Acute response to bronchodilator. An imperfect guide for bronchodilator therapy in chronic airflow limitation.

We conducted a four-period cross-over randomized trial in which we found that patients with chronic airflow limitation demonstrated symptomatic improvement with both inhaled albuterol and oral theophylline. The response, however, was not uniform. We therefore tested the ability of acute change in forced expired volume in one second (FEV1) following inhaled beta agonist to predict long-term symptomatic response to albuterol and theophylline. We found that the reproducibility of acute change in FEV1 over three repetitions was poor (intraclass correlation 0.17). Furthermore, the mean improvement FEV1 following inhaled albuterol across the three repetitions did not relate closely to symptomatic response to either albuterol or theophylline. We conclude that acute response to inhaled beta agonist is not useful for identifying patients with chronic airflow limitation who are likely to benefit from bronchodilator treatment.

A measure of quality of life for clinical trials in chronic lung disease.

Since the relationships between pulmonary function, exercise capacity, and functional state or quality of life are generally weak, a self report questionnaire has been developed to determine the effect of treatment on quality of life in clinical trials. One hundred patients with chronic airflow limitation were asked how their quality of life was affected by their illness, and how important their symptoms and limitations were. The most frequent and important items were used to construct a questionnaire evaluating four dimensions: dyspnoea, fatigue, emotional function, and the patient's feeling of control over the disease (mastery). Reproducibility, tested by repeated administration to patients in a stable condition, was excellent: the coefficient of variation was less than 12% for all four dimensions. Responsiveness (sensitivity to change) was tested by administering the questionnaire to 13 patients before and after optimisation of their drug treatment and to another 28 before and after participation in a respiratory rehabilitation programme. In both cases large, statistically significant improvements in all four dimensions were noted. Changes in questionnaire score were correlated with changes in spirometric values, exercise capacity, and patients' and physicians' global ratings. Thus it has been shown that the questionnaire is precise, valid, and responsive. It can therefore serve as a useful disease specific measure of quality of life for clinical trials.

Bronchodilators in chronic air-flow limitation. Effects on airway function, exercise capacity, and quality of life.

We conducted a trial of inhaled salbutamol and orally administered theophylline in patients whose acute response to inhaled salbutamol was less than 25% of their baseline FEV1. Patients underwent 4 treatment periods, each of 2 wk duration, during which they received the following combinations: placebo-placebo, placebo-salbutamol, placebo-theophylline, and salbutamol-theophylline. The 19 patient who completed the study were all males with a mean age of 65 +/- 7.4 yr, mean FEV1 of 1.02 +/- 0.38, and mean VC of 2.73 +/- 0.19. Outcomes included twice-daily recordings of peak flow rates, spirometry, the distance patients could walk in 6 min, and clinical symptoms of dyspnea, fatigue, and emotional function. Clinically important and statistically significant differences between the 4 periods were noted on both physiologic and functional outcomes. For the group as a whole, improvement with inhaled salbutamol and orally administered theophylline was comparable, and additional benefit was gained from a combination of the 2 drugs. We conclude that both inhaled salbutamol and orally administered theophylline can improve airflow obstruction, functional exercise capacity, and quality of life in patients with primarily fixed air-flow limitation.

Quality of life in patients with chronic airflow limitation.

One hundred patients with chronic airflow limitation (CAL) randomly selected from over 600 such patients seen in the previous 2 years at a respiratory referral centre were asked about the ways in which their lives were adversely effected by their lung problems. Major problem areas included dyspnoea on day-to-day activities, fatigue and certain areas of emotional function including embarrassment, depression, anxiety and frustration. Severity of airflow limitation was only weakly related to patients' problems. Patients did not volunteer items easily, and most problems were elicited by specific probes. In 36 subjects, relatives were asked about the patients' problems. Relatives tended to identify fewer items, but items identified were judged more important; there was a limited relation between spouses' and patients' assessment of CAL-related problems (Pearson's r = 0.42-0.60). These results suggest that physicians cannot rely on severity of airflow limitation as an indicator of the impact of CAL on patients' lives. Patients should be specifically asked about problem areas, especially emotional difficulties, and spouses' view of the problems should be obtained.

The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure.

Cycle and treadmill exercise tests are unsuitable for elderly, frail and severely limited patients with heart failure and may not reflect capacity to undertake day-to-day activities. Walking tests have proved useful as measures of outcome for patients with chronic lung disease. To investigate the potential value of the 6-minute walk as an objective measure of exercise capacity in patients with chronic heart failure, the test was administered six times over 12 weeks to 18 patients with chronic heart failure and 25 with chronic lung disease. The subjects also underwent cycle ergometer testing, and their functional status was evaluated by means of conventional measures. The walking test proved highly acceptable to the patients, and stable, reproducible results were achieved after the first two walks. The results correlated with the conventional measures of functional status and exercise capacity. The authors conclude that the 6-minute walk is a useful measure of functional exercise capacity and a suitable measure of outcome for clinical trials in patients with chronic heart failure.

Effect of long-term administration of digoxin on exercise performance in chronic airflow obstruction.

We have studied the effect of long-term digoxin on exercise performance in 15 patients with pulmonary heart disease due to severe chronic airflow obstruction (FEV1/VC ratio 29 +/- 6%: mean +/- SD). Digoxin (0.25 mg/day) was given for 8 weeks in a randomized, double-blind crossover, placebo-controlled trial. All patients were ambulatory and had clinical features of right ventricular dysfunction but no clinical evidence of left ventricular dysfunction. Assessments included progressive and steady-state exercise, pulmonary function studies and evaluation of right and left ventricular function. In all patients the right ventricular ejection fraction was reduced; in 4 patients the left ventricular ejection fraction was also reduced. In patients whose left ventricular ejection fraction was initially abnormal, 8 weeks of digoxin increased left ventricular ejection fraction to normal. In spite of the improvement in resting ventricular function, exercise performance, the cardiopulmonary response to exercise, pulmonary function and general health status did not improve. We conclude that in patients with pulmonary heart disease: 1) digoxin improves ventricular function only if left ventricular function is reduced, and 2) despite the improvement in ventricular function digoxin does not improve pulmonary function, cardiopulmonary response to exercise or general feeling of well being.

How should we measure function in patients with chronic heart and lung disease?

To elucidate the characteristics of measures of function in patients with chronic heart failure and chronic lung disease we administered four functional status questionnaires, a 6-min walk test and a cycle ergometer exercise test, to 43 patients limited in their day to day activities as a result of their underlying heart or lung disease. Correlations between these measures were calculated using Spearman's rank order correlation coefficient. The walk test correlated well with the cycle ergometer (r = 0.579), and almost as well with the four functional status questionnaires (r = 0.473-0.590) as the questionnaires did with one another (0.423-0.729). On the other hand, correlations between cycle ergometer results and the questionnaires was in each case 0.295 or lower, and none of these correlations reached statistical significance. These results suggest that exercise capacity in the laboratory can be differentiated from functional exercise capacity (the ability to undertake physically demanding activities of daily living) and that the walk test provides a good measure of function in patients with heart and lung disease.

Effect of encouragement on walking test performance.

Walking tests, frequently used to document effects of treatment on exercise capacity, have never been standardised. We studied the effects of encouragement on walking test performance in a randomised study that controlled for the nature of the underlying disease, time of day, and order effects. We randomised 43 patients with chronic airflow limitation or chronic heart failure or both to receive or not receive encouragement as they performed serial two and six minute walks every fortnight for 10 weeks. Simple encouragement improved performance (p less than 0.02 for the six minute walk), and the magnitude of the effect was similar to that reported for patients in studies purporting to show beneficial effects of therapeutic manoeuvres. Age and test repetition also affected performance. These results demonstrate the need for careful standardisation of the performance of walking tests, and suggest caution in interpreting studies in which standardisation is not a major feature of the study design.

Effect of diuretics on cardiopulmonary performance in severe chronic airflow obstruction. A controlled clinical trial.

In a randomized, controlled trial, ten patients with pulmonary heart disease due to severe chronic airflow obstruction were stratified into two groups: group 1 had clinical features of congestive heart failure during respiratory failure and were regularly receiving diuretics; group 2 had no such clinical features and were not receiving diuretics. In group 1, when placebo was substituted for diuretics, pulmonary edema developed in three patients; exercise performance and ventricular function of the remaining two patients deteriorated. In group 2, there was no difference in exercise tolerance or ventricular function between placebo and diuretic therapy. The clinical deterioration in group 1 was related to abnormal left ventricular function. Thus, diuretics benefit only patients who have clinical features of congestive heart failure. In patients with isolated abnormal right ventricular function, diuretics may be harmful.

Occupational asthma without bronchial hyperresponsiveness.

Current asthma (variable air-flow obstruction) is often excluded by the presence of normal bronchial responsiveness. We report a patient with occupational asthma that was presumed to be caused by sensitization and exposure to toluene diisocyanate (TDI). Variable air-flow obstruction measured by peak flow rates (PFR), and symptoms of asthma reversed by salbutamol, occurred after natural exposure to TDI when methacholine bronchial responsiveness was well into the nonasthmatic range. The asthma occurred at the end of, or just after work, suggesting the occurrence of late asthmatic responses. While the patient continued at work, the late asthmatic responses became progressively more severe as methacholine responsiveness progressively increased into the asthmatic range. This suggests that, in individual subjects, the degree of bronchial responsiveness is a determinant of the severity of the late asthmatic response. When the patient stopped work, spontaneous symptoms of asthma and increased diurnal variation of PFR recurred spontaneously until methacholine responsiveness returned into the normal range. These observations indicate that asthma can occur at a time when methacholine bronchial responsiveness is normal, providing the stimulus is strong enough. They further demonstrate that the magnitude and ease of bronchoconstriction relates to the degree of methacholine responsiveness.

Detrimental effects of hydralazine in patients with chronic air-flow obstruction and pulmonary hypertension. A combined hemodynamic and radionuclide study.

The acute effects of intravenously administered hydralazine on pulmonary hemodynamics and ejection radionuclide angiography were evaluated in 9 patients with chronic airflow obstruction (forced expiratory volume in one second, 1.2 +/- 0.8 L, mean +/- SD), pulmonary hypertension (mean pulmonary artery pressure (PAP), 29 +/- 13 mmHg), and sleep hypoxemia (maximal sleep desaturation, 20 +/- 16%). The effect of hydralazine was measured during both normoxia and hypoxia and compared with the effect of hyperoxia. Hydralazine increased cardiac index from 3.7 +/- 0.2 to 4.5 +/- 0.8 L/min/m2 (mean +/- SE, p less than 0.05, n = 9), but there were no significant changes in PAP (29 +/- 4 to 32 +/- 4 mmHg), mean pulmonary vascular resistance index (PVRI) (390 +/- 80 to 360 +/- 80 dyn.s.cm.-5.m2), mean right ventricular stroke work index (12.7 +/- 2.7 to 15.0 +/- 2.2 g.m/m2), and mean pulmonary capillary wedge pressure (12 +/- 1 to 12 +/- 2 mmHg). Mean right ventricular ejection fraction and mean right ventricular end diastolic volume also were not changed after treatment with hydralazine. Hyperoxia was used to assess the reversibility of pulmonary hypertension and to compare this with hydralazine. Hyperoxia increased arterial oxygen saturation (SaO2) from 91 +/- 1 to 96 +/- 1% and decreased the cardiac index from 3.8 +/- 0.1 to 3.1 +/- 0.2 L/min/m2 (p less than 0.02, n = 6) but, as with hydralazine, there was no significant change in PAP (28 +/- 6 to 25 +/- 6 mmHg) and PVRI (350 +/- 120 to 360 +/- 80 dyn.s.cm-5).m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone pulmonary toxicity.

Numerous cytoplasmic lamellar bodies were seen in many cell types in an open lung biopsy from a patient on amiodarone therapy. These membrane-bound lamellar bodies were characterized by distinct, concentric parallel membranes and peripheral granular densities. Their morphology and distribution suggest a metabolic disorder of phospholipid degradation induced by this drug. The differential diagnosis of lamellar body accumulation in the lung is discussed. This case emphasizes the desirability for ultrastructural study of lung biopsies in such potentially reversible lung disease.

The effect of intravenously administered almitrine, a peripheral chemoreceptor agonist, on patients with chronic air-flow obstruction.

Almitrine, a peripheral chemoreceptor agonist, was given intravenously in a dose of 0.5 mg/kg/h for 2 h in a randomized double-blind manner with placebo, to 11 patients with severe chronic air-flow obstruction and hypoxemia (SaO2 less than 90%). There was no significant placebo effect. Maximal respiratory effect occurred at the end of the almitrine infusion with an increase in ventilation from 8.2 + 0.9 to 11.6 + 1.5 L/min (mean +/- SEM), and improvements in SaO2 from 83 +/- 3 to 90 +/- 2%, in PaO2 from 48 +/- 2 to 55 +/- 3 mmHg, and in PaCO2 from 54 + 3 to 47 +/- 4 mmHg. Venous admixture was reduced from 38 +/- 4% to 22 +/- 3%. In 4 patients, blood gas values substantially improved, but there was no change in total ventilation for ventilatory pattern. This study of acute effects showed that almitrine improved arterial PO2 and PCO2 in patients with chronic air-flow obstruction both by increasing ventilation and by improving ventilation-perfusion relationships.

Effect of digoxin on right ventricular function in severe chronic airflow obstruction. A controlled clinical trial.

The effect of digoxin on the right and left ventricular ejection fractions in 15 patients with pulmonary heart disease caused by severe chronic airflow obstruction was studied in a double-blind, randomized, placebo-controlled trial. All patients were ambulatory and had clinical features of right but not left ventricular dysfunction. Equilibrium radionuclide angiography showed reduced right ventricular ejection fraction in all patients and reduced left ventricular ejection fraction in four. After 8 weeks of digoxin treatment, the abnormal left ventricular ejection fractions were normal; right ventricular ejection fractions increased only in those patients who had had abnormal left ventricular ejection fractions. We conclude that in patients with pulmonary heart disease, the right ventricular ejection fraction is abnormal and improves with digoxin treatment only when the left ventricular ejection fraction also is initially abnormal.

Interpretation of blood gas analysis by physicians in a community teaching hospital.

Forty-two interns and residents on the staff of a community teaching hospital were questioned to assess their understanding of blood gas abnormalities. Misunderstandings were such that 24% of the residents and interns might have given inadequate care had their interpretations dictated practice. Few therapeutic misadventures in fact occurred, largely because of supervision. Even without supervision, it is unlikely that much harm would have come about, partly because pattern recognition and rules of thumb provided adequate guidance and partly because no notice was taken of the results of the blood gas analysis anyway. Those who wish to promote rational practice should direct their educational efforts to improved understanding of the mechanisms of hypoxaemia and of the chemical, physiological and pathophysiological interactions of PCO2, bicarbonate and pH in the various acid-base disorders.

Care for patients with severe chronic airflow obstruction and respiratory failure.

The successful care of patients with disorders causing chronic airflow obstruction (CAO) and potential chronic respiratory failure and pulmonary heart disease (cor pulmonale) requires the following:1. Recognize CAO as the cause of a patient's problem.2. Describe and measure airflow obstruction and the individual's response to it.3. Undertake therapeutic trials to maximize airflow.4. Teach patients monitoring skills and interventions in order to prevent acute respiratory failure and hospital admission.5. Maintain optimism and interest in the patient's chronic illness, appreciating its impact on the total person and his daily life.

Subsittution of inhaled beclomethasone dipropionate for ingested prednisone in steroid-dependent asthmatics.

The effect of inhaled beclomethasone dipropionate (dose, 400 mug daily) was investigated in 31 prednisone-dependent asthmatics. In a double-blind noncrossover study of 25 patients dependent on a daily prednisone dose of 17.5 mg or less, the dose of ingested prednisone was significantly diminished through the use of beclomethasone as compared with placebo (P < 0.001). In a subsequent single-blind study of the 12 patients who had received placebo, a similar decrease in prednisone dose was possible when these patients received beclomethasone. In all 25 patients the effect of beclomethasone was maintained for 2 years; 9 came to require less beclomethasone and 1 required more. In an additional single-blind study of six patients with severe asthma, dependent on prednisone in a dose of 20 to 25 mg/d, the response to beclomethasone was more variable and less significant (P < 0.01). However, at 2 years there was no significant benefit (P > 0.05) and there were two treatment failures.In patients in whom reduction of dose or discontinuation of prednisone was possible plasma cortisol values before and after corticotropin administration increased significantly (P < 0.001). Prednisone reduction was associated with the appearance of mild musculoskeletal steroid-withdrawal symptoms of short duration in 15 patients, and recurrence of symptoms of rhinitis in 15 patients. Side effects of beclomethasone included episodes of hoarseness in 6 and easily treated oropharyngeal Candida albicans infection in 14.