Risk of mortality from cardiovascular and respiratory causes in patients with chronic obstructive pulmonary disease submitted to follow-up after lung resection for non-small cell lung cancer

AIM: Considerable controversy surrounds mortality from non-neoplastic diseases during the postoperative follow-up of patients with non-small cell lung cancer (NSCLC) and chronic obstructive pulmonary disease (COPD). This study investigated the incidence of mortality from cardiovascular and respiratory (CVR) causes in patients with COPD submitted to follow-up after lung resection for NSCLC, and identified preoperative and postoperative risk factors. METHODS: A total of 398 patients with mild or moderate COPD were followed up in our department after lung resection for NSCLC (median follow-up 61 months). Statistical analysis of the data was carried out to determine the incidence and the prognostic factors of postoperative death from CVR causes. RESULTS: Of the 398 resected patients, 186 survived without tumor recurrence; 24/186 (12.9%) died of CVR causes (acute respiratory failure, pneumonia, pulmonary embolism, acute pulmonary edema, acute myocardial ischemia or stroke). These 24 patients had a higher frequency of pre-existing coronary artery disease or heart failure (P=0.0003), predicted postoperative FEV1 <1000 mL (P=0.0008), exertional dyspnea (P=0.0000), and 30-day operative cardiopulmonary complications (P=0.001). Protective features were young age (<40 years), early stage disease, and minor resection (lobectomy). Independently significant adverse prognostic factors were stage III-IV disease (cumulative CVR death rate 47% at 5-10 years; P=0.028 vs. stage I-II) and completion pneumonectomy or partial resection of the other lung for a second primary tumor (cumulative CVR death rate 50% and 57%, respectively, at 5-10 years; P=0.0016 vs. all other resections). Older age and tumor histology were significant risk factors only in patients with advanced stage disease. CONCLUSION: The findings suggest that postoperative CVR death may be expected in patients with COPD and advanced stage NSCLC or in those undergoing completion pneumonectomy or partial resection of the other lung for a second primary tumor. Other risk factors are previous coronary artery disease and/or heart failure, exertional dyspnea and predicted postoperative FEV1 <1000 mL.     

Morphometry of pulmonary arteries from angiograms in chronic obstructive lung disease.

The application of morphometric techniques based on Strahler orders to the study of pulmonary angiograms is described. When the pulmonary arterial tree is ordered by Strahler's method, peripheral branches have the lowest orders and the main pulmonary artery the highest order. The mean diameter of vessels in each order can then be determined. Pulmonary angiograms were obtained from 16 patients, 10 of whom had chronic obstructive lung disease (COLD), the other six having normal angiograms. Six orders of branching were found in vessels of 1 mm diameter or greater, and a plot of log mean diameter versus order from the normal angiograms was linear. The mean diameters of orders 2, 3, and 4 (diameter 2 to 7 mm) from COLD patients were significantly reduced ((p less than 0.01) and the log mean diameter versus order plot was concave upwards. These changes were more marked when TLC was raised than when it was normal. Plots of diameters of vessels from zones of the lung in which the pathology was well advanced (as judged by radiological changes) showed even greater reduction in the middle orders. These changes are probably the result of stretching of vessels in emphysematous lesions and diminution of blood flow from loss of capillary bed.     

Respiratory symptoms and 30 year mortality from obstructive lung disease and pneumonia

BACKGROUND: As little is known about the long term relationship between respiratory symptoms and mortality from non-malignant respiratory diseases, a study was undertaken to investigate the predictive value of respiratory symptoms and symptom load for mortality from obstructive lung disease (OLD) and pneumonia in the long term in a Norwegian population. METHODS: In 1972, 19 998 persons aged 15-70 years living in Oslo were randomly selected for a respiratory survey. The response rate was 89%. All were followed for 30 years. The association between cough, asthma-like symptoms, two levels of dyspnoea on exercise, a symptom score, and mortality from OLD and pneumonia were investigated separately for men and women by multivariable analyses, with adjustment for age, occupational exposure to air pollution, and smoking habits. RESULTS: OLD accounted for 43% and pneumonia for 50% of all deaths from respiratory causes. In men the hazard ratio for mortality from OLD varied from 4.0 (95% confidence interval (CI) 2.4 to 6.5) for cough to 9.6 (95% CI 5.1 to 18.3) for severe dyspnoea, and in women from 5.1 (95% CI 2.3 to 11.3) for moderate dyspnoea to 13.0 (95% CI 6.0 to 28.3) for severe dyspnoea. The symptom score was strongly predictive of death from OLD in a dose-response manner. CONCLUSIONS: There is a significant, positive, strong association between respiratory symptoms and 30 year mortality from OLD. The association between respiratory symptoms and mortality from pneumonia is weaker and not significant.     

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease

BACKGROUND: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown. METHODS: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality. RESULTS: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93). CONCLUSIONS: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years.     

C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease

BACKGROUND: Although C-reactive protein (CRP) levels are increased in chronic obstructive pulmonary disease (COPD), it is not certain whether they are associated with adverse clinical outcomes. METHODS: Serum CRP levels were measured in 4803 participants in the Lung Health Study with mild to moderate COPD. The risk of all-cause and disease specific causes of mortality was determined as well as cardiovascular event rates, adjusting for important covariates such as age, sex, cigarette smoking, and lung function. Cardiovascular events were defined as death from coronary heart disease or stroke, or non-fatal myocardial infarction or stroke requiring admission to hospital. RESULTS: CRP levels were associated with all-cause, cardiovascular, and cancer specific causes of mortality. Individuals in the highest quintile of CRP had a relative risk (RR) for all-cause mortality of 1.79 (95% confidence interval (CI) 1.25 to 2.56) compared with those in the lowest quintile of CRP. For cardiovascular events and cancer deaths the corresponding RRs were 1.51 (95% CI 1.20 to 1.90) and 1.85 (95% CI 1.10 to 3.13), respectively. CRP levels were also associated with an accelerated decline in forced expiratory volume in 1 second (p < 0.001). The discriminative property of CRP was greatest during the first year of measurement and decayed over time. Comparing the highest and lowest CRP quintiles, the RR was 4.03 (95% CI 1.23 to 13.21) for 1 year mortality, 3.30 (95% CI 1.38 to 7.86) for 2 year mortality, and 1.82 (95% CI 1.22 to 2.68) for > or =5 year mortality. CONCLUSIONS: CRP measurements provide incremental prognostic information beyond that achieved by traditional markers of prognosis in patients with mild to moderate COPD, and may enable more accurate detection of patients at a high risk of mortality.     

Exercise-induced airway obstruction in relation to chronic obstructive lung disease

Gimeno, F., Berg, W. Chr., Steenhuis, E. J., de Vries, K., Peset, R., and Sluiter, H. J. (1974).Thorax,29, 16-20. Exercise-induced airway obstruction in relation to chronic obstructive lung disease. Forty-two patients with chronic obstructive lung disease and clinically suspected exercise-induced airway obstruction were studied to ascertain whether those with proven exercise-induced airway obstruction had specific distinguishing features. Exercise-induced airway obstruction (defined as a fall of FEV₁ of at least 10% of the pre-exercise values) was detected in 20 of the 42 patients. These 20 were found to have a lower elastic recoil but were otherwise identical with the remainder as regards clinical and physiological abnormality. It is postulated that exercise-induced airway obstruction can be a manifestation of chronic obstructive lung disease.     

Structure of central airways in current smokers and ex-smokers with and without mucus hypersecretion: relationship to lung function.

Forty-five patients who underwent thoracotomy and lung resection for tumour were studied to compare the structure of the central airways in current smokers and ex-smokers. The patients were divided into four groups: current smokers with mucus hypersecretion (n = 15), current smokers without mucus hypersecretion (n = 14), ex-smokers with mucus hypersecretion (n = 5), and ex-smokers without mucus hypersecretion (n = 11). Quantitative histological studies of the airway wall showed no difference in gland size, smooth muscle, connective tissue, or Reid index between the groups. The central airways of patients with mucus hypersecretion showed increased mucosal inflammation. The five ex-smokers in whom mucus hypersecretion persisted after they had stopped smoking had both central and peripheral airways affected by the inflammatory response, and these patients also had an abnormal result in the nitrogen washout test.     

Vertebral compression fractures and mineral metabolism in chronic obstructive lung disease.

Chronic obstructive lung disease has been reported as a cause of osteoporosis, though whether this association is due to the disease itself or to corticosteroid treatment has not been elucidated. We studied 44 male patients with chronic obstructive lung disease (mean (SD) FEV1 39% (14%) of predicted normal) who were not having long term corticosteroids. No differences in a vertebral deformity score or in metacarpal index were found between them and a control group of similar age. Indices of bone formation (serum osteocalcin) and bone resorption (urinary hydroxyproline) were normal and parathyroid hormone and 1,25-dihydroxyvitamin D were also normal. Serum 25-hydroxyvitamin D was decreased, indicating depleted vitamin D. Calcitonin concentrations were higher in the patient than in the control group of the same age. There was no increase in the prevalence of osteoporosis in patients with chronic obstructive lung disease who had not received long term corticosteroid treatment. Increased concentrations of calcitonin may protect the skeleton from the detrimental effect of hypovitaminosis D.     

Effects of fenoterol on ventilatory response to hypercapnia and hypoxia in patients with chronic obstructive pulmonary disease

BACKGROUND: It has previously been shown that fenoterol, a beta 2 adrenergic agonist, increases the ventilatory response to hypoxia (HVR) and hypercapnia (HCVR) in normal subjects. The effects of beta 2 adrenergic agonists on chemoreceptors in patients with chronic obstructive pulmonary disease (COPD) remain controversial. This study was designed to examine whether fenoterol increases the HVR and HCVR in patients with COPD. METHODS: The HCVR was tested in 20 patients using a rebreathing method and the HVR was examined using a progressive isocapnic hypoxic method. The HCVR and HVR were assessed by calculating the slopes of plots of occlusion pressure (P0.1) and ventilation (VE) against end tidal carbon dioxide pressure (PETCO2) and arterial oxygen saturation (SaO2), respectively. Spirometric values, lung volumes, and respiratory muscle strength were also measured. The HCVR and HVR were examined after the oral administration of fenoterol (15 mg/day) or placebo for seven days. RESULTS: Fenoterol treatment increased the forced expiratory volume in one second (FEV1) and inspiratory muscle strength. In the HCVR the slope of P0.1 versus PETCO2 was increased by fenoterol from 0.35 (0.23) to 0.43 (0.24) (p < 0.01). Moreover, the P0.1 at PETCO2 of 8 kPa was higher on fenoterol than on placebo (p < 0.05) and the VE was also greater (p < 0.01). In the HVR fenoterol treatment increased the P0.1 at 80% SaO2 from 0.90 (0.72) to 0.97 (0.55) kPa (p < 0.05) while the slopes of the response of P0.1 and VE were not changed. CONCLUSIONS: Fenoterol increases the ventilatory response to hypercapnia in patients with COPD, presumably by stimulation of the central chemoreceptor. The hypoxic ventilatory response is only slightly affected by fenoterol.


     

Errors in the measurement of total lung capacity in chronic obstructive lung disease.

The standard plethysmographic method of measuring total lung capacity (TLC) has been reported to result in spuriously high estimates in patients with severe airway obstruction. The helium-dilution method is known to underestimate TLC in the same patients. To determine the magnitude of these possible errors we measured TLC by four methods in 20 patients with varying degrees of chronic obstructive lung disease and in 11 normal subjects. TLC was measured by (1) helium dilution (TLCHe); (2) a volume-displacement body plethysmograph, box volume being plotted against mouth pressure (TLCm); (3) the same body plethysmograph with volume plotted against pressure measured with an oesophageal balloon (TLCes); and (4) a radiological technique (TLCxr). In normal subjects there was no difference between TCLm (6.57 +/- 1.20) and TLCes (6.51 +/- 1.24). In the patients with chronic obstructive lung disease TLCm gave results significantly higher than those of any other method. If TLCes is taken as the closest estimate of true TLC, TLCm consistently overestimates and TLCHe underestimates TLC. There was no relationship between the degree of airway obstruction and (TLCm - TLCes) but there was between (TLCes - TLCHe) and severity of airway obstruction. We conclude that using mouth pressure in the plethysmographic measurement of TLC in patients with chronic obstructive lung disease results in consistent but slight overestimation of TLC.     

Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.

BACKGROUND: Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. METHODS: Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. RESULTS: At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. CONCLUSIONS: In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.