We have previously demonstrated a depression of airway, vascular, and cutaneous H2-histamine receptor function in sheep with experimental allergic asthma. In the present investigation, we wished to determine if there is a depression of gastric H2-receptor function in subjects with allergic bronchial asthma. In eight normal subjects and seven subjects with allergic bronchial asthma and bronchial reactivity to ragweed antigen, gastric H2-receptor function was assessed by measuring basal and maximal stimulated acid output following pretreatment with a placebo or the H2-antagonist, cimetidine. Maximal stimulated acid output was defined as the peak acid output (PAW mEq/hr) of hydrochloric acid following a subcutaneous injection of histalog (1.5 mg/kg), and selective H2-stimulation as delta PAO = PAOplacebo-PAOcimetidine. While basal acid output was not different between the two groups, mean (+/- SD) PAO was significantly lower in the asthmatic group (14.0 +/- 8.2 mEq/hr) than the normal group (27.9 +/- 9.4 mEq/hr) (p less than 0.01). Mean PAO expressed as percent of predicted maximum was 112 +/- 36 percent in the normal group and 61 +/- 34 percent in the asthmatic group (p less than 0.01). Mean delta PAO was significantly higher in the normal group (17.1 +/- 4.8 mEq/hr) than in the asthmatic group (7.0 +/- 5.3 mEq/hr) (p less than 0.005) indicating suppressed selective H2-receptor stimulation in the latter. We conclude that in subjects with bronchial asthma and marked bronchial hyperreactivity to ragweed antigen, there is a depression of gastric H2-histamine receptor function.

On the occasion of this Fourth World Conference on Lung Cancer, I am privileged to present the opening keynote address. This presentation has been sponsored by the Ontario Cancer Treatment and Research Foundation. In 1952, the Foundation established an annual lectureship in memory of one of their prominent physicians. Dr. Gordon Earle Richards was one of Canada's pioneer radiologists and radiotherapists who was appointed Director of the Institute of Radiotherapy at Toronto General Hospital at a time when radium and high-voltage x-rays were just coming into common use for the treatment of malignant disease. He established an international reputation for his contributions to clinical radiotherapy, and was subsequently appointed Professor of Radiology at the University of Toronto. He was Managing Director of the Ontario Cancer Treatment and Research Foundation between 1945 and 1949. I wish to thank the Foundation for the privilege of presenting the 33rd Gordon Richards Memorial Lecture.

A placebo-controlled, double-blind cross-over trial was conducted to assess whether 16 men with chronic obstructive pulmonary disease (COPD) would benefit from orally taken corticosteroids. Two weeks of treatment with 40 mg of prednisone daily did not result in improvement of pulmonary symptoms or function in the group as a whole, although one patient had small improvement in airflow. The baseline spirometric data and beta-agonist responsiveness of the patients in the study were then compared to a reference population consisting of 264 men who fulfilled a criteria for chronic obstruction out of 730 men who comprised a systematic sample drawn from all patients referred for spirometry at three hospitals. Our study subjects and those of five similar trials of corticosteroids in COPD had more severe obstruction than this reference group. Furthermore, the proportion of steroid responders found in each study was inversely related to the baseline FEV1 of the patients examined. It appears that previous studies of corticosteroids in COPD may have overestimated the number of COPD patients who might benefit from corticosteroids, due to a bias resulting from the selection of severely obstructed subjects.

The role of surgical resection in the management of patients with small cell lung cancer remains to be defined. Some data suggest the potential benefit of resection in the few patients with very limited disease (peripheral T1N0 and T2N0 lesions), and there are chemotherapy regimens with 80-85% response rates in patients with more extensive but still localized disease. Interest has been reawakened in the role of adjuvant surgical resection in selected patients by 2 approaches: in patients with peripheral T1 or T2 lesions with negative mediastinal exploration, initial surgical resection followed by an adequate chemotherapeutic regimen and prophylactic cranial irradiation has resulted in an 80% disease-free survival at 30 months; initial chemotherapy in patients with only localized disease is followed by resection in the responders. Approximately 30% of the responders have undergone exploratory thoracotomy after completion of the chemotherapy. Local irradiation, as well as prophylactic cranial irradiation, generally has been used postoperatively. Early pilot studies suggest benefit of this approach in patients found to have T1-3 N0-1 disease but not in those with N2 disease. Prospective, randomized, clinical trials by the Lung Cancer Study Group in North America and its counterparts in Europe are now being carried out in hopes of supplying definitive data relative to this multi-modality therapy in small cell lung cancer. Unfortunately, no data are available to date.

Three parenteral routes of albuterol sulfate were compared with placebo in their effects on serum potassium and glucose levels, heart rate, and pulmonary function in adult asthmatic subjects. In addition, the metabolic effects of subcutaneous epinephrine were compared directly with subcutaneous albuterol. Intravenous (IV) albuterol (250 micrograms) caused similar decreases in serum potassium (mean 0.6 +/- 0.3 mEq/L) as 500 micrograms albuterol by intramuscular (IM) or subcutaneous routes. With the combined data from all three albuterol routes, glucose increases (mean 25 +/- 15 mg/dl) and heart rate increases (mean 11 +/- 6 beats/min) were clinically less important than potassium decreases. Subcutaneous epinephrine (0.3 ml, 1:1,000) gave changes in serum potassium, serum glucose, and heart rate statistically similar to those of subcutaneous albuterol (500 micrograms). Peak FEV1 improvement (mean 61 percent) was similar with IV albuterol (250 micrograms), IM albuterol (500 micrograms) or subcutaneous albuterol (500 micrograms). Although the efficacy of albuterol in the doses studied was similar, the decrement in serum K+ produced was also similar and comparable to that produced by a standard dose of epinephrine. The potassium decrease may have important clinical implications.

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.