Bronchodilator responses to both nebulized albuterol (salbutamol) and ipratropium bromide and aerosol delivery to the tracheobronchial tree have been assessed in eight patients with chronic stable asthma (mean baseline FEV1, 50 percent; reversibility greater than 20 percent). Two commercially available nebulizer systems were used, namely, a Turret nebulizer operated at a compressed gas flow rate of 12 L/min (droplet MMD, 3.3 mu) and an Inspiron nebulizer driven at 6 L/min (MMD, 7.7 mu). Albuterol was given as doses of 250 micrograms, 250 micrograms, 500 micrograms, and 1,000 micrograms (cumulative dose, 2 mg) and ipratropium bromide as doses of 50 micrograms, 50 micrograms, 100 micrograms, and 200 micrograms (cumulative dose, 400 micrograms) at intervals of 35 minutes. For albuterol, bronchodilatation was significantly (p less than 0.05) greater at all dosage levels with the Turret. For ipratropium, bronchodilatation was similar for both nebulizers. Measurements of aerosol deposition using 99mTc-labelled pentetic acid (diethylenetriamine pentaacetic acid; DTPA) showed that 9.1 +/- 1.1 percent and 2.7 +/- 0.2 percent of the dose reached the lungs during nebulization to dryness for Turret and Inspiron, respectively (p less than 0.01); distribution within the lungs was similar for the two aerosols. Selection of nebulizer apparatus can influence delivery of aerosol and subsequent bronchodilator response to albuterol in patients with chronic stable asthma but is less important for aerosol delivery of ipratropium bromide in these patients.

A randomized, double-blind, crossover study was conducted to assess the efficacy of five weeks' treatment with terbutaline, 15 mg daily, compared with placebo in 17 evaluable patients with moderate to severe chronic airflow limitation (CAL) with a minor reversible component. A significant improvement after terbutaline treatment compared with placebo was observed in subjective assessments of breathlessness after two of the activities of daily living, and in daily peak flow measurements recorded in patient diaries. At the clinical assessment after five weeks' terbutaline therapy, 12 of 17 patients had improved pulmonary symptom scores compared with placebo, and a slight increase in FEV1 was observed relative to placebo (0.09 L, p less than 0.05). Thus, five weeks' treatment with oral terbutaline in patients with CAL resulted in significant improvements in several subjective assessments, despite a lack of effect on the majority of the objective variables.

The aim of this study was to investigate whether ACE-inhibitors could influence bronchial reactivity and interfere with inflammatory skin responses. Ten hypertensive subjects, who had reacted with coughs during ACE-inhibitor therapy, were treated in a double-blind crossover fashion for two weeks with enalapril and with placebo. Enalapril reduced the PC20 value for histamine and augmented the dermal response. Circulating eosinophilic leukocyte level in venous blood dropped markedly after the histamine bronchoprovocation performed during enalapril treatment. Plasma substance P was reduced after histamine provocation performed during placebo treatment, whereas this reduction was abolished by enalapril. In this study, we have demonstrated ACE-inhibitor-induction of moderately increased bronchial reactivity in subjects with suspected ACE-inhibitor-elicited coughs. It is suggested that coughing during ACE-inhibitor therapy is due to an increased inflammatory state in the airways.

The bronchodilator response to metaproterenol delivered by metered-dose inhaler (MDI) with a spacer device (Aerochamber [A]) and by jet nebulizer was studied in 44 asthmatic patients who presented to the emergency department with acute severe (FEV1 less than 50 percent predicted) airflow obstruction. The delivery method was randomized, double-blinded and placebo controlled. The A group received one puff of metaproterenol every five minutes for a total of three puffs (1.95 mg). The jet nebulizer group received 15 mg of metaproterenol by continuous nebulization over ten minutes. Only about 2.75 mg of the original 15 mg delivered by jet nebulizer was calculated to be available for inhalation due to the inefficiencies of the delivery system. The mean percentage of improvement in FVC and FEV1 in the A group was 33.5 and 49.0 percent, respectively. The mean percentage of improvement in FVC and FEV1 in the jet nebulizer group was 22.8 and 33.0 percent, respectively. There was no significant difference in the mean percentage of improvement values between the two groups. We were unable to demonstrate a difference in bronchodilator response to metaproterenol delivered by MDI-A and jet nebulizer in emergency department asthmatics with acute severe airflow obstruction.

Thrombolytic therapy in AMI restores infarct artery patency, preserves LV function, and decreases hospital mortality. Although hemorrhagic complications including stroke can occur, the incidence of stroke is not increased compared with control groups. Aspirin must be administered as soon as possible to inhibit platelet function, and an adjunctive role for early beta-blocker therapy may be important. Acute cardiac catheterization and coronary angioplasty need not be routinely performed in stable patients after tPA therapy, but should be considered in unstable patients. Two trials suggest that aggressive use of coronary angioplasty or bypass graft surgery before hospital discharge to preserve infarct artery patency and to prevent postinfarction ischemia is associated with an important improvement in long-term prognosis. Thrombolytic therapy should be considered standard care for patients whose ischemic chest pain lasts 20 min to at least 6 h in duration and who have an injury current on their ECG unless they are at increased risk for bleeding. The need for and timing of cardiac catheterization, coronary angioplasty, and surgical revascularization after AMI requires further evaluation.

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.