The effects of immunization with killed influenza virus vaccine were assessed by comparison with placebo in a double-blind study of 318 adult patients with chronic asthma. The patients were randomly allocated to active vaccine and placebo. No difference was observed in peak expiratory flow rate or in clinical symptoms of bronchial obstruction between the groups receiving active vaccine and placebo during the first week after immunization. The data were analyzed separately for age, sex, duration of the disease, hypersensitivity to aspirin (acetylsalicylic acid), atopic status, patients with a history of attacks of asthma induced by viral infections, patients with a diurnal variation of baseline peak expiratory flow of 20 percent or more, and patients receiving continuous oral steroid medication, but none of these factors seemed to predict any short-term adverse effects of vaccination. Follow-up for eight months after the vaccination revealed no differences in asthmatic symptoms between the patients treated with active vaccine and those receiving placebo. The antiviral antibody response to vaccination was normal. The possible protection provided by the vaccination against exacerbation of asthma induced by influenza could not be evaluated, since the influenza epidemic expected during the season failed to occur in Finland. It is concluded that immunization with killed influenza vaccine is safe and is not associated with any significant side effects in adult patients with chronic asthma.

Postoperative pulmonary complications, alveolar-arteriolar oxygen difference ([A-a]O2-diff), peak expiratory flow (PEF) and forced vital capacity (FVC) were compared in patients using continuous positive airway pressure (CPAP) and positive expiratory pressure (PEP) administered by face mask against those of a control group using a deep-breathing device (Triflo). Forty-three consecutive, randomized patients undergoing elective upper abdominal surgery were included. CPAP, PEP and Triflo were administered for 30 consecutive breaths in every waking hour for three days postoperatively. The (A-a)O2-difference increased equally and significantly in the three groups after surgery, reaching a maximum on the first postoperative day. After this day, however, (A-a)O2-diff decreased in the CPAP and PEP groups, being significantly lower in the PEP group compared to the control group, two days postoperatively (p less than 0.05) and significantly lower in both the PEP and CPAP groups three days postoperatively (p less than 0.001 and p less than 0.05, respectively.) PEF did not differ significantly between the groups before or after surgery, while FVC was significantly higher in the PEP and CPAP groups, compared to control, on the third postoperative day (p less than 0.05). Atelectatic consolidation was observed in six of 15 patients in the control group three days postoperatively, the incidence being significantly lower in both the PEP group (0 of 15, p less than 0.001) and the CPAP group (one of 13, p less than 0.05). We concluded that periodic face mask administration of CPAP and PEP are superior to deep breathing exercises with respect to gas exchange, preservation of lung volumes and development of atelectasis after upper abdominal surgery. We also conclude that the simple and commercially available PEP mask is as effective as the more complicated CPAP system.

To determine the potential benefit of incentive spirometry, which has been advocated to prevent pulmonary complications after upper-abdominal surgery, we compared a group of patients receiving incentive spirometry to another group receiving no specialized postoperative respiratory care. Forty patients in the American Society of Anesthesiologists' class 1 and 2 who were undergoing cholecystectomy (through right subcostal incision) were included in the study and were randomly allocated to one of the two groups. Patients receiving incentive spirometry were encouraged by a specialized respiratory physiotherapist to breathe deeply for five minutes hourly, 12 times daily, for three postoperative days. No statistically significant difference between the two groups was found in the radiologic evidence of postoperative pulmonary complications, arterial oxygen pressure, spirometric measurement, and clinical evaluation at the second or fourth postoperative day (or both). In particular, deterioration on the chest x-ray film at the fourth postoperative day was observed in eight of 20 patients in the group receiving incentive spirometry and in six of 20 in the control group. Our study confirms the postoperative deterioration of respiratory function after upper-abdominal surgery and demonstrates the lack of therapeutic values of incentive spirometry in these patients at low risk for pulmonary complications.

Supplemental oxygen therapy delivered at concentrations which increase PaO2 greater than 60 mm Hg often has minimal effects on either pulmonary hemodynamics or the oxygen tension of mixed venous blood (PvO2). Since mixed venous hypoxemia has been shown to contribute to pulmonary vasoconstriction in experimental conditions and is a determinant of survival in chronic obstructive pulmonary disease (COPD), we evaluated the hemodynamic effects of oxygen therapy titrated to raise PvO2 in 12 COPD patients who underwent right heart catheterization. After room air measurements of mean pulmonary artery pressure, cardia output, and pulmonary vascular resistance, they were randomized to either supplemental oxygen therapy given to raise PaO2 greater than or equal to 60 mm Hg (group 1, n = 6) or to raise PvO2 greater than or equal to 36 mm Hg (group 2, n = 6). An oxygen-conserving nasal cannula and oxygen concentrator were used. Baseline PaO2, PvO2, and hemodynamics were identical in each group and hemodynamics after four hours and 48 hours of continuous oxygen therapy were unchanged. Ten patients were catheterized after four months of continuous oxygen therapy (group 1, n = 4; group 2, n = 6). Although PvO2 in group 2 had been raised to normal levels (39.2 +/- 1.2 mm Hg), there was no significant improvement in pulmonary hemodynamics. Our preliminary study suggests that oxygen titrated to raise PvO2 to the normal range has no greater hemodynamic effect than oxygen therapy as it is currently prescribed.

Although caffeine is a universal drug and has multiple pharmacologic and physiologic actions in man, there are surprisingly few objective data about its effect on pulmonary function. We conducted a short-term, double-blind, randomized crossover study in nine asthmatic adults who ingested decaffeinated coffee containing varying amounts of added caffeine (mean of 0.2,2.5,5.6, and 7.2 mg/kg of body weight) on different days. The subjects also ingested decaffeinated coffee and aminophylline (200 mg) on a separate day of study. Baseline and post-drug determinations of serum levels of caffeine and theophylline, forced expired volume and flow, specific airway conductance (Gaw/VL), vital signs, and reported symptoms were obtained. Peak increases in serum caffeine concentrations (mean, 12.4 micrograms/ml +/- 1.5 micrograms/ml) occurred 45 minutes following the highest dose of caffeine (7.2 mg/kg), whereas the peak theophylline level (mean 3.8 micrograms/ml +/- 0.4 micrograms/ml) occurred 90 minutes following oral administration of aminophylline (mean theophylline, 2.6 mg/kg). Comparable peak increases in the forced expiratory volume in one second (FEV1), the forced expiratory flow during the middle half of the forced vital capacity (FEF25-75%), and Gaw/VL occurred at 120 minutes following aminophylline and the highest dose of caffeine, indicating that caffeine is an effective bronchodilator but is only 40 percent as active as an equivalent molar dose of theophylline. Regression analysis revealed statistically significant dose-response relationships between peak increases in serum caffeine concentrations and increases in FEV1, FEF25-75%, and Gaw/VL from baseline values. These findings have diagnostic and therapeutic implications regarding the use of caffeine prior to tests of pulmonary function and as a dietary agent, alone or in combination with theophylline.

Three doses of fenoterol were administered by metered-dose inhaler to 20 adult subjects with asthma in order to determine the optimal dose for routine administration. Inhaled doses of 100 micrograms, 200 micrograms, and 400 micrograms of fenoterol with isoproterenol and placebo controls were administered in a randomized double-blind crossover regimen. We found that 200 micrograms of fenoterol by metered-dose inhaler produced a longer duration of action, greater peak response, and greater overall time-weighted responses in the forced expiratory volume in one second, in the mean forced expiratory flow during the middle half of the forced vital capacity, and in airway resistance than did the other drug regimens. The 400 micrograms dose of fenoterol produced no increase in response over that seen after the 200 micrograms dose. Side effects were minimal and no greater than with isoproterenol.

In five supine normal subjects breathing spontaneously, we studied the effects of high-frequency chest wall oscillation (HFCWO), which was achieved by oscillating the pressure in an air-filled cuff wrapped around the lower thorax. Oscillations of 3.5 and 8 Hz (in randomized order) were applied for 15 minutes each at both maximal (mean of 90 to 102 cm H2O) and half-maximal peak tolerable cuff pressures. Fifteen minutes of control spontaneous ventilation preceded each HFCWO maneuver. The HFCWO resulted in a significant decrease in spontaneous minute ventilation (VES) at maximal and half-maximal pressures by 35 and 40 percent, respectively, at 3 Hz and by 26 and 35 percent, respectively, at 5 Hz, with little change in VES at 8 Hz. This occurred despite an unchanging arterial carbon dioxide tension at all frequencies. Arterial oxygen pressure increased at 3 Hz at maximal pressure but remained statistically unchanged at 3 Hz at half-maximal pressure and at 5 Hz and 8 Hz both at maximal and half-maximal pressures. We conclude that HFCWO may potentially assist ventilation in spontaneously breathing man without requiring an endotracheal tube.

Forty-one patients were studied in a randomized double-blind placebo-controlled crossover trial to compare the antianginal actions of nicardipine 30 mg thrice daily and nifedipine 10 mg thrice daily. Efficacy was assessed using objective criteria from computer-assisted multistage graded exercise testing, performed after a two-week placebo run-in period and at the end of each four-week active treatment period. Thirty-seven patients completed both legs of the crossover trial. The mean (+/- standard error of the mean) baseline exercise time to development of angina was 6.7 +/- 0.4 min and this increased to 9.5 +/- 0.6 min on nicardipine (p less than 0.001) and 9.5 +/- 0.5 min on nifedipine (p less than 0.001 vs baseline; NS vs nicardipine). Both drugs significantly prolonged the time to the development of 1mm ST segment depression. The baseline resting heart rate of 83 +/- 2 beats/min increased to 87 +/- 3 beats/min during nicardipine (p less than 0.05) and remained unaltered at 83 +/- 2 beats/min during nifedipine therapy (p = NS vs baseline and p less than 0.02 vs nicardipine). Similarly, both drugs increased significantly the maximal heart rate at peak exercise. One patient was lost to follow-up during the placebo run-in period and four patients (two each on nicardipine and nifedipine) were withdrawn due to adverse effects. Our results indicate that nicardipine is comparable in efficacy to nifedipine and has a similar adverse effect profile and can also be considered a useful therapeutic agent for the treatment of chronic stable angina pectoris.

To determine if eating between initial and delayed thallium images alters the appearance of the delayed thallium scan, a prospective study was performed; 184 subjects sent for routine thallium imaging were randomized into two groups, those who ate a meal high in carbohydrates between initial and delayed thallium myocardial images (n = 106), and those who fasted (n = 78). The 201Tl images were interpreted in blinded fashion for global myocardial and pulmonary clearance of 201Tl myocardial defects. The eating group had a significantly lower incidence of transient myocardial defects compared to the noneating group (7 percent vs 18 percent, respectively; p less than 0.05). The time between initial and delayed images and the incidence of exercise-induced ischemic ST-segment depression or pathologic Q waves on the electrocardiogram were not significantly different between the two groups. These data suggest that eating a high-carbohydrate meal between initial and delayed 201Tl images causes increased 201Tl myocardial clearance rates and may alter 201Tl myocardial redistribution over time.

To evaluate comparative bronchodilator efficacy with chronic airflow obstruction (CAO), we randomly administered to ten patients week-long treatments consisting of: inhaled metaproterenol from a metered dose canister (1.30 mg six times a day) and doses of a sustained-release theophylline formulation sufficient to achieve plasma levels of 10-15 micrograms/ml; metaproterenol-placebo; theophylline-placebo; or placebo-placebo. At the end of each period, treatment responses were evaluated by spirometric tests, by exercise tolerance (12 minute walk and progressive cycle ergometry) and by subjective perception of dyspnea (oxygen cost diagram and breathlessness rating). Metaproterenol as a single treatment caused statistically significant improvements in spirometric variables and in the breathlessness rating. Theophylline as a single treatment caused significant changes in none of the test variables, though favorable trends were observed. Combined drug therapy was significantly better than metaproterenol only in the case of the breathlessness rating. We conclude that in the treatment of patients with CAO, inhaled metaproterenol is superior to oral theophylline. Our results permit no definite conclusion concerning added benefits of combined drug therapy.

Almitrine, a new triazine derivative, was studied in a double-blind, randomized, parallel study in 16 patients with hypoxic chronic airflow obstruction (eight almitrine and eight placebo). At rest, compared to placebo, a 3 mg/kg single dose of almitrine given orally significantly increased the partial pressure of oxygen (mean increase: +12.0 +/- SEM 2.1 mm Hg, p less than 0.001) and decreased the partial pressure of carbon dioxide (mean decrease: -6.0 +/- 0.7 mm Hg, p less than 0.001); this improvement in arterial blood gases persisted on exercise. The lack of significant change in ventilation and the decrease in the alveolar-arterial oxygen gradient (mean decrease -10.0 +/- 1.9 mm Hg; p less than 0.001) at rest suggests a change in the distribution of the ventilation-perfusion ratio in the lung; such a change was confirmed by a krypton 81m isotopic study. Pulmonary hemodynamic responses were studied at rest and on exercise; a significant but slight increase in mean pulmonary artery pressure at rest (+4.0 +/- 1.5 mm Hg, p less than 0.05) was found.

The purpose of this study was to evaluate the effects of inhaled atropine sulfate on the exercise capacity and cardiopulmonary responses to exercise in patients with chronic airflow obstruction (CAO). Eighteen patients underwent duplicate incremental (15 watts/min) maximal cycle ergometer exercise tests 60 minutes after either inhaled atropine (0.075 mg/kg) or placebo, in double blind randomized fashion on consecutive days. Bronchodilator medications were withheld before each study. Spirograms were obtained before and 60 minutes after each aerosol treatment. Atropine increased the FEV1 by 25 percent, from 1.37 +/- 0.49 to 1.71 +/- 0.52 L (p less than 0.001), as compared to placebo. Although the ventilation at exhaustion (VEmax) increased significantly (from 52.3 +/- 11.5 to 55.9 +/- 10.0 L/min, P less than 0.05) after atropine, the increase in the mean maximum work load (95 +/- 28 vs 101 +/- 19 watts) did not achieve significance. The drug resulted in a significant decrease in oxygen consumption at all equivalent workloads greater than "0" watts (unloaded cycling), presumably because the improvement in airway mechanics decreased the oxygen cost of ventilation. Atropine-induced increases in FEV1 did not result in a significant group mean increase in maximum exercise capacity, but the drug did result in a lower oxygen cost of performing work in patients with CAO.

A prospective study of 104 patients was undertaken to determine the frequency of severe heparin-induced thrombocytopenia in patients receiving either bovine lung or porcine mucosal heparin. One of 54 patients randomized to receive bovine heparin and two of 50 patients randomized to receive porcine heparin developed heparin-induced thrombocytopenia (platelet count less than 100,000/microliters). Although three previous studies suggest a remarkably high frequency of bovine heparin-induced thrombocytopenia, or a high frequency compared to porcine heparin, our study supports other evidence that clinically important, severe heparin-induced thrombocytopenia (platelet count less than 100,000/microliters) occurs in 10 percent of patients or less receiving heparin, and that there is no significant difference of occurrence between bovine and porcine heparin.

Many patients with irreversible chronic obstructive pulmonary disease (COPD) claim symptomatic improvement with steroid therapy, despite a lack of objective improvement in their spirometric data. To determine if steroids actually increase the exercise capacity of these individuals, 13 clinically stable patients (mean age, 63 +/- 4 years; 12 male patients) were given methylprednisolone (32 mg once daily) or placebo in a randomized double-blind crossover fashion. Spirometric data and minute ventilation, oxygen consumption (VO2), carbon dioxide production, and heart rate during incremental exercise were measured at each visit. Methylprednisolone did not produce a significant change in any of the measured parameters. Three patients had an increase in maximal VO2 of greater than 2 ml/kg/min during therapy with methylprednisolone, while two experienced a decline in maximal VO2 of similar magnitude. The change in exercise capacity was unrelated to the change in the forced expiratory volume in one second in individual patients (r = 0.08). We conclude that in the absence of any improvement in the usual tests of airway mechanics, steroid therapy does not improve exercise performance in patients with COPD.

Twenty-six patients undergoing coronary bypass graft surgery were randomized in two groups. In group 1, 14 patients were subjected to inspiratory pressure support during spontaneous ventilation (IPSSV) and 12 patients in group 2 were treated with conventional ventilation (CV). The outcome of IPSSV was a definite advantage over the conventional ventilation. The patients in IPSSV group needed +/- 3 h of pressure support before tracheal extubation. The other patients in CV group 2 needed +/- 6 h of mechanical ventilation before being weaned off the ventilator.

The present study investigated the effects of oxygen therapy upon human information processing for hypoxemic COPD patients. Each of ten patients was admitted to a general clinical research center for a two-day period. In a randomly counter-balanced factorial design, patients breathed either room air or enriched oxygen for either six hours or 20 minutes prior to testing. The tests evaluated speed of information processing, ability to detect correct sequence of tones, and serial memory. In addition, patients were evaluated on critical flicker fusion and story recall. The results suggested that acute oxygen therapy does not reverse information processing deficits observed in hypoxemic COPD patients.

The effect of theophylline on the penetration of an inhaled radioaerosol in the lung, bronchial clearance, and tracheal mucociliary transport rate (TMTR) was investigated in 13 healthy volunteers. Following a randomized, double-blind, crossover protocol, subjects ingested 4 mg/kg twice daily of theophylline or placebo for three days which resulted in stable, low therapeutic serum levels. Aerosol penetration, assessed by the skew of the initial distribution of lung radioactivity, was more peripheral (p less than 0.025) with theophylline, indicating bronchodilation that was not detectable by standard pulmonary function tests. The TMTR increased in ten of 13 subjects after theophylline, but not to a significant level. Bronchial clearance was not significantly different with theophylline despite the longer clearance pathway created by the increased peripheral aerosol deposition. This finding suggests that mucus transport rates in the intrapulmonary airways were increased by theophylline.

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.