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Left ventricular function is modified by respiration and pericardial constraint. The aim of this study was to compare left ventricular systolic and diastolic function during inspiration and expiration in four patient groups: patients (1) without cardiac disease, (2) with severe pulmonary disease, (3) with cardiac amyloid and (4) with pericardial constriction (before and after pericardiectomy). Using blood-pool left ventriculography with modified gating, we obtained time-activity curves at the onset of inspiration and expiration. On inspiration and expiration, patients with pericardial constriction and patients with cardiac amyloid were significantly different from those without cardiac disease and those with severe pulmonary disease, in that left ventricular ejection fraction (LVEF) was less, peak filling rate was greater, time to peak filling rate was shorter, and rapid filling fraction was increased. When inspiration and expiration were compared, time to left ventricular peak filling rate was shorter (P = 0.05) on inspiration (118 +/- 48 ms) than on expiration (168 +/- 35 ms) in patients with pericardial constriction. No other measures differed between inspiration and expiration in pericardial constriction, and left ventricular function was unaffected by respiration in the other groups. Time to left ventricular peak filling rate was 49 +/- 69 ms less on inspiration than on expiration in pericardial constriction and this difference was significantly different (P = 0.04) from that in patients with cardiac amyloid (34 +/- 58 ms greater), patients without cardiac disease (2 +/- 69 ms greater) and patients with severe pulmonary disease (19 +/- 63 ms less). In pericardial constriction, pericardial resection caused an increase in LVEF without a change in left ventricular diastolic filling but abolished the differences present between inspiration and expiration in time to left ventricular peak filling rate. This respiratory response in time to left ventricular peak filling rate may be valuable in the diagnosis of pericardial constriction.

A survey of American College of Chest Physicians (ACCP) members was conducted to determine their degree of involvement in the diagnosis and prevention of occupational and environmental respiratory disease (OERD). Although the response rate was relatively low, the results are likely to be representative. Calculations based on the data estimate that in the prior year, chest physicians on the average saw 15 patients with OERD caused by work, 13 worsened by work, and 28 affected by the home environment. Asthma appears to be a more common occupational or environmental concern than pulmonary fibrosis. Chest physicians clearly perceived a need for more education in OERD. The survey also demonstrated that although many chest physicians perform routine industrial surveillance testing, it is often done without using standardized methods. Furthermore, chest physicians are actively involved with medical/legal aspects of OERD. Overall, the survey documents the role of chest physicians in the area of OERD and emphasizes significant educational needs.

Previous studies of lung function in relation to smoking cessation have not adequately quantified the long-term benefit of smoking cessation, nor established the predictive value of characteristics such as airway hyperresponsiveness. In a prospective randomized clinical trial at 10 North American medical centers, we studied 3, 926 smokers with mild-to-moderate airway obstruction (3,818 with analyzable results; mean age at entry, 48.5 yr; 36% women) randomized to one of two smoking cessation groups or to a nonintervention group. We measured lung function annually for 5 yr. Participants who stopped smoking experienced an improvement in FEV(1) in the year after quitting (an average of 47 ml or 2%). The subsequent rate of decline in FEV(1) among sustained quitters was half the rate among continuing smokers, 31 +/- 48 versus 62 +/- 55 ml (mean +/- SD), comparable to that of never-smokers. Predictors of change in lung function included responsiveness to beta-agonist, baseline FEV(1), methacholine reactivity, age, sex, race, and baseline smoking rate. Respiratory symptoms were not predictive of changes in lung function. Smokers with airflow obstruction benefit from quitting despite previous heavy smoking, advanced age, poor baseline lung function, or airway hyperresponsiveness.

Some patients are denied curative pulmonary resection for lung carcinoma because of pulmonary insufficiency. To identify factors that affect postoperative morbidity and mortality, we reviewed 85 consecutive patients (53 men and 32 women) with a preoperative forced expiratory volume in 1 second of less than 1.2 L who underwent pulmonary resection for lung cancer between January 1986 and December 1990.Median age was 70 years (range, 49 to 82 years). Sixty patients (71%) had been previously denied operation because of pulmonary insufficiency. Preoperative pulmonary function demonstrated a median preoperative forced expiratory volume in 1 second of 1.0 L (44% of predicted normal; range, 0.5 to 1.2 L) and a diffusing capacity of the lung for carbon monoxide of 60% of predicted normal (range, 22% to 104%).Pneumonectomy was done in 6 patients (7.1%), bilobectomy in 6 (7.1%), lobectomy in 38 (44.7%), segmentectomy in 12 (14.1%), and wedge excision in 29 (27.1%). The median predicted postoperative forced expiratory volume in 1 second was 0.83 L (34% of predicted normal; range, 0.45 to 1.14 L), and the median predicted postoperative diffusing capacity of the lung for carbon monoxide was 48% of predicted normal (range, 19% to 87%). Seventy-two patients (85%) received postoperative epidural analgesia. Median hospitalization was 15 days (range, 5 to 66 days). Operative mortality was 2.4%, and complications occurred in 49%. We did not identify any factors that predicted postoperative morbidity and mortality. Median follow-up was 3.2 years (range, 0.2 to 9 years). Seven patients (8%) required supplemental home oxygen. A predicted postoperative percent forced expiratory volume in 1 second less than 43% correlated with the need for home oxygen (p0.05). Overall 5-year survival was 44.0%. Survival for stage I cancer was 54.2%; stage II, 33.1%; and stage IIIa, 21.3%.We conclude that some patients with lung cancer and compromised pulmonary function can safely undergo pulmonary resection if selected appropriately.

During running exercise above the lactate threshold (LT), it is unknown whether free fatty acid (FFA) mobilization can meet the energy demands for fatty acid oxidation. This study was performed to determine whether FFA availability is reduced during running exercise above compared with below the LT and to assess whether the level of endurance training influences FFA mobilization. Twelve marathon runners and 12 moderately trained runners ran at a workload that was either above or below their individual LT. Fatty acid oxidation (indirect calorimetry) and FFA release ([1–14C]palmitate) were measured at baseline, throughout exercise, and at recovery. The plasma FFA rate of appearance increased during exercise in both groups; running above or below the LT, but the total FFA availability for 30 min of exercise was greater (P < 0.01) in the below LT group (marathon, 23 +/- 2 mmol; moderate, 21 +/- 2 mmol) than in the above LT group (18 +/- 3 and 13 +/- 3 mmol, respectively). Total fatty acid oxidation (indirect calorimetry) greatly exceeded circulating FFA availability, regardless of training or exercise group (P < 0.01). No statistically significant exercise intensity or training differences in fatty acid oxidation were found (above LT: marathon, 71 +/- 12, moderate, 64 +/- 17 mmol/30 min; below LT: marathon 91 +/- 12, moderate, 60 +/- 5 mmol/30 min). In conclusion, during exercise above or below LT, circulating FFA cannot meet the oxidative needs and intramuscular triglyceride stores must be utilized. Further marathon training does not enhance effective adipose tissue lipolysis during exercise compared with moderate endurance training.

A survey of American College of Chest Physicians (ACCP) members was conducted to determine their degree of involvement in the diagnosis and prevention of occupational and environmental respiratory disease (OERD). Although the response rate was relatively low, the results are likely to be representative. Calculations based on the data estimate that in the prior year, chest physicians on the average saw 15 patients with OERD caused by work, 13 worsened by work, and 28 affected by the home environment. Asthma appears to be a more common occupational or environmental concern than pulmonary fibrosis. Chest physicians clearly perceived a need for more education in OERD. The survey also demonstrated that although many chest physicians perform routine industrial surveillance testing, it is often done without using standardized methods. Furthermore, chest physicians are actively involved with medical/legal aspects of OERD. Overall, the survey documents the role of chest physicians in the area of OERD and emphasizes significant educational needs.

Nicotine gum is an important adjunct for smoking cessation for many smokers, and long-term use of nicotine gum will occur in a small percentage of patients. To date, no method of cessation in long-term users has been studied in a randomized trial. We enrolled 26 subjects at the Mayo Clinic site of the Lung Health Study who had used nicotine gum for more than 6 months to participate in a trial where subjects were randomly assigned to: (1) abrupt cessation, (2) taper with placebo gum, or (3) taper with active gum. At the end of the 6-week trial, the percentage of subjects abstinent from gum use and not smoking was not different among the three groups: 66.7% for the abrupt cessation group, 71.4% for the taper with placebo gum group and 60% for the taper with active gum group. One subject in the taper with placebo gum group relapsed to smoking during the trial but was abstinent from smoking again at long-term follow-up. Long-term follow-up (median 284 days) showed 65% of subjects were abstinent from all nicotine products. Motivated subjects can stop long-term nicotine gum use without relapse to gum use or smoking by either abrupt cessation or brief tapering.

2546 Background: AFP464 (NSC 710464) is a lysyl derivative of aminoflavone metabolized by cytochrome P450 (CYP)1A1 and CYP1A2 (Kuffel et al, Mol Pharmacol 62:143, 2002) to reactive species that cov...

The circadian pattern of aqueous formation and the effect of timolol on aqueous flow was studied in 12 patients with cystic fibrosis. Cystic fibrosis is a disease characterized by a defect in a chloride channel-associated regulatory protein found in epithelial cells. Improper regulation of these chloride channels, causes abnormal composition of exocrine secretions, including respiratory tract, gastrointestinal tract, exocrine pancreas, and sweat glands. Ocular findings previously reported include abnormal endothelial cell permeability, decreased tear secretion, and abnormal tear composition. In this study, aqueous humor flow was measured by fluorophotometry. No statistically significant difference was found when flow rates measured during the morning, during the afternoon, at night, and after topical timolol treatment were compared to normal values. The conclusion is that the beta adrenergically regulated chloride selective channels defective in patients in cystic fibrosis do not play a major role in the formation of aqueous humor or they are not regulated by the cystic fibrosis transmembrane conductance regulator (CFTR).

Objective. —To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease. Design. —Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention. Setting. —Ten clinical centers in the United States and Canada. Participants. —A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease. Interventions. —Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler. Main Outcome Measures. —Rate of change and cumulative change in FEV1over a 5-year period. Results. —Participants in the two smoking intervention groups showed significantly smaller declines in FEV1than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study. Conclusions. —An aggressive smoking intervention program significantly reduces the age-related decline in FEV1in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1. (JAMA. 1994;272:1497-1505)

Seven adult mongrel dogs were exposed to SO2 gas at 2 different concentrations (15 and 50 ppm) on a daily basis for 5 to 11 months. Mucous hypersecretion and airway obstruction (a sustained increase in pulmonary resistance) developed in 4 dogs exposed to 50 ppm SO2. Histologic examination of the dogs' airways demonstrated epithelial thickening and an increase in size of the mucous glands. No inflammatory cell infiltration of the airways was noted and, in addition, responsiveness to inhaled histamine and methacholine did not change. The increase in lung resistance correlated with increase in mucous gland volume and airway wall thickening, but not with any change in airway responsiveness. Dogs exposed to 15 ppm SO2 showed minimal histologic and physiologic changes compared with control dogs. Previous work with a similar model of chronic bronchitis, using higher level SO2 exposure, has demonstrated an association of airway inflammation with decreased responsiveness to inhaled bronchoconstrictors. In the present study, with a lower exposure level to SO2 (50 versus 200 ppm), we found similar histologic findings associated with airway obstruction, but in the absence of airway inflammation, responsiveness to inhaled bronchoconstrictors was unchanged. This supports the theory that chronic airway inflammation may be associated with decreased responsiveness to inhaled bronchoconstrictors. This contrasts with the hyperresponsiveness induced by acute exposure to irritant gases noted by others.

Chronic bronchitis was induced in 6 mongrel dogs by exposure to SO2 gas for 6 to 18 months. All of the dogs developed cough and mucus hypersecretion. Chronic airway obstruction and decreased airway responsiveness to inhaled histamine developed in 5 of the dogs. Histologic changes in dogs evaluated after SO2 exposure included significant mucous gland hypertrophy and hyperplasia, epithelial thickening, and a decrease in the number of luminal cells containing undischarged secretory granules. Acute and chronic inflammation were found in the dogs with airway obstruction and decreased responsiveness to histamine, but such inflammation was absent in the one dog that failed to develop physiologic changes. After a period of recovery from SO2 exposure of 9 to 21 months, inflammation regressed dramatically and the other histologic changes returned toward normal. Physiologic changes regressed somewhat in those dogs that had had changes. These findings suggest that inflammation may be an important factor influencing the development of airway obstruction and altered airway responsiveness in the setting of chronic bronchitis.

The bronchoconstrictor activity of an aerosol of leukotriene E4(LTE4) was compared with that of histamine in 5 normal and in 6 asthmatic subjects to define the relative potency of LTE4 between the groups using 3 indices of airway response. The FEV1 and the flow rate measured at 30% of vital capacity from partial and maximal expiratory maneuvers (V30-P and V30-M) were measured. The geometric mean (GSEM) concentration of LTE4 required to reduce the V30-P by 30% was 0.30 (1.46) mM in the normal subjects, and 0.058 (1.63) in the asthmatic subjects; LTE4 was 39-fold more potent than histamine in the former and 14-fold in the latter group. Further, we observed that when normal and asthmatic subjects were compared at a degree of bronchoconstriction resulting in a 30% decrement in the V30-P after inhaling LTE4, there was a greater response in the asthmatic group than in the normal group of the accompanying change in the FEV1. The decrements in the FEV1 were not significantly different between the 2 groups after inhaling histamine. This study demonstrates that LTE4 is a potent bronchoconstrictor agonist in humans and suggests that airway responsiveness to this agonist differs substantially with the index of bronchoconstriction used for assessment of airway response.

We measured lung and chest wall compliance as well as rib cage and abdominal dimensions in the supine position in five acute C4-7 quadriplegics. Studies were performed serially from 1 to 12 months after injury. Results were compared with those of control groups of chronic (greater than 1 yr after injury) quadriplegics and normal volunteers. We found that lung compliance was lower in acute and chronic quadriplegics (0.129 +/- 0.023 and 0.176 +/- 0.043 L/mm Hg, respectively) than in normal subjects (0.278 +/- 0.086 L/mm Hg) and that these changes apparently occurred within 1 month of injury. Specific lung compliance appeared to be reduced to a lesser degree, suggesting that the changes in lung compliance were partly due to reduced lung volumes and partly to altered mechanical properties of the lung. During respiratory maneuvers, abdomen and rib cage dimensional changes demonstrated rib cage distortion. This distortion was less severe in chronic than in acute quadriplegics. The improvement in chest wall stability was likely due to increased strength of cervical accessory muscles of respiration and improved coupling of the various rib cage elements in chronic quadriplegics.