Intravenous rtPA (total dose, 100 mg over 3 h) was compared with placebo in a prospective, randomized, double-blind trial in 5,011 patients with suspected AMI of less than 5 h duration. No ECG or enzymatic confirmation of the diagnosis was required for study entry. At 1 month 9.8% of patients given placebo had died compared with 7.2% of those who received rtPA (2.6% actual reduction, 26% relative reduction, with 95% confidence intervals of 11-39%). The majority of deaths occurred in patients who had an in-hospital diagnosis of MI (72% in both groups), with a 1-month infarct mortality of 13.1% in the placebo limb and 9.4% in the rtPA limb (relative reduction 28%, 95% CI, 14-41%). Approximately 18% of patients in both groups had a normal ECG on entry to the trial, and at 1 month the fatality was 1.6% in the rtPA group and 3.0% in the placebo group. Treatment with rtPA did not reduce the number of patients with normal ECGs from developing MI (28% rtPA vs 24% placebo). Treatment with rtPA was associated with significantly more bleeding episodes, the vast majority of which were clinically minor. The risk of all strokes in the rtPA group was similar to that in the placebo group (1.1% vs 1.0%). Treatment with rtPA was unaccompanied by either allergic or hypotensive episodes, and, among rtPA treated patients, there was no increase in clinically important ventricular dysrhythmias. Neither age nor time from onset of symptoms reduced the benefit from rtPA.

The purpose of this study was to determine if there is a relationship between improvement in exercise capacity with supplemental oxygen and the magnitude of hypoxic ventilatory drive in patients with CAO. We hypothesized that those patients with the highest hypoxic drives would be the most likely to have increased exercise tolerance with supplemental oxygen. Seventeen patients with CAO (mean FEV1 = 0.99 +/- 0.45 L) underwent identical maximal cycle ergometry exercise tests on two occasions 45 minutes apart while breathing either air or 30 percent oxygen in a randomized single-blind fashion. With supplemental oxygen, the ventilation decreased and the PaCO2 increased significantly at rest. The patients had a significantly greater exercise tolerance on supplemental oxygen (76.7 vs 69.1 watts, p less than 0.005) but no increase in the maximal ventilation. When the nine patients who improved were compared to the eight patients who did not improve, the two groups were basically identical. Specifically, there were no significant differences in the mean ventilatory or mouth occlusion responses to hypoxia or in the blood gases. The patients who did improve tended to have a greater reduction in their ventilatory response to exercise while exercising on oxygen as compared to when they were exercising on room air. From this study, it was concluded that measurements of hypoxic ventilatory drive are not helpful in predicting which patients with CAO are likely to have improved exercise capability while breathing supplemental oxygen.

We conducted a randomized, controlled double-blind study to determine whether intravenous administration of methylprednisolone early in the therapy for acute exacerbations of COPD would improve pulmonary function in the Emergency Department and reduce the need for hospitalization. Ninety-six patients completed the study. All were at least 50 years of age and had no history of asthma. Patients received aminophylline and hourly administration of aerosolized isoetharine. Methylprednisolone (100 mg) or physiologic saline solution was given within one-half hour of arrival in the Emergency Department. Spirometry was performed initially and after the third and fifth aerosol treatments. We found no greater improvement in FEV1 in the group receiving the steroid (37 percent) than in the control group (43 percent; NS). There was also no difference in the rate of hospitalization (33 percent in the steroid-treated group vs 30 percent in the control group; NS). We conclude that early administration of methylprednisolone does not affect the emergency phase of treatment for acute exacerbations of COPD.

To determine whether nasal oxygen therapy at 2 L/min would (1) reverse nocturnal hypoxemia and (2) improve neuropsychologic function in men who snore heavily.

We investigated the effect of small inspiratory resistive loads on the breathing patterns of patients with COPD admitted to the ICU for acute respiratory failure. Patients were in stable clinical condition three days after weaning from the acute-phase ventilation. Healthy nonsmokers served as controls. Breathing patterns were recorded for 20-min periods during unloaded breathing (R0), then with small inspiratory resistive loads (R1 = 2.5 cmH2O L/s and R2 = 5.2 cmH2O L/s) applied in random order. Respiratory parameters were memorized in real time and blood gases measured continuously with a transcutaneous PO2/PCO2 monitor and compared periodically with arterial blood gases. Minute volume (VE) and respiratory rate decreased with no modification in blood gas values. In the COPD patients, R1 was too small to be perceived; when R2 was applied, no increase in TI was observed, and VT and VT/TI decreased. The VE could not be maintained despite a shortening of expiratory time. The COPD patients did not have significant increase of occlusion pressure (P0.1). Mean blood gas values did not change during the testing, but the coefficient of variation of tcPCO2 increased. During the critical period following weaning from artificial ventilation, COPD patients did not respond in the same manner as normal subjects to inspiratory resistive loads, but did not have modified gas exchange during the 20-min period.

At the onset of exercise, both cardiac output and ventilation increase abruptly. We investigated the hypothesis that a rapid change in cardiac output, as effected by an immediate increase in heart rate at the start of exercise and a decrease in heart rate at the termination of exercise, affects the responses of oxygen uptake. Five patients in whom programmable pacemakers had been previously inserted for complete heart block were studied. Responses in ventilation and gas exchange were recorded breath by breath during studies in which each subject performed 16 transitions between rest and moderate exercise on a cycle ergometer. In a randomized fashion, in half of the transitions, heart rate was accelerated from a low rate to a high rate as exercise began; in the other half, heart rate was held constant at the low rate as exercise began. Oxygen uptake increased by 30 percent in the first 20 seconds of exercise, when heart rate was constrained, while it increased by 70 percent when heart rate was abruptly accelerated. Similarly, smaller changes were observed at the cessation of exercise when the heart rate was constrained, as compared to an abrupt decrease in heart rate. Despite this difference in the responses of oxygen uptake, at the transitions in exercise, the ventilatory responses were indistinguishable. We have demonstrated that ventilation-independent changes in oxygen uptake can be induced at the onset and cessation of exercise. These alterations in oxygen uptake are predictable from differences in blood flow which occur as a consequence of the differences in time course of the heart rate.

Survivors of high-risk surgical operations were previously observed to have significantly higher mean CI, DO2, and VO2 than nonsurvivors. The hypothesis was proposed that increased CI and DO2 are circulatory compensations for increased postoperative metabolism. We tested this hypothesis in two series. In series 1, prospectively allocated by services, mortality and morbidity of the control group were significantly greater than those of the protocol group. In series 2, patients who fulfilled previously defined high-risk criteria were preoperatively randomized to one of three monitoring/treatment groups: CVP-control group, PA-control group and PA-protocol group. Postoperative mortalities in the CVP-control and PA-control groups were not statistically significantly different, but PA-protocol group mortality was significantly reduced compared with its control group. The PA-protocol group had reduced complications, duration of hospitalization, duration in ICU, and mechanical ventilation, and reduced costs when the PA catheter was placed preoperatively and used to augment circulatory responses.

A prospective, double-blind, randomized study of the role of corticosteroids in the treatment of tuberculous pleurisy was performed in 40 patients. All patients received adequate antituberculosis chemotherapy (isoniazid, 300 mg/day; rifampin, 450 mg/day; ethambutol, 20 mg/kg/day) for more than nine months. They were randomly assigned to take prednisolone 0.75 mg/kg/day orally or placebo for the initial treatment, which was tapered gradually for the next two to three months. Twenty-one were treated with steroids and 19 were given a placebo. The two groups were identical with regard to age, sex, duration from onset of symptoms to diagnosis, and initial amount of pleural effusion. The mean duration from symptoms (fever, chest pain, dyspnea) to relief was 2.4 days in the steroid-treated group, and 9.2 days in the placebo group (p less than 0.05). Complete reabsorption of pleural effusion occurred an average of 54.5 days in the steroid-treated group and 123.2 days in the placebo group (p less than 0.01). The development of residual pleural thickening was not influenced by the administration of corticosteroids. No serious side effects were noted during the treatment in either group. We conclude that the administration of corticosteroids, in conjunction with antituberculosis chemotherapy, will resolve the clinical symptoms more quickly and hasten the absorption of pleural effusion in patients with tuberculous pleurisy.

The effect of a new H2-antagonist, famotidine, on theophylline pharmacokinetics was compared with placebo and cimetidine in 26 patients affected by COPD. Cimetidine, placebo, and famotidine were administered, four days each drug at random, to all the subjects. Results suggest that famotidine, contrary to cimetidine, does not influence theophylline metabolism in man.

Since parenteral beta 2-adrenergic stimulation can induce hypokalemia, we postulated that administration of beta 2 adrenoreceptor agonists by inhalation could induce the same. We administered the usual clinical doses of three commonly used bronchodilators to each of six subjects receiving assisted mechanical ventilation in line with the ventilator: two beta 2-adrenoreceptor agonists, metaproterenol, 5 percent solution, and isoetharine, 1 percent solution; and the anticholinergic agent atropine as a control. Each bronchodilator was nebulized over 10 to 15 minutes in random order, four hours apart, and given to every subject. Plasma potassium was measured at five-minute intervals and arterial blood gases at 15-minute intervals, for a total of 50 minutes after administration of each bronchodilator. Following administration of each drug, plasma potassium showed an average decline. The mean decline in plasma potassium from baseline was statistically significant for metaproterenol (p = 0.04) and atropine (p = 0.001) but not for isoetharine (p = 0.09). Although there were no statistically significant differences among the declines in plasma potassium induced by the three drugs, metaproterenol caused the greatest decline (-0.6 mEq/L).

To compare intravenous and orally administered corticosteroids and theophylline in treating acute episodes of airways obstruction, patients with recent worsening of obstructive symptoms were randomly divided into two groups. Group A received methylprednisolone, 80 mg/24 h, and aminophylline by continuous infusion. Group B received a comparable dose of a sustained-release theophylline and methylprednisolone, 80 mg in two equally divided doses, by mouth. Assessment of response was based on daily spirometric tests and evaluation of dyspnea and wheezing. Arterial blood gas and serum theophylline levels were also measured. The groups were comparable with respect to age, sex distribution, smoking history, and spirometric evidence of obstruction. Initial spirometric test results showed moderate obstruction, equal in the two groups. Obstruction improved markedly by both spirometric and clinical criteria in the four-day study period. The improvement in FEV1 and dyspnea index was slightly greater for group B, but the differences were not significant. We conclude that oral administration of steroids and theophylline is as effective as intravenous use in treating hospitalized patients with moderate exacerbations of airways obstruction.

In a double-blind randomized trial, 40 patients with acute severe asthma were given either nebulized salbutamol, 5 mg, or salbutamol, 5 mg mixed with ipratropium bromide 500 micrograms, on admission to hospital and again two hours later. There was no significant difference between the mean peak flows of the two treatment groups at any time. However, two hours after each treatment, there were fewer subjects in the ipratropium and salbutamol group whose peak flow rates had fallen back toward baseline levels than in the salbutamol only treatment group. Thus, although ipratropium did not improve the overall maximal bronchodilator response, it may have prolonged the duration of the response, which would be a clinically useful effect.

In a prospective randomized trial, we examined the value of routine postlobectomy fiberoptic bronchoscopy (FOB) in preventing postoperative atelectasis. Twenty patients who underwent lobectomy were randomly assigned to either chest physical therapy alone (group 1) or immediate bronchoscopy (group 2). Both group 1 and group 2 were placed on a standard physical therapy regimen consisting of aerosol bronchodilator therapy, chest percussion, and incentive spirometry. It was concluded that routine postlobectomy bronchoscopy offers no advantage over the usual physical therapy measures in preventing the development of postoperative atelectasis.

Fifty patients with malignant pleural effusion were randomized to receive one or two doses of tetracycline sclerotherapy. We found that a single sclerotherapy treatment with tetracycline at a dose of 20 mg/kg was as effective as two sclerotherapy treatments and provided symptomatic relief in 46 of the 50 patients.

We verified the utility of an oxygen economizer (Pendant Oxymizer) in assuring greater protection than nasal prongs against worsening of oxyhemoglobin resting desaturation (delta SaO2) induced by muscular exercise in 16 patients (ten with chronic obstructive pulmonary disease [COPD] and six with restrictive pulmonary disease). This worsening was quantified as desaturation surface accumulated within five minutes of exercise and was expressed in arbitrary units (au). Each patient carried out the same exercise three times, in a randomized fashion (breathing air or breathing supplemental oxygen [3 L/min] delivered by either nasal prongs or by oxygen economizer). In patients with obstructive disease, delta SaO2 was reduced from 38 +/- 12.0 au when they were breathing air to 18.1 +/- 11.7 au when breathing oxygen by nasal prongs (p less than 0.001) and to 10.1 +/- 9.5 au when breathing oxygen by economizer (p less than 0.001). In patients with restrictive disease, delta SaO2 was reduced from 35.6 +/- 9.9 au when breathing air to 14.9 +/- 10.2 au breathing oxygen by nasal prongs (p less than 0.01) and to 13.7 +/- 10.3 au breathing oxygen by economizer (p less than 0.01). The difference between breathing by economizer and nasal prongs was significant (paired t-test; p less than 0.01) only in patients with COPD. One explanation could lie in the different values of the respiratory rate, which was significantly greater in patients with restrictive disease (20.7 +/- 1.2 breaths per minute at rest and 25.8 +/- 1.5 with exercise) than in patients with obstructive disease (15.3 +/- 1.2 breaths per minute at rest and 20.8 +/- 1.4 with exercise).

We have studied the antitussive effects of two anticholinergic agents, oxitropium bromide (200 micrograms) and ipratropium bromide (80 micrograms), and a combined beta-agonist and anticholinergic preparation containing fenoterol hydrobromide (200 micrograms) and ipratropium bromide (80 micrograms), in 16 normal and ten asthmatic volunteers in a double-blind, randomized, placebo-controlled crossover trial. Cough was induced by inhalation of ultrasonically nebulized distilled water and hypotonic saline solution. All treatments significantly reduced the cough response to inhaled distilled water aerosol when compared with placebo (p less than 0.001). There was no difference between oxitropium bromide and ipratropium bromide (p greater than 0.05), but the combination preparation displayed a greater antitussive effect than either oxitropium bromide (p less than 0.05) or ipratropium bromide (p less than 0.025). Cough frequencies in response to hypotonic 0.18 and 0.32 percent saline aerosol were lower than those obtained with distilled water (p less than 0.005) for all treatments. Asthmatic patients coughed less frequently than normal volunteers in response to all solutions when placebo was given (p less than 0.05), but there is no evidence to suggest that the response to treatment was different in the two groups. Our results suggest that inhaled anticholinergic bronchodilators alone or in combination with beta 2-adrenergic agonists might be effective in the treatment of pathologic cough.

Twenty seven healthy individuals were divided randomly into three groups. The first group of nine subjects received only a routine bronchoscopic examination. The second group of nine subjects was examined with the bronchoscope followed by bronchoalveolar lavage (BAL) with 200 ml of 25 degrees C normal saline solution. The third group of nine subjects received a bronchoscopic examination followed by BAL, but with 200 ml of 37 degrees C normal saline solution. Examination in all groups included arterial blood gas (ABG) analysis and pulmonary function test (PFT), both pre- and post-procedure. In group 1 there was no statistical difference in the pulmonary function test result after routine bronchoscopic examination except for decrease in PaO2. The results in group 2 showed a statistical difference in both ABG and PFT data, especially PaO2, FEF 200-1200, FEF25%-75%, FEF25%, FEF50%, and FEF75%. In group 3, there was a significant decrease of PaO2 and no significant difference in PFT before and after BAL. From these data we conclude that BAL is a safe examination. However, the administration BAL fluid (BALF) with 25 degrees C normal saline solution can affect the results of the PFT significantly. Much of this adverse reaction can be minimized by using body temperature (37 degrees C) saline solution. At 37 degrees C, the ABG data showed a decrease in PaO2, but pulmonary function was not affected significantly.

We studied the effects of oral nutritional supplementation on respiratory muscle (RM) performance in 25 ambulatory patients with severe chronic obstructive pulmonary disease (COPD). There was a relationship between body weight and anthropometric parameters of nutritional status (triceps skinfold thickness [r = 0.67; p less than 0.005], midarm muscle circumference (r = 0.53; p less than 0.005), but body weight did not correlate with daily caloric intake, serum albumin, transferrin, or blood lymphocyte count. None of these measurements of nutritional status correlated with any measure of RM strength or endurance. In a randomized observer-blinded crossover trial, patients were allocated to one of two groups. In the first eight weeks of the study, group A received nutritional supplementation, and patients in group B were control subjects. In the second eight weeks, patients in group A were control subjects, and group B received supplement. Mean daily caloric intake and body weight increased in both groups while receiving supplement (both p less than 0.05). Calories provided by the supplement were frequently substituted for normal dietary calories. Any increases in RM performance in the group receiving supplement were matched by increases (due to learning) in controls. We conclude that oral dietary supplements have no important effects on RM performance in ambulatory patients with COPD.

A cooperative, prospective, randomized study to evaluate the effectiveness of preoperative irradiation in curatively resected esophageal carcinoma was performed in 364 cases in eight institutions from August 1982 to November, 1983. Based on the survival curves, postoperative irradiation alone was superior to preoperative plus postoperative irradiation. Because of the progression of the disease and complications after operation, there were many inevaluable cases in this study. However, analysis revealed there was no bias caused by a greater number of unfavorable patients being selectively included in inevaluable cases in the postoperative irradiation only group. Our data question the value of preoperative irradiation being performed in addition to resection plus postoperative irradiation.

In the absence of clinical trials, positive end-expired pressure (PEEP) has been accepted as efficacious for treatment of postoperative decreases in arterial oxygen tension (PaO2) from a variety of causes including adult respiratory distress syndrome (ARDS). PEEP is thought to increase PaO2 by alveolar recruitment, which in turn, has been hypothesized to play a decisive role in pulmonary recovery. One hundred and eighteen patients were followed prospectively, and after development of decreased PaO2, randomized to receive recruitive PEEP (determined by blood gas criteria) or supportive PEEP (the minimal PEEP required to maintain PaO2 above 60 mm Hg on .5 inspired O2 fraction (FIO2). No prognostic factors were significantly different between the two groups. Recruitive PEEP application in 22 patients yielded a significantly increased incidence of hypotension (55 percent), pneumothorax (20 percent), and death during treatment (27 percent) when compared to the 28 supportive PEEP patients who had no hypotension or pneumothorax and only one death during treatment (4 percent). After PEEP treatment, deaths in each group were similar (19 percent and 15 percent, respectively). We find no evidence that PEEP treatment promotes beneficial outcomes and conclude that recruitment attempts may be harmful.