolized normal saline, atropine, or metaproterenol. Patients were classified as responders (R; n = 9) or nonresponders (NR; n = 12) to inhaled isoproterenol when they were taking no medications. Atropine and metaproterenol caused a significant additional increase in FEV1 for R (p less than .05), whereas only atropine resulted in a significant increase for NR (p less than .05). For R, the increase due to atropine was significantly greater compared to metaproterenol (p less than .05). We conclude that inhaled atropine (an anticholinergic drug) may be preferable to inhaled metaproterenol (a beta-adrenergic agonist) when additional bronchodilation is needed in patients with chronic obstructive pulmonary disease and high-normal serum theophylline levels.