Patients with nocturnal asthma have their lowest pulmonary function and lowest serum epinephrine level at 4 to 6 AM. We studied a new long-acting beta-adrenergic agonist, procaterol, in ten patients with nocturnal asthma. The patients received 0.1 mg of procaterol one night and a placebo the other night in random order. Pulmonary function tests were performed every two hours from 10 PM to 8 AM. Pulmonary sounds were recorded using a modified stethoscope and were subsequently analyzed to estimate the proportion of time occupied by wheezing (est Tw/Ttot). The forced expiratory volume in one second (FEV1) while receiving the placebo and procaterol were similar at 10 PM (placebo, 1.35 +/- 0.18 L [mean +/- SE]; procaterol, 1.48 +/- 0.20 L); however, by 4 AM, the FEV1 had dropped significantly lower on the night with the placebo (1.01 +/- 0.14 L) than the night with procaterol (1.30 +/- 0.19 L; p less than 0.05). The est Tw/Ttot was similar at 12 AM for both nights, but at 4 AM, there was a significant increase in the est Tw/Ttot for the group with placebo but not the group with procaterol. The use of a long-acting beta-adrenergic sympathomimetic agent reversed the obstruction of the airways seen with nocturnal asthma.

The cardiovascular effects of smoking, including the occurrence of ventricular arrhythmias, were examined in 52 patients with ischemic heart disease. The study was a randomized, crossover comparison between smoking six cigarettes and nonsmoking with observer-blinded primary outcome measurements. Continuous Holter ECG recording for four hours showed no significant differences in the proportion of patients experiencing ventricular ectopy or the total number and complexity of ventricular premature beats during smoking vs nonsmoking. Aside from the first cigarette, smoking did not significantly alter blood pressure or heart rate. Mean (+/- SEM) plasma epinephrine (pg/ml) increased (p = 0.02) from baseline (52 +/- 4) to a maximum of 64 +/- 6 at 240 minutes with younger subjects exhibiting a more marked rise (p = 0.02) than subjects over 55 years of age. Plasma norepinephrine was unchanged by smoking. A power calculation confirmed the conclusion that the resumption of smoking after overnight abstention does not acutely increase the occurrence of ventricular ectopic activity in patients with ischemic heart disease.

From November 1, 1982 through December 31, 1985, there were 19 centers and 382 patients that evaluated the effect of methylprednisolone sodium succinate (MPSS) on the septic syndrome. Seventeen of these centers enrolled 304 patients in a prospective, randomized, double-blind, placebo-controlled study to determine if early treatment with MPSS would decrease the incidence of severity of the adult respiratory distress syndrome (ARDS) in patients at risk of ARDS from sepsis. To ensure early institution of the MPSS or placebo therapy (PLA), patients with the presumptive diagnosis of sepsis were identified. That diagnosis was based on the presence of fever or hypothermia (temperature greater than 38.3 degrees C or less than 35.5 degrees C, rectal), tachypnea (greater than 20 bpm), tachycardia (greater than 90 bpm) and the presence of one of the following indices of organ dysfunction: a change in mental status, hypoxemia, elevated lactate levels or oliguria. The treatment, either MPSS 30 mg/kg or PLA, was given in four 20-minute infusions six hours apart and was initiated within two hours of the presumptive diagnosis of sepsis. The development and reversal of the adult respiratory distress syndrome (ARDS) was followed and resulted in data on 304 of the 382 randomized patients. A trend toward increased incidence of ARDS was seen in the MPSS group 50/152 (32 percent) compared to the placebo group 38/152(25 percent) p = 0.10. Significantly fewer MPSS patients reversed their ARDS 15/50 (31 percent) compared to placebo 23/38 (61 percent) p = 0.005. The 14-day mortality in patients with ARDS treated with MPSS was 26/50 (52 percent) compared to placebo 8/22 (22 percent) p = 0.004. We conclude that early treatment of septic syndrome with MPSS does not prevent the development of ARDS. Additionally, MPSS treatment impedes the reversal of ARDS and increases the mortality rate in patients with ARDS.

The role played by serotonin (5-HT) in the regulation of bronchomotor tone has up to now been a much debated question, although there is good evidence that it induces intense bronchoconstriction after inhalation in asthmatic patients. Serotonin has been found to contract the tracheobronchial smooth muscle of different animals. Some data suggest that tracheobronchial contraction due to serotonin is mediated by its interaction with the S2-receptor. The blockade of this receptor by ketanserin, a serotoninergic antagonist which primarily binds to S2-serotoninergic receptors, produces bronchodilation. The respiratory effects of intravenously administered ketanserin (10 mg) or placebo were compared in a double-blind crossover study in 14 patients with chronic obstruction of the airways. The forced expiratory volume in one second (FEV1) and the instantaneous forced expiratory flow after 50 percent of the forced vital capacity has been exhaled (FEF50%) did not change after placebo, but they increased significantly after administration of ketanserin. The results suggest that in patients with chronic obstructive pulmonary disease, serotonin may play a role in the development of obstruction of the airways, even if the mechanism remains undefined.

In a randomized study, we determined the clinical and financial effects of replacing arterial blood gas measurements with finger pulse oximeter readings during the process of tapering supplemental oxygen in hospitalized patients. The 16 patients in the control group, whose management followed conventional practice in our hospital, received a total of 57 arterial blood gas measurements during the 6.6 (mean) days it took for them to taper to their discharge supplemental oxygen level (usually room air). The 13 patients randomized to the oximeter study group had their arterial oxygen saturation monitored by pulse oximetry. The physicians of patients in the oximeter group were at liberty to obtain arterial blood gas determinations during the study if they desired. The oximeter study group had fewer (p less than 0.005) arterial punctures for blood gas measurements (total of 16 for the group) and fewer (p less than 0.001) days on supplemental oxygen (mean of 2.7 days per patient). We conclude that substituting noninvasive pulse oximetry for arterial blood gas measurements during reductions of supplemental oxygen shortened the days of oxygen use and decreased the number of arterial blood gas determinations in our patients. In addition to reducing the discomfort to patients, the use of oximetry was of financial benefit in that it reduced medical personnel time, blood gas analyzer use, and duration of oxygen administration.

Several microprocessor exercise physiology systems have been introduced recently. Comparison of the data output between these systems and more traditional nonautomated systems has not been reported extensively. Twelve normal adult men were exercised in random sequence on different days on a Sensormedics MMC Horizon system, the Medical Graphics Corporation System 2000, and a nonautomated system. heart rate, minute ventilation, tidal volume, respiratory frequency, oxygen consumption, and carbon dioxide production were compared at each level of work during a maximal incremental test and during a constant work load test. The overall data output between the three systems was comparable. However, minute ventilation was consistently higher on the Medical Graphics system, oxygen consumption was consistently lower on the Horizon system, and a technical error was discovered in the Medical Graphics system which resulted in a systematic overestimation of carbon dioxide production. Different methods of analyzing the data from the same test (60-s average, 15-s average, breath-by-breath, and 8-breath average) resulted in differences of up to 20 percent in the maximal values. This was greater than the differences between the three systems. Despite the comparability of the data output, important differences did exist which can be potentially significant when data output from one system are compared to predicted normal values obtained under different conditions.

Patients with chronic lung disease productive of sputum are generally encouraged to drink a large amount of fluid to facilitate sputum production. This clinical practice has not been tested systematically. Twelve outpatients with chronic obstructive pulmonary disease in clinically stable condition who had daily sputum production were asked in random sequence: 1) to drink one glass of fluid every waking hour after supper and upon waking the next morning (hydration), 2) to drink no fluid after supper and upon waking the next morning (dry), and 3) to drink fluid ad lib (ad lib). Each morning sputum collection was started upon waking and continued for four hours. The differences in volume, elasticity of sputum, respiratory symptoms, and ease of expectoration were not significant. We conclude that moderate hydration and dehydration have no effect on volume expectorated, the elasticity of sputum, respiratory symptoms or forced expiratory volume in one second.

Ambroxol is a mucolytic agent which is widely used in chronic bronchitis in Europe. We conducted a double-blind randomized controlled trial of ambroxol vs matched placebo in 90 patients with chronic bronchitis and difficulty clearing secretions. It was concluded that there was no advantage to taking ambroxol.

A prospective, double blind study was conducted to determine the degree of concordance of pen and palpation methods of measuring skin induration to Mantoux tuberculin tests. One hundred thirty-five skin tests were performed in patients with previously bacteriologically proved tuberculous disease. An experienced reader who was only able to see the forearm of the patient measured the induration by the palpation technique. The measurement was then repeated by the pen method under the same conditions, on the same day. Results of the study indicated that the pen method yielded statistically the same frequency distribution of indurations as the palpation method and the pen method appeared to be more sensitive.

We assessed the importance of Streptococcus pneumoniae and immunologic response to 14-valent pneumococcal vaccine in a randomized (saline placebo or vaccine) double-blind pilot study involving 103 patients with chronic obstructive pulmonary disease (COPD). Antibody titers, the flora of the sputum, respiratory infections or pneumonias, and deaths were monitored. The patients' antibody titers before immunization were higher than healthy control subjects. Titers rose normally in those vaccinated but declined more rapidly. Differences between the group receiving placebo and vaccine were not significant at 12 and 24 months. The incidence of pneumonia was high before and after vaccine (47/1,000 vs 41/1,000 patient-years). Nonpneumococcal causes predominated (73 percent of pneumonias; 83.4 percent of lethal pneumonias). Isolates from sputum were predominantly nonvaccine types (50 to 62.5 percent). Twenty-seven patients died; pneumonia occurred in six (one pneumococcal in a vaccinated patient) as a terminal complication of other diseases. Thus, although pneumonia occurred frequently in these patients with COPD and contributed to mortality in 22 percent (six) of the 27 deaths, the predominance of nonpneumococcal causes and the data on antibodies and sputum suggest that pneumococcal vaccine may not be as beneficial for patients with COPD as was hoped. More observations are needed.

Abnormal mucociliary transport is improvement by the action of theophylline, and this effect can be attributed to several mechanisms. The drug may directly and indirectly mediate the increase in the secretory output of bronchial glands, and this effect is enhanced by the vagal gastropulmonary reflex which is stimulated by the irritant action of theophylline on the stomach. Theophylline can increase the transepithelial secretion of fluid into the respiratory tract lumen by stimulating the chloride pump which is controlled by cyclic AMP. Ciliary motility is stimulated by theophylline; most of this effect is confined to the proximal part of the respiratory tree. However, much of the improvement in mucociliary clearance may be a consequence of the bronchodilation induced by theophylline, since the improved airway patency is generally a prerequisite for enhanced mucokinesis. Nevertheless, the multiple sites of action of theophylline in the respiratory tract suggests that this drug should be considered to be of significant value in any disorder characterized by mucostasis.

One of the important modes of action of theophylline in asthma and chronic obstructive airway disease may be the inhibition of airway inflammation. This hypothesis is based on in vitro and in vivo studies demonstrating that theophylline at therapeutic concentrations has an inhibitory activity on airway inflammation induced by allergic and nonallergic stimuli. Indirect evidence suggests that airway inflammation is an important determinant in the long-term outcome of chronic obstructive airway disease. The effect of theophylline on the long-term evolution of chronic obstructive lung disease remains to be proven.

Dyspnea is influenced by both physiologic and psychologic factors. Breathlessness is common in patients with chronic obstructive pulmonary disease (COPD) and often is the reason that the individual patient seeks medical attention. In order to evaluate the different clinical studies involving the use of theophylline in COPD patients, it is important to consider the three distinct approaches for measuring dyspnea--psychophysical testing, clinical methods, and ratings during exercise. Four randomized, double-blind, placebo-theophylline trials from one to four weeks in duration have evaluated the impact of theophylline on lung function and breathlessness. In these studies, the overall improvement in forced expiratory volume in one second was quite consistent for theophylline compared with placebo therapy. When appropriate clinical methods for measuring dyspnea were used, theophylline showed a positive reduction in breathlessness. These reports suggest that theophylline provides modest objective and subjective improvement in patients with symptomatic chronic air flow obstruction.

Thirty-four otherwise healthy patients having to undergo elective upper abdominal surgery were randomly assigned to two equal groups. In the treatment group, constant positive airway pressure (CPAP) with an expiratory pressure of 12 cm H2O was applied at one hour following extubation, and at daily intervals for the first five days following surgery for a continuous period of three hours. The control group received no CPAP treatment. All patients were given postoperative physiotherapy. In patients who received postoperative CPAP with an end-expiratory pressure of 12 cm H2O, marked normalization of pulmonary function was noted.

The bronchodilating action of theophylline in COPD has been examined, with emphasis on its combined use with inhaled beta 2 agonists. The suggestion is made that failure to recognize the nonlinearity of the dose-response curves for bronchodilators has resulted in underestimating their combined action. Recent studies suggest that systemic theophylline has somewhat different actions on the airways in COPD than inhaled beta agonists, and that more bronchodilation may be possible when the two are used together than large doses of either one. By analogy, with asthma the suggestion is also made that the addition of theophylline is also likely to provide a more constant bronchodilation, reducing peak-trough variations in flow. The most complete clinical comparison to date suggests that, in currently sanctioned doses, a regimen containing both theophylline and an inhaled beta 2 agonist provides significantly greater bronchodilation than either drug alone, with fewer patient withdrawals. Further carefully designed studies are needed to resolve this issue, and particularly, to identify those patients who will derive the greatest benefit from a combined regimen.

Increased airway responsiveness occurs in asthma, chronic bronchitis, cystic fibrosis, and other diseases. Theophylline and beta 2 agonists commonly are used as maintenance therapy for symptoms associated with the increased responsiveness. Both drugs can reduce airway responsiveness to a variety of provocational stimuli. With currently used dosing regimens, theophylline appears to produce relatively constant levels of effect on airway responsiveness and clinical efficacy around the clock, while inhaled beta 2 agonists appear to have insufficient effects at the end of longer dosing intervals. Improved dosing strategies for beta 2 agonists may improve the efficacy of these agents in the future.

Nineteen patients (12 men) mean age, 63.4 years (range, 32 to 78), with stable chronic airflow limitation, mean FEV, 0.55 L (range, 0.3 to 1.05 L), completed an eight-week, double-blind, double cross-over study comparing nebulized salbutamol and salbutamol from a metered-dose inhaler (MDI). Salbutamol from both delivery systems produced bronchodilation. The doses of salbutamol inhaled via the nebulizer and MDI producing maximal bronchodilation were established by cumulative dose-response curves. The contents of the nebulizer and MDI were inhaled four times a day, one system containing salbutamol and the other a placebo. Cross-over of salbutamol from one system to the other occurred every two weeks. There was no significant difference between the two delivery methods in daily peak expiratory flow rate (PEFR), severity of symptoms, or extra bronchodilator usage. Two weekly laboratory assessments of spirometry, PEFR, and exercise tolerance also showed no significant differences. Careful assessment is recommended before the provision of domiciliary nebulizers.

We studied the antihistaminic property of a new compound, azelastine, on histamine-induced bronchoconstriction and compared it with ketotifen and placebo. In 12 patients with bronchial asthma we performed histamine bronchial challenges before and four hours after ingestion of placebo, 2.0 mg ketotifen, and 4.4 mg azelastine given in a double-blind, randomized, cross-over fashion. Ketotifen and azelastine provided significant protection compared with placebo. No statistically significant difference between ketotifen and azelastine could be detected. As the antihistaminic effect of azelastine does not predict the therapeutic usefulness in the maintenance therapy of bronchial asthma, further studies are indicated.

We conducted a single-bind placebo controlled study using 24-hour continuous ambulatory electrocardiographic recordings. The arrhythmogenic potential of the combination of salbutamol and theophylline was investigated in 25 ambulatory subjects with severe chronic airflow obstruction (mean age 65 +/- 8 SD, mean FEV1 31 percent +/- 13 SD predicted). Asymptomatic arrhythmias were very prevalent in the study population: 76 percent of the patients had runs of supraventricular tachycardia while 24 percent had runs of ventricular tachycardia. Individual arrhythmia frequency showed greater between-test variability than previously described in non-COPD subjects. The mode of administration of salbutamol may have affected arrhythmia frequency in that subjects using aerosol nebulizers had more ventricular extrasystoles than those using metered dose inhalers. Although the addition of theophylline to salbutamol significantly increased heart rate and supraventricular extrasystoles, there was no statistically significant increase in ventricular arrhythmias.