Inhaled ipratropium bromide (IPR) is effective in the management of COPD. The purpose of this study was to determine if doubling the standard dose of IPR resulted in greater bronchodilation and if the addition of an inhaled beta-agonist was superior to standard dose IPR alone. Twelve male patients with stable COPD completed a double blind, randomized trial. On each of three consecutive days, following baseline spirometry, all patients inhaled two puffs of IPR. This was followed by either two additional puffs of IPR, two puffs of metaproterenol (META), or two puffs of placebo. All inhalants were delivered by an InspirEase spacer. Spirometry was repeated at 30, 60, 120, and 180 minutes. The group mean percentage increases in the FEV1 and FVC from baseline were similar at all times tested for the three protocols. In conclusion, for the group, there was no objective benefit to doubling the standard dose of IPR or combining IPR with META. Two of 12 patients benefited from combining the two bronchodilators. A potential sequence for bronchodilator testing is suggested.

The use of thrombolytic therapy to treat AMI has reawakened interest in thrombolysis for acute pulmonary embolism (PE). We have investigated the use of recombinant human tissue-type plasminogen activator (rtPA) in patients with acute PE. In an open label study, rtPA achieved more than 90% efficacy and safety. In a trial comparing rtPA with an FDA-approved dose of urokinase (UK), rtPA appeared more rapid and safer. We are now conducting a comparative trial of rtPA with a novel dosing regimen of UK. In addition, a concurrent trial is comparing rtPA vs heparin for improvement in right ventricular function, assessed by echocardiography, among PE patients. However, the greatest challenge in PE research is to undertake a large-scale trial that compares thrombolysis and heparin for reduction of clinically relevant end points such as mortality and recurrent PE.

During a recent one-year period, 44 clinical centers in the United States saw 2,539 patients with diagnoses of pulmonary embolism as supported by high probability lung scans and/or positive pulmonary angiograms. In developing proposals for a clinical trial of Thrombolysis in Pulmonary Embolism (TIPE), investigators in the 44 clinical centers reviewed the 2,539 patients' medical charts for contraindications to thrombolytic therapy. Overall, 1,345 (53.5%) patients surveyed in the TIPE clinical centers would have been acceptable for treatment with thrombolytic therapy, a proportion higher than generally anticipated. Risks of major blood loss were the most frequent contraindications to thrombolytic therapy and were found in 838 (33.3%) patients. Risks to the CNS were found to contraindicate thrombolytic therapy in 453 (17.9%) patients. Risks of bleeding into special compartments were found to contraindicate thrombolytic therapy in 76 (3.0%) patients. Pulmonary embolism is underdiagnosed in most clinical settings, and even more patients than found in the TIPE survey could benefit from appropriate diagnosis and treatment. The question remains as to whether pulmonary embolism patients will benefit from thrombolytic therapy. Only a randomized clinical trial will provide a satisfactory answer.

Despite enthusiasm for using thrombolytic therapy to treat proximal deep venous thrombosis (DVT), the proportion of patients eligible for this therapeutic strategy is unknown. Therefore, we screened all patients at Brigham and Women's Hospital who underwent leg venography in 1987. Of 240 patients with suspected DVT, 87 (36%) had positive venograms. Of those with positive venograms, 72 (83%) had proximal DVT, and 15 (17%) had DVT limited to calf veins. Overall, 22% of patients with proximal DVT were eligible for thrombolytic therapy. The major exclusion criteria were: (1) recent trauma or surgery, (2) recent GI bleeding, and (3) history of a bleeding disorder. Thus, thrombolytic therapy could be given to approximately one-fifth of our patients with proximal DVT.

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.

Thrombolysis is well established as effective therapy in AMI. Two thrombolytic agents, streptokinase and tissue plasminogen activator (tPA), are now widely available for clinical use. These agents have different effects, and there has been considerable debate as to which is superior. Both are effective in preserving myocardial function and reducing mortality. However, the confidence limits of these findings overlap, and no firm conclusions can be made from comparing trials enrolling different populations with different baseline characteristics and ancillary treatments such as angioplasty. There have been few "head-to-head" comparisons. These trials show that tPA achieves better lysis rates than streptokinase, but the theoretic advantage of fibrin specificity does not result in fewer adverse effects or greater preservation of LV function. Although each drug may have specific indications, the drugs appear similar in clinical benefit, and further comparison trials are required.

Serious respiratory depression has been described in COPD patients receiving hypnotics during acute exacerbations. There are few studies quantifying the effects of hypnotics on oxygenation during sleep in patients with stable hypoxemic COPD. In this study, the effects of single therapeutic doses of nitrazepam and flunitrazepam on SaO2, apneas during sleep and other sleep variables were measured in 14 COPD patients. All patients used theophylline. Sleep-induced decrease in mean SaO2 was 1.3 percent after placebo, 1.4 percent after nitrazepam and 1.9 percent after flunitrazepam (no significant differences). Sleep apneas were not more common or longer after nitrazepam or flunitrazepam, but sleep quality seemed to improve. It is concluded that oxygenation during sleep in these nonobese patients with stable hypoxemic nonhypercapnic COPD, all on maintenance theophylline therapy, was affected very little by single therapeutic doses of nitrazepam or flunitrazepam.

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.

Ten patients with CF who were more than 18 years old, participated in a double-blind, placebo-controlled study evaluating the efficacy of inhaled ipratropium bromide and metaproterenol as bronchodilators. The mean FEV1 of the group improved 17.1 percent after treatment with ipratropium bromide, 12.5 percent after metaproterenol treatment, and 16.6 percent after treatment with both of these medications together. There was no significant difference between these responses and patients who responded to one treatment tended to respond to the others. The side effects with these medications were minimal. When compared with patients in previous studies, our patients, who were much older as a group, demonstrated a greater degree of bronchodilation with ipratropium bromide and metaproterenol, as well as a greater degree of bronchoconstriction with placebo.

Rapid exposure of unacclimatized persons to high altitude causes the syndrome acute mountain sickness (AMS). Prophylactic treatment with frequent high doses of dexamethasone has been shown to prevent AMS. To determine whether lower, less frequent doses were effective in preventing AMS, 28 men between the ages of 18 and 32 were exposed to a simulated altitude of 4,570 m for 45 h in a hypobaric chamber on two occasions while taking one of three doses of dexamethasone (4 mg, 1 mg, or .25 mg every 12 h) or a placebo in a double-blind, crossover design. The 4-mg dose of dexamethasone reduced the incidence of AMS symptoms compared with placebo and the other dose levels. Dexamethasone did not alter fluid balance or plasma volume changes, but treatment with 1 mg and 4 mg suppressed cortisol secretion. There was no evidence of adrenal cortical suppression after treatment with dexamethasone or placebo 48 h after discontinuing altitude exposure and drug treatment. The results indicate that 4 mg of dexamethasone twice daily is an effective prophylactic treatment for AMS, while lower doses are relatively ineffective.

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.

The effects of two cardioselective beta-adrenergic blocking agents--celiprolol (claimed to have bronchodilator properties) and atenolol (without such claims)--on respiratory function and control of asthma were studied in ten asthmatic patients with mild to moderate essential hypertension. Following a beta-2 agonist-free period of ten hours, administration of 100 mg of atenolol was associated with bronchoconstriction (p less than 0.05), whereas 400 mg of celiprolol was not. Responsiveness to beta-2 agonist therapy was retained with both agents (p less than 0.05). Day-to-day asthma control, interpreted from patient recordings of peak flow, inhaler use and symptom scores, were all no different on either agent from placebo. When given acutely, celiprolol appeared to have acute bronchosparing properties, possibly providing a greater margin of respiratory safety than atenolol.

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.