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Measurement of nitric oxide levels in exhaled air is commonly performed using a chemiluminescence detector. However, water vapour and carbon dioxide affect the chemiluminescence process. The influence of these gases at the concentrations present in exhaled air, has not yet been studied. For this in vitro study, mixtures of 50, 100 and 200 parts per billion (ppb) NO in air were prepared and fed into the NO analyser either directly or bubbled through water. Mixtures with CO2 were prepared by adding 0-10% CO2 to the diluent air. We found a significant decrease in NO readings in the water-saturated samples compared to the dry gas (p < 0.001), strongly dependent on the partial pressure of water. NO levels in exhaled air (mean 10 +/- 2 ppb) showed a decrease of 17 +/- 3% when water vapour was not absorbed. From the experiments with CO2 we found a decrease in NO reading of 1.04 +/- 0.07% per volume CO2 (%). Presence of water vapour, thus, leads to a systematic underestimation of NO levels. Insertion of a water absorber might, therefore, be advantageous. The influence of CO2 concentrations in the normal respiratory range is negligible. With high expiratory CO2 levels as applied in permissive hypercapnia, the effects may be substantial.

Unlabelled: We evaluated the suitability of fluorocarazolol for in vivo studies of cerebral beta-adrenoceptors because (S)-1'-[18F]fluorocarazolol has a higher affinity to beta-adrenoceptors than to serotonergic receptors (pKi beta 1 9.4, beta 2 10.0, 5HT1A 7.4, 5HT1B 8.1) and rapidly crosses the blood-brain barrier., Methods: The (S)-[18F]fluorocarazolol (74 MBq, > 37 TBq/mmol) was intravenously administered to healthy volunteers on two separate occasions with an interval of at least 1 wk. The initial injection was without pretreatment, but before the second injection, the volunteers received the beta blocker (+/-)-pindolol (3 x 5 mg orally, during 18 hr). The brain was studied with a PET camera in dynamic mode., Results: Uptake of radioactivity delineated gray matter and was particularly high in the posterior cingulate, precuneus and striatum. Low uptake occurred in the thalamus, whereas the lowest uptake was observed in the white matter of the corpus callosum. After pindolol pretreatment, uptake was reduced and its distribution became homogeneous throughout the brain. The ratio of total-to-nonspecific binding was about 2 at 60 min, increasing to 2.5-2.75 at longer intervals., Conclusion: Fluorocarazolol is the first radioligand that can visualize cerebral beta-adrenoceptors and may enable monitoring of these binding sites during disease.

High doses of tumor necrosis factor-alpha (TNF) seem to be effective in the treatment of solid tumors in the extremities. By applying current intensive care technology, systemic administration of high doses of TNF levels might be feasible for the treatment of cancer in other localizations. To establish the early and late effects of high systemic TNF levels on the lungs, we determined lung function parameters in 12 patients before and after hyperthermic isolated limb perfusion (HILP) with TNF and melphalan. Because of leakage during perfusion, mean maximum systemic TNF levels of 60.0 ng/ml (range, 0.3-356 ng/ml) were obtained. Significant alterations in the vital capacity (VC), the capillary blood volume (Vc), the diffusing capacity of the alveolocapillary membrane (Dm), and the transfer capacity of the lungs for carbon monoxide per unit alveolar volume (KCO) were observed 1 week after HILP. Eight weeks after HILP, they returned to pretreatment value. Alterations in lung functions were not related to the maximum systemic TNF level. In conclusion, disturbances in pulmonary functions are observed in patients after HILP with TNF and melphalan. These disturbances, which are probably partly caused by high systemic TNF levels, are reversible and would not preclude administration of systemic TNF in high doses.

Unlabelled: S-1'-[18F]fluorocarazolol was administered to healthy volunteers to assess its potential for noninvasive measurement of regional pulmonary and myocardial beta-adrenoceptor densities., Methods: High-specific activity fluorocarazolol was intravenously injected on two separate occasions within a 1-wk interval. The initial injection was without pretreatment, but before the second injection, the volunteers either inhaled salbutamol (2 x 200 micrograms aerosol) or they ingested pindolol (3 x 5 mg during a 12-hr interval). Twenty-eight PET time frames of 31 planes were acquired over a period of 60 min after each injection. Blood samples were drawn and analyzed for the presence of fluorocarazolol and radioactive metabolites., Results: Uptake of fluorocarazolol in the target tissues was hardly affected by salbutamol but was strongly depressed by pindolol. Pulmonary and myocardial tissue-to-plasma concentration ratios of fluorocarazolol reached plateau values of 11.6 +/- 0.6 (lungs) and 18.1 +/- 1.0 (heart) at 45-50 min postinjection. These values were reduced to 2.0 +/- 0.4 and 2.0 +/- 0.6 after treatment with pindolol., Conclusion: These data indicate that: 1. Pulmonary and myocardial uptake of radioactivity after intravenous administration of S-1'-[18F]fluorocarazolol represents radioligand binding to beta-adrenoceptors. 2. Pulmonary binding occurs mainly in alveoli rather than in airway smooth muscle under these conditions. 3. Binding kinetics do not preclude quantification of receptors with compartment models.

In studies with a long-term follow-up, peak expiratory flow (PEF) meters are often used to assess bronchial obstruction. The question arises whether data obtained with these frequently used meters are still reliable after several years of use, and whether the old meters should be renewed after a certain period. In the present study, we tested the reliability of PEF values measured with mini-Wright PEF meters that had been used frequently for 5 yrs. The values obtained with these meters were compared with values measured with identical but new meters, in 50 patients with obstructive airways disease. Though statistically significant, there was no clinically significant difference in mean PEF measured with the old and new meters in most patients (mean difference 10.2 L.min-1). However, on an individual basis, the differences between old and new meters could be large (upper and lower limits of agreement (mean +/- 2 SD) being 63.6 and -43.2 L.min-1, respectively). We conclude that mean peak expiratory flow values measured with frequently used mini-Wright peak expiratory flow meters are still reliable after 5 yrs. In long-term studies, renewal of peak expiratory flow meters should be restricted to cases of obvious malfunction.

Quantitation of muscarinic receptors in the lungs in vivo with positron emission tomography (PET) is of clinical interest. For that purpose we decided to develop [11C]-labeled ligands with a high affinity (KD < 0.1 nM). Three quaternary muscarinic antagonists, racemic N-methylpiperidin-4-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide 1a (pKB = 10.39), its (R)-isomer 1b (pKB = 11.08), and (R,R)-quinuclidin-3-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate methiodide 2 (pKB = 11.28), were labeled by reacting [11C]CH3I with their tertiary amine precursors. The enantiomerically pure tertiary amine precursors were prepared by stereoselective synthesis starting from (R)-(-)-mandelic acid. In vitro binding assay of 1b and 2 demonstrated that both ligands bind with very high affinity to the muscarinic receptor subtypes M1, M2, and M3. They are more potent than the muscarinic antagonist (R)-N-methylquinuclidinyl benzilate ((R)-MQNB). Distribution studies with 1a, 1b, and 2 in control and atropine-treated male Wistar rats demonstrated significant specific binding (90-99% of total issue uptake) in tissues containing cholinoceptors (heart, intestine, lung, pancreas, spleen, stomach, submandibular gland). Because the tissue/plasma concentration ratios of 1b are most favorable, this ligand was used for further evaluation. Analysis of plasma samples showed a very rapid clearance (t1/2 = 0.3 min) of the radioligand 1b and a relatively slow appearance of a hydrophilic metabolite. At 15 min postinjection of 1b, analysis of heart, lungs, and liver showed that respectively 99%, 88%, and 8% of the tissue radioactivity corresponded with the parent compound. Ligand 1b appears to be an excellent candidate for PET studies of mAChR receptors in heart and lungs.

Our aim was to study the extent of pulmonary toxicity after high-dose chemotherapy and radiotherapy in breast cancer patients. In a retrospective study the pulmonary symptoms and chest X-rays were analyzed before, during and after treatment in 17 patients, treated with loco-regional radiotherapy to the breast/chest wall and the regional lymph nodes after the completion of high-dose chemotherapy and autologous bone marrow transplantation for locally advanced breast cancer. Lung function was evaluated between 15 and 46 months after completion of the irradiation. Nine patients (53%) had pulmonary symptoms during and/or within two months from irradiation. Radiographic changes were seen in twelve patients (71%) and a decreased diffusion capacity occurred in nine patients (53%). The spirometric values (VC and FEV1) were abnormal in two patients (12%). There is a high incidence of radiation pneumonitis, although no consistent correlation between the various parameters (pulmonary symptoms, chest X-rays and lung function tests) could be found.

Background: Patients with airway obstruction may spontaneously breathe with a positive expiratory pressure by pursing their lips during expiration, especially in case of dyspnea. Dyspnea seems to be related to increased activity of the respiratory muscles. A potential explanation for the use of pursed lips breathing (PLB) is that this type of breathing leads to a reduction of respiratory muscle activity. The purpose of this study was to assess the effect of breathing with a positive expiratory pressure of 5 cm H2O, simulating pursed lips breathing (SPLB), on respiratory muscle activity and pulmonary function during induced airway obstruction., Methods: In twelve asthmatic patients, tonic and phasic electromyographic (EMG) activity of the following muscles was obtained: scalene muscle, parasternal muscle, and abdominal muscles. Pulmonary function and EMG measurements were performed before and after propranolol induced airway obstruction., Results: Simulated pursed lips breathing resulted in a significant increase of functional residual capacity and tidal volume both at baseline and during airway obstruction. Phasic respiratory muscle activity during PEP breathing increased especially at baseline. We conclude that beneficial effects of breathing with a positive expiratory pressure of 5 cm H2O, which is similar to pursed lips breathing, cannot be explained by changes in respiratory muscle activity or pulmonary function.

We examined whether cisplatin-induced nephrotoxicity augmented bleomycin-induced pulmonary toxicity in patients with testicular cancer treated with etoposide and cisplatin with (BEP) or without bleomycin (EP). Before and at 3-week intervals during chemotherapy, creatinine clearance and lung functions were measured. In patients receiving BEP, deterioration of renal function correlated with a decrease in transfer factor of the lungs for carbon monoxide (TLCO) and vital capacity (VC), parameters known to reflect bleomycin-induced pulmonary effects. Other lung functions did not correlate with renal function. In the EP group, no relationships were observed at all. These observations suggest enhanced pulmonary effects of bleomycin when combined with cisplatin. Therefore, attention should be paid to the potential development of bleomycin-induced pulmonary toxicity in patients treated with BEP.

To test the hypothesis that surfactant nebulization improves pulmonary function and reduces bronchial responsiveness to histamine, we studied 12 children with asthma. We measured before and after inhalation of 100 mg nebulized natural-derived bovine surfactant (Alveofact (registered)) and after nebulization of 0.9% NaCl the change in peak expiratory flow, vital VC, FEV1, and forced expiratory flows at 50 and 75% of the flow-volume curve. In addition, we performed a histamine inhalation challenge. We did not find any significant changes in these parameters after nebulization of surfactant. These findings indicate that the inhalation of nebulized surfactant does not alter airflow obstruction and does not alter bronchial responsiveness to histamine in asthmatic children with airflow obstruction.

We investigated whether 12 weeks of rehabilitation at home in patients with chronic obstructive pulmonary disease (COPD) had a beneficial effect on lactate production, metabolic gas exchange data, workload of the inspiratory muscles, and dyspnoea during a maximal bicycle ergometer test. A second aim was to assess whether a change in dyspnoea was related to a change of inspiratory muscle workload. Forty three COPD patients with severe airways obstruction were included in the study: mean forced expiratory volume in one second (FEV1) 1.3 +/- 0.4 L (44% predicted), mean FEV1/inspiratory vital capacity (IVC) 37 +/- 8%. Twenty eight patients started a rehabilitation programme, whilst 15 patients received no rehabilitation. Rehabilitation was carried out at home; patients were supervised by a general practitioner, a physiotherapist and a nurse. Exercise tolerance was measured by means of a 6 min walking distance test (6MWD) and maximal workload (Wmax) during an incremental symptom-limited cycle ergometer test. Inspiratory muscle workload at Wmax was assessed with the Tension Time Index (TTI), and dyspnoea at Wmax with the Borg scale. After 12 weeks, the rehabilitation group showed a significantly larger increase in 6MWD (from 438 to 447 m) and in Wmax (from 70 to 78 W) compared with the control group. A significant improvement in oxygen consumption (V1O2) (from 1.0 to 1.1 L), lactate level (from 3.7 to 3.1 mEq.L(-1)), dyspnoea (from 6.0 to 4.5) and TTI (from 0.10 to 0.08) at Wmax occurred in the rehabilitation group during the programme. The reduction in TTI was not significantly correlated with the fall in dyspnoea, as assessed by the Borg scale. We conclude that 12 weeks of rehabilitation at home in COPD patients increases symptom-limited V1O2 in combination with an increased Wmax. At this significantly higher Wmax, there was a reduction in dyspnoea, lactate level and inspiratory muscle workload. The reduction in dyspnoea was not related to a decreased inspiratory muscle workload. This study shows that rehabilitation at home can produce beneficial physiological improvements during exercise in patients with chronic obstructive pulmonary disease.

Regular monotherapy with inhaled beta 2-agonists may lead to a temporary increase of airway obstruction and increase of airway responsiveness after cessation of treatment. We investigated whether anti-inflammatory therapy may affect these rebound phenomena. In a double-blind, placebo-controlled study, we assessed lung function (FEV1) and airway responsiveness (PC20 methacholine [PC20]) during and after cessation of 2 wk of regular treatment with placebo and low-dose (250 micrograms) and high-dose (1,000 micrograms) inhaled terbutaline three times daily. Patients with mild allergic asthma (means [+/- SD] age of 28.2 +/- 6.6 yr, mean FEV1% of 91.9 +/- 14.6%, and geometric mean PC20 of 0.25 mg/ml) were studied. One group (n = 16) was randomized to budesonide treatment, 400 micrograms three times daily; the other group (n = 14) to placebo. PC20 and FEV1 were measured 10, 14, 34, and 82 h after the last terbutaline or placebo inhalation. A different method of statistical analysis was used, in that measurements performed at 10, 14, and 34 h were expressed relative to 82 h values in each period as an area-under-the-curve (AUC) value. FEV1 did not significantly change during placebo and budesonide treatment. Mean PC20 and morning and evening peak expiratory flow were significantly higher during budesonide treatment (p < 0.01). PC20 did not significantly change after cessation of terbutaline treatment in both placebo and budesonide treatment groups. AUC-FEV1 values after cessation of treatment with both doses of terbutaline were significantly different from the 82 h values (p < 0.05). The decrease in FEV1 was significantly greater after the last terbutaline and placebo inhalation in the placebo group compared with the budesonide treatment group (p = 0.02). We conclude that cessation of regular treatment after 2 wk with both low-dose and high-dose inhaled terbutaline does not result in a significant rebound airway responsiveness in patients with mild asthma. However, the results suggest a small rebound bronchoconstriction that does not occur when asthmatic patients are also treated with budesonide.

In order to examine changes in pulmonary function in patients with locally advanced non-small-cell lung cancer (NSCLC) before, during, and after standard radiotherapy or combined chemoradiotherapy, we conducted a prospective study involving patients with such cancer, who were treated with radiation alone or with concurrent radiation and carboplatin from October 1992 to February 1994 at the University Hospital in Groningen, the Netherlands. Thirty-five patients were treated. Two patients were excluded because of pulmonary emphysema. Pretreatment values of TLC, VC, the gas-transfer coefficient (Kco), the pulmonary diffusing membrane factor (Dm), and pulmonary capillary blood volume (Vcap) were lower than in normal subjects and patients with chemotherapy-naive germ-cell carcinoma who had a similar pulmonary tumor load as the result of hematogenous metastases. The NSCLC patients' reduced Kco was explained by a decrease in Dm, a measure of alveolar-capillary membrane disturbance, and a similar decrease in Vcap. Pretreatment TLC did not correlate with Vcap or Dm, indicating extra- rather than intrapulmonary vascular and lymphatic obstruction as an explanation for the reduced Vcap and Dm. Locally advanced NSCLC was treated with radiation (n = 16) or combined continuous carboplatin infusion and radiation (n = 17). No changes in TLC, VC, Kco, Dm, or Vcap were observed during and 2 wk after the end of either treatment, nor were any differences in pulmonary function observed with the two treatments, indicating an absence of additional acute pulmonary toxicity caused by continuously infused carboplatin in this patient group.(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence of abnormalities in lung elasticity in patients with asthma or chronic obstructive pulmonary disease (COPD) is still unclear. This might be due to uncertainties concerning the method of analysis of quasistatic deflation lung pressure-volume curves. Pressure-volume curves were obtained in 99 patients with moderately severe asthma or COPD. These patients were a subgroup from a Dutch multicentre trial; the entire group was selected on the basis of a moderately lowered % predicted forced expiratory volume in one second (FEV1), and a provocative concentration of histamine producing a 20% decrease in FEV1 (PC20) < 8 mg.mL-1 obtained with the 2 min tidal breathing technique. The curves were fitted with an exponential (E) model and an exponential model which took the linear appearance in the mid vital capacity range into account (linear-exponential (LE)). The linear-exponential model showed a markedly better fit ability, yielding additional parameters, such as the compliance at functional residual capacity (FRC) level as slope of the linear part (b), and the volume at which the linear part changed into the exponential part of the curve (transition volume (Vtr)). Vtr (mean value Vtr/total lung capacity (TLC) = 0.79 (SD 0.07)) showed a close positive linear correlation with obstruction and hyperinflation variables, which might be due to airway closure, already starting at elevated lung volumes. The exponential shape factor K was closely correlated with b and mean values (K = 1.32 (SD 0.05) kPa-1; b = 2.96 (SD 1.16) L,kPa-1) and the relationship with age was comparable with data reported in healthy individuals. The shape factor of the linear-exponential fit showed no correlation with any elasticity related variable. Neither the elastic recoil at 90% TLC, as obtained from the linear-exponential fit, nor its relationship with age were significantly different from healthy individuals. We conclude that, for a more accurate description of the lung pressure-volume curve, a linear-exponential fit is preferable to an exponential model. However, the physiological relevance of the shape parameter (KLE) is still unclear. These results indicate that patients with moderately severe asthma or COPD had, on average, no appreciable loss of elastic lung recoil as compared with healthy individuals.

In a double-blind, placebo-controlled study, we assessed the efficacy of inhaled budesonide on the course of newly diagnosed pulmonary sarcoidosis and whether budesonide treatment could postpone oral corticosteroid treatment. We evaluated: 1) symptoms; 2) chest radiography; 3) angiotensin-converting enzyme (ACE) in serum; and 4) lung function. Patients with histologically confirmed pulmonary sarcoidosis with chest radiographic stages I, II or III, and with an abnormal lung function (inspiratory vital capacity (IVC) < 79% of predicted or transfer factor of the lungs for carbon monoxide (TL,CO) < 77% pred) were included. Patients with radiographic stage II or III but with normal lung function were included when more than 20% of the total cell population in bronchoalveolar lavage fluid (BALF) was lymphocytes. Forty seven patients received placebo or budesonide (1.2 mg) once daily via a Nebuhaler for 6 months, followed by 6 months without treatment. Based on predetermined criteria, 11 patients were excluded during the blind treatment period as they needed oral prednisone: seven (28%) patients in the placebo group (n = 25) and four (18%) patients in the budesonide group (n = 22). Patient's Global Clinical Impression (GCI) score showed a significant difference in favour of budesonide. IVC showed a significant difference of 7.9% predicted between the two groups during the active treatment period. This difference persisted during follow-up, when the difference was 9.4% pred. TL,CO remained nearly unchanged over time, with no difference between the groups. Improvements in chest radiographic appearance and changes in serum ACE were similar for the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The validity of peak inspiratory mouth pressure (P.PI-max) as a measure of inspiratory muscle strength was investigated by comparing it with sniff Pes in patients with COPD with respect to (1) learning effect, (2) reproducibility, and (3) measures of agreement. To assess the discriminating capacity of P.PImax, we compared the values in patients with COPD with those of healthy elderly subjects. Thirty-four patients (mean age, 62.5 years) with severe airways obstruction (FEV1, 44% predicted; FEV1/IVC, 37% predicted) and 149 healthy subjects (age > or = 55 years) were included. P.PImax was assessed during a maximal static inspiratory maneuver, while sniff Pes was assessed during a maximal sniff maneuver. Both maneuvers were performed from residual volume ten times on the same day. P.PImax showed no learning effect, while the sniff maneuver used seven attempts to obtain a maximal value. The intraindividual coefficients of variation of P.PImax and sniff Pes were 11.2% and 6.0%, respectively. Measures of agreement showed no significant discrepancies between the mean P.PImax and mean sniff Pes (0.29 kPa, p = 0.49). There was a significant correlation (r = 0.57, p < 0.001) between both measurements. P.PImax was significantly (p < 0.001) lower in both male (8.2 kPa) and female (6.2 kPa) patients with COPD compared with healthy men (11.0 kPa) and healthy women (8.8 kPa). We conclude that P.PImax is a valid and noninvasive assessment of inspiratory muscle strength.

The effect of breathing with a positive expiratory pressure of 5 cm H2O was investigated in eight patients with COPD (mean [SD]FEV1 = 54 [13] percent predicted). Specific work of breathing (Wsp) and myoelectrical activity of the following respiratory muscles were measured at rest: scalene muscle, parasternal muscle, and abdominal muscles. Minute ventilation (VE), end-tidal CO2 (FETCO2), physiologic dead space ventilation (VD/VT), oxygen uptake (VO2), and carbon dioxide output (VCO2) were measured at rest and during an incremental bicycle exercise test. Dyspnea sensation during exercise was quantified using the CR10 Borg-scale. All measurements were performed with and without positive expiratory pressure (PEP). During PEP breathing at rest mean (SEM) Wsp increased from 0.54 (0.13) J/L to 1.08 (0.10) J/L. The SEM VE decreased from 12.4 (1.0) L/min to 10.5 (1.1) L/min, and SEM VD/VT decreased from 0.39 (0.03) to 0.34 (0.03). There was a tendency for an increased phasic respiratory muscle activity during PEP breathing of all three muscles as compared with undisturbed breathing, but the changes were not statistically significant. During the exercise test with PEP, VE, VD/VT, VO2, and VCO2 were significantly lower, and FETCO2 was significantly higher as compared with the values obtained during the exercise test with undisturbed breathing. Dyspnea sensation during the exercise test with PEP, however, was higher than during the test with undisturbed breathing. The PEP breathing at rest may be useful in patients with COPD as it increases the efficiency of ventilation by reducing dead space ventilation. This beneficial effect also occurs during exercise, but here it is accompanied by increased dyspnea sensation.

In a double-blind, double-placebo, randomized crossover study, we compared the effects of 6 wk of treatment with the anti-inflammatory drug nedocromil sodium (16 mg/day) with 6 wk of treatment with the bronchodilator drug albuterol (800 micrograms/day) in 29 adults with allergic asthma. After 3 and 6 wk of treatment with nedocromil sodium, patients were significantly less hyperresponsive to propranolol (p = 0.002 and p = 0.02) and almost significantly less hyperresponsive to histamine (p = 0.071 and p = 0.065). FEV1 and FVC percent predicted tended to be higher, morning PEF values increased significantly (p = 0.038 and p = 0.03), and diurnal and day-to-day PEF variation decreased (p = 0.03 and p = 0.093, p = 0.005 and p = 0.096, respectively) with nedocromil sodium treatment compared with albuterol treatment. Almost all symptoms (daytime and nighttime asthma, wheezing, shortness of breath) and the additional bronchodilator use were significantly reduced with nedocromil sodium treatment compared with albuterol treatment. Treatment with the anti-inflammatory drug nedocromil sodium was shown to be superior to treatment with the bronchodilator drug albuterol. The patient's clinical situation may deteriorate when beta 2-agonists are used continuously. Nedocromil sodium has good clinical effect, and it may serve as a first-line choice for antiinflammatory therapy in asthma.

The purpose of this study was to investigate the relationship between bronchoalveolar lavage (BAL)-derived parameters of interstitial lung disease and clinical and lung function parameters in 34 patients with sarcoidosis and 23 patients with idiopathic pulmonary fibrosis (IPF). BAL findings of healthy individuals served as controls. Cell content and differentiation of BAL fluid were determined. Oxygen radical (O2-) production of BAL cells and of blood polymorphonuclear (PMN) cells was measured. Phenotypes of lung and blood lymphocytes were determined by immunoperoxidase staining. In addition, lung function was assessed, chest X-rays were made and serum ACE was measured. Lymphocyte alveolitis in sarcoidosis was associated with increased alveolar macrophage (AM) O2- production (P < 0.025 vs. sarcoidosis with normal lymphocyte counts). Patients with extrapulmonary sarcoidosis had higher CD4/CD8 ratios in BAL (P < 0.025) and shorter disease duration (P < 0.01) than those with strictly pulmonary sarcoidosis. Disease duration in sarcoidosis correlated inversely with the number of BAL cells (r = -0.38, P < 0.05), the relative and absolute number of lymphocytes in BAL fluid (r = -0.34, P < 0.05 and r = -0.44, P < 0.01, respectively) and the percentage of CD4-positive cells and the CD4/CD8 ratio (r = -0.43, P < 0.05 and r = -0.48, P < 0.025, respectively). Although significant increases in O2- production by BAL cells were observed in both IPF and sarcoidosis, only in sarcoidosis was a higher AM O2- production associated with a significantly lower total lung capacity (r = -0.67, P < 0.005) and pulmonary diffusing capacity TLCO (r = -0.50, P < 0.05). In conclusion, our findings show that lung lymphocyte phenotypes differ among patients with pulmonary and extrapulmonary sarcoidosis and that O2- production is upregulated in active sarcoidosis. In addition, our findings suggest that different relationships between BAL data and lung function in patients with sarcoidosis and IPF may be explained by differences in disease duration. In IPF, disease duration is likely to be underestimated because of its insidious onset. In sarcoidosis, the presence of extrapulmonary symptoms, helpful to establish an early diagnosis, is associated with significant BAL lymphocytosis.

We examined the relationship between peripheral blood and bronchoalveolar lavage (BAL) lymphocyte phenotypes and lung function in 19 patients with SLE, and evaluated their association with disease activity. Lung function assessment showed a mildly restrictive pattern with frequent impairment of transfer factor for carbon monoxide (T1,co) and diffusing capacity of the alveolocapillary membrane (Dm), of late-expiratory airflow rates and with a high prevalence of increased airway resistance. T1,co, Kco and Dm correlated inversely with the numbers of CD8+ cells and CD56+/CD16+/CD3- (NK) cells in BAL. Oxygen radical production, both by stimulated and unstimulated BAL cells and blood polymorphonuclear leucocytes (PMN) was significantly increased in SLE. In comparison with healthy controls, patients with SLE had a lower percentage of CD19+ B cells in the BAL versus an increased percentage of these cells in peripheral blood. HLA-DR expression on CD4+ and CD8+ lung lymphocytes was markedly increased in SLE. Current SLE disease activity was not associated with changes in BAL or peripheral blood lymphocyte phenotypes. Our data suggest that an ongoing cell-mediated immune response is present in the lungs in SLE, particularly involving activated CD8+ T cells and CD56+/CD16+/CD3- NK cells. It is associated with up-regulated local production of oxygen radicals and with impaired pulmonary diffusing capacity. This inflammatory process seems to be independent of general SLE disease activity.

The purpose of this study was to register breathing patterns, in healthy subjects, during breathing with a positive expiratory pressure. Integrated electromyographic (IEMG) activity of the following muscles was assessed: scalene muscle, parasternal muscle and abdominal muscles, using surface electrodes. Inspiration time, expiration time, total breathing cycle time, tidal volume and breathing frequency were measured using a water-sealed spirometer. Functional residual capacity was measured using a body plethysmograph. Oxygen uptake and carbon dioxide output were measured using an automatized ergometry set-up. All measurements were performed during undisturbed breathing and during breathing with positive expiratory pressures of 5 and 15 cmH2O. Phasic activity, but not tonic activity, of the scalene muscles and the abdominal muscles increased significantly during breathing with the expiratory pressures. No significant change was observed in phasic or tonic activity of the parasternal muscle. Mean (SD) tidal volume increased significantly from 0.8(0.2) l during undisturbed breathing to 1.1(0.3) l and 1.5(0.7) l during breathing with the expiratory pressures of 5 cmH2O and of 15 cmH2O, respectively. Respiration times, breathing frequency, oxygen uptake, carbon dioxide output and functional residual capacity remained unchanged. It can be concluded that, in healthy subjects, positive expiratory pressure increases tidal volume by activity of both expiratory and inspiratory muscles, while functional residual capacity remains unchanged. The changes appeared to be pressure dependent.

A new method has been developed to measure airway functions in unanaesthetized, unrestrained guinea-pigs. The technique utilizes a specially designed pneumotachograph that is placed inside the trachea, and a saline-filled balloon, placed inside the pleural cavity. The pneumotachograph consists of a stainless steel cylinder with coaxial and perpendicular tubes attached to it, measuring the total pressure and the lateral pressure in the trachea, respectively. Via air-filled silicon conducting tubes, subcutaneously driven and permanently attached to the neck of the animal, the pressures are fed into a differential pressure transducer, yielding a pressure difference proportional to the airflow in the trachea. Via a saline-filled tubing, the pleural balloon is similarly attached to the neck of the animal, and pleural pressure (Ppl) is measured using a second pressure transducer. These data permit calculation of airway functions in conscious, unstressed animals. Control values for airway resistance (RAW), Ppl, tidal volume and respiratory frequency are all in the range of results reported previously for this species. A very significant correlation between RAW and Ppl (P < 0.001) was observed, indicating that sole Ppl-measurement can be used as a relatively simple and sensitive method to assess bronchial obstructive reactions in unrestrained guinea-pigs. Using a specially designed provocation cage, which allowed the animals to remain in a stress-free, unrestrained condition, the method has been successfully applied for the assessment of the dose-dependent bronchoconstrictor sensitivity to histamine as well as to allergen-induced early and late phase airway reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated separate and interactive effects of corticosteroids and bronchodilators on airflow obstruction and airway hyperresponsiveness. Twelve allergic subjects with asthma were treated in a double-blind, crossover, randomized study with budesonide, 1.6 mg daily for 3 weeks, prednisone, 40 mg daily, for 8 days, and placebo. After each period, dose-response curves were measured on 4 study days with doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo until a plateau in FEV1 was reached. A histamine challenge was then performed, and the provocation concentration causing a 20% fall in FEV1 (PC20) was calculated. The budesonide and prednisone regimens were equipotent. FEV1 was 81.2% of predicted after budesonide, 81.0% predicted after prednisone, and 67.5% predicted after placebo, bronchodilatation thus being 13.7% predicted (budesonide) and 13.5% predicted (prednisone). PC20 improved with 2.17 doubling concentrations (DCs) after budesonide, and 1.86 DCs after prednisone, compared with that of placebo. Salbutamol caused stronger bronchodilatation than ipratropium (26.2% versus 14.7% predicted) and a better protection against histamine challenge (3.95 versus 1.12 DC). The effects of corticosteroids and bronchodilators on FEV1 and PC20 were, in general, additive. This study emphasizes different modes of action on both airflow obstruction and airway hyperresponsiveness by corticosteroids and bronchodilators, and it demonstrates no enhancement of bronchodilator action by corticosteroids.

In order to assess the diagnostic usefulness of the A60 (ANDA Biological, Strassbourg, France) sero-diagnostic enzyme-linked immunosorbent assay (ELISA) kit for tuberculosis in Africa, sera of 53 pulmonary smear-positive tuberculosis (TB) patients, 30 apparently healthy control subjects and 6 AIDS suspects were sampled in Agogo Hospital in the forest area of Ghana. These sera were analyzed for antibodies to HIV-1 and HIV-2, and IgG-antibodies to the A60 BCG-antigen, while the non-HIV individuals were tested for total IgG levels. One healthy control subject, all of 6 AIDS suspects and 7 of the TB patients has HIV infections. In the non-HIV TB group, the sensitivity and specifity of the A60 ELISA was 78% and 86%, respectively, which was much poorer than expected from published reports about the A60 test. The A60 test failed, completely however, to discriminate between TB and non-TB in the HIV-positive group. In the non-HIV groups, total IgG levels were significantly higher in TB patients than in controls. It seems that the usefulness of the A60 ELISA test to diagnose tuberculosis is very limited in this high-incidence area, and that it seems to be of no value in patients infected with HIV.

A better outcome of patients with chronic obstructive pulmonary disease (COPD) appears to be determined by higher FEV1, smoking cessation, lower airway hyperresponsiveness, and, at least in the presence of therapy, with a higher reversibility of airflow obstruction. In our opinion, these findings provide a firm ground for smoking cessation and most likely for institution of early treatment directed at both the reversible part of airflow obstruction and airway hyperresponsiveness in patients with COPD. But there are large gaps in our understanding of the effects of bronchodilator and antiinflammatory drugs on airway hyperresponsiveness. After acute administration, sympathomimetics cause a larger reduction of airway hyperresponsiveness than do anticholinergics, both in asthma and in COPD. What happens after longer periods of treatment is not yet clear in COPD, whereas in asthma there may occur a deterioration of airway responsiveness. Corticosteroids appear to have a beneficial effect on lung function and the severity of airway hyperresponsiveness in asthma. In COPD, however, no definite conclusion can be drawn as to the beneficial effect of corticosteroids, but short-term effects are not promising. The available data from the literature strongly suggest the need for long-term studies with large groups of patients in order to assess a potential treatment effect. In this way, also, a subgroup of patients with COPD who improve with corticosteroids and/or bronchodilators may be found. It seems advisable to include both subjective (i.e., quality of life, complaints, symptoms) and objective (i.e., hospitalization, survival, FEV1, PEFR, PC20, and reversibility) data as investigational tools for outcome analysis.

In Agogo Hospital in the hills of Ashanti, Ghana, default and cure rates among 569 consecutive sputum-smear positive pulmonary tuberculosis (PTB) patients registered between 1984 and 1987 in a rural ambulatory non-supervised service program were analysed. Female gender, shorter home-to-clinic distances and younger age were significantly associated with higher cure and lower default rates. Within the district where liaison health workers paid home visits to PTB patients, the home-to-clinic distance effect on default was overruled by the effect of follow-up. Data from two surveys held in 1985 and 1987, among 68 and 49 PTB patients respectively, revealed that many patients visited healing churches but few admitted to having consulted traditional healers; that financial expenses for transport outweighed hospital charges; that lower educational levels were not associated with poorer compliance to therapy and that health education had improved significantly over the 2-year-period. It is concluded that intervention with liaison health workers and simple health education results in improved outcome in rural service tuberculosis programme.

Purpose: The aim of this study was to evaluate whether pulmonary microvascular damage is part of a more generalized involvement of the microvasculature in the spectrum of scleroderma (Scl)-like syndromes., Patients and Methods: We studied four groups of patients, all with Raynaud's phenomenon (RP), distinguished by the extent and nature of their underlying connective tissue disease. Twenty-two patients had primary RP (pRP), another 22 patients had RP and an undifferentiated connective tissue disease (uCTD), 15 patients had Scl, and eight patients had the CREST syndrome (CREST). Pulmonary vascular damage in these groups was assessed by measuring the pulmonary diffusing capacity (T1,CO) and its components: the diffusing capacity of the alveolocapillary membrane (Dm) and the pulmonary capillary blood volume (Vc). Results were compared with morphologic abnormalities of the nailfold capillaries, as determined by nailfold capillary microscopy, and related to the presence of antinuclear antibodies., Results: Vc was below normal in 38% and 43% of patients with pRP and uCTD, respectively (versus 52% in patients with Scl or CREST combined). In contrast, Dm was below normal in only 5% and 26% of patients with pRP and uCTD, respectively (versus 61% in patients with Scl or CREST combined). In patients with Scl and CREST, Dm was significantly decreased as compared with the former groups (p less than 0.01). Dm was also the pulmonary function parameter that correlated most strongly with both nailfold capillary abnormalities and the presence of antinuclear antibodies, whereas Vc did not., Conclusion: Early pulmonary involvement in Scl syndromes is functionally characterized by a lowered Dm, correlating with morphologic changes of the nailfold capillaries. Decreased Vc is probably a reflection of RP of the pulmonary vasculature.

We evaluated the cardiopulmonary exercise test results before and after long-term (16 weeks) treatment with the dihydropyridine calcium antagonist, felodipine (10 mg b.i.d., n = 9), and the ACE inhibitor, enalapril (10 mg b.i.d., n = 11), in 20 patients with New York Heart Association class III congestive heart failure. There were no significant differences at baseline. After 16 weeks patients in the enalapril group showed a significant increase in exercise duration and VO2max, without changes in arterial pressures and heart rate. In the felodipine group, exercise duration and VO2max did not change significantly, but arterial pressures and heart rate were significantly reduced at all exercise levels. Between group analysis showed a significant reduction in arterial pressures and heart rate in the felodipine group compared with enalapril, but no differences in aerobic capacity and exercise duration. These results demonstrate that felodipine and enalapril have essentially different effects on cardiopulmonary exercise results in patients with congestive heart failure.

Carbon-11 labeled d-oxyphenonium iodide, a cholinergic antagonist is synthesized for in vivo visualization of muscarinic receptor-sites on airway tissue by positron emission tomography (PET). Methylation with [11C]CH3I of d-demethyloxyphenonium, followed by HPLC purification affords the desired radiopharmaceutical with a radiochemical yield of 66% (based on [11C]CH3I, and corrected for decay) and with a specific activity of 110-300 Ci/mmol. The biologically active labeled d-enantiomer is prepared within 40 min after EOB. Optical and chemical purity proved to be better than 99.9%. Radiochemical purity was determined to be higher than 99%.

To study subclinical pulmonary toxicity of bleomycin we measured the single-breath carbon monoxide transfer factor (TLCO) and its components, pulmonary capillary blood volume (Vc), diffusing capacity of the alveolar-capillary membrane (Dm), and vital capacity (VC) in a homogenous group of 18 patients with testicular nonseminomatous germ cell tumor treated with bleomycin, vinblastine, and cis-diammine-dichloroplatinum (DDP). The most prominent finding was a substantial decrease in Vc (p less than 0.001) with only minor, though significant, changes in the other parameters. No recovery of pulmonary function had taken place 4 months after the last dose of bleomycin. The importance of correcting TLCO for hemoglobin concentration is shown. We conclude that vascular damage may be an important feature of subclinical pulmonary injury caused by bleomycin given in combination with vinblastine and DDP. In the postbleomycin phase, other forms of potentially lung-toxic treatment should be instituted with care.

We performed a double-blind crossover study to compare the effects of long-term treatment of inhaled budesonide and terbutaline on bronchial hyperreactivity in 17 patients with allergic asthma. Both drugs were administered for 4 weeks with a placebo-treatment period before and after each active-treatment period. To assess bronchial hyperreactivity, standardized inhalation provocation tests with histamine and propranolol were performed every 2 weeks. Before each inhalation provocation the drugs were withheld for at least 12 hours. Before the budesonide treatment the FEV1 value (percent predicted) was 85.3 +/- 4.1% (mean +/- SEM). After 2 and 4 weeks of treatment with this drug, the value increased significantly to 89.4 +/- 4.1% and 96.2 +/- 3.8%, respectively (p less than 0.05 and p less than 0.005). The histamine provocation concentrations causing a decrease in FEV1 of 20% (PC20) on the same days were 4.0, 7.2, and 9.5 mg/ml, respectively (both p less than 0.001). The PC20 values for propranolol, which were measured 1 hour after the histamine provocation, were 11.7, 13.3, and 14.0 mg/ml (ns). The FEV1 values before and after 2 and 4 weeks of treatment with terbutaline were 86.2 +/- 4.0%, 84.8 +/- 4.1%, and 87.0 +/- 4.6%, respectively. The histamine PC20 values on the same days were 4.7, 3.1 (p less than 0.05), and 3.8 mg/ml, respectively. The propranolol PC20 values were 14.2, 8.7, and 10.1 mg/ml (p less than 0.001 and p less than 0.05, respectively. We conclude that budesonide improves bronchial hyperreactivity, possibly by a dampening of late allergic reactions, whereas treatment with terbutaline may lead to a temporary increase of bronchial hyperreactivity, possibly as a result of beta-receptor desensitization.

Forty-two patients presenting with Raynaud's phenomenon (RP) were prospectively evaluated for pulmonary function changes over a 6-year followup period. Fifteen patients had secondary RP at presentation, 27 patients had nonsecondary RP. In the latter group, decreased pulmonary diffusing capacity (Tlco) was observed in only 2 patients (7%) whereas 9 patients with secondary RP (60%) had decreased Tlco. In the group of patients with nonsecondary RP exhibiting one or more autoantibodies, Tlco values were lower than in the group without autoantibodies (p less than 0.01). In patients with nonsecondary RP the duration of disease was correlated with the level of Tlco (r = 0.55), probably explained by a higher prevalence of truly primary RP in patients with longstanding nonsecondary RP. During followup no significant changes in pulmonary function were observed in the group with nonsecondary RP. We conclude that pulmonary function testing in patients presenting with nonsecondary RP without autoantibodies does not appear of clinical value.

Pulmonary function tests, including T1CO, and renal function tests were performed and GFR and ERPF measured in 18 patients with disseminated testicular non-seminoma before and after remission induction according to the Einhorn regimen. We found a significant positive correlation between delta GFR and delta T1CO (p less than 0.05). No significance could be demonstrated between delta ERPF and delta T1CO. It is concluded that caution should be exercised in administrating bleomycin to patients with severely impaired renal function.

Pulmonary function tests, including the transfer factor for carbon monoxide of the lungs (T1CO) and pulmonary capillary blood volume (Vc), were measured in 43 patients with disseminated testicular carcinoma and in eight patients with disseminated malignant melanoma before the start of a bleomycin-containing cytostatic combination. Their relation to the development of bleomycin-induced pulmonary toxicity was evaluated. We found two subgroups of patients, one group with and one group without an abnormal pretreatment T1CO and Vc. In the latter group the risk of bleomycin-induced pulmonary toxicity is not increased. Reduction in bleomycin dose during treatment is not necessary. The hypothesis is formulated that tumor embolism could be the explanation for this phenomenon.

In 24 patients with a cadaveric renal allograft, serial measurements after transplantation were made of the diffusing capacity for carbon monoxide (DLCO) together with serial measurements of C3d, the stable conversion product of the complement factor C3, and determinations of the anaphylatoxin C3a. Twelve patients were studied during an active cytomegalovirus (CMV) infection, and 12 patients were studied during allograft rejection or during a stable phase after renal transplantation (control subjects). No patients had pulmonary symptoms nor abnormal chest radiographs or arterial blood gas determinations. During an active CMV infection, DLCO was significantly reduced compared with the measurements made during allograft rejection or during a stable phase after renal transplantation. This was true both with (p less than 0.01) and without (p less than 0.01) correction for the hemoglobin concentration. Serum C3d levels were increased in 8 of the 12 patients with a CMV infection, but not in any of the patients in the control group. In 8 patients with a CMV infection, measurements were made of the anaphylatoxin C3a, and were found to be significantly higher than the levels in the control population (p less than 0.01). We conclude that our data are consistent with pulmonary dysfunction in every patient with an active CMV infection. The concomitant findings of complement activation and formation of anaphylatoxins suggest a causal relationship of the complement activation and a decreased DLCO, although further studies are warranted to determine the exact role of complement in the pulmonary events during an active CMV infection after renal transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Due to the solubility of xenon-133 in blood and tissues, errors are introduced in the determination of regional pulmonary ventilation. We investigated these errors by comparing the results from ventilation measurements with Xe-133 and N-13 in five normal subjects (both at rest and during exercise) and in seven patients after a pneumonectomy. In the normal subjects at rest, the upper lung fields showed no significant difference in the uptake rates of the two gases. In the middle and lower lung fields, however, the uptake rate for Xe-133 was higher than for N-13. During exercise a significant increase of the specific ventilation was found in the upper lung fields for N-13 compared with Xe-133. In the pneumonectomy patients the overall uptake rate for Xe-133 in the intact hemithorax was 25% larger than for N-13. Over the pneumonectomized hemithorax the uptake of the fastest component of Xe-133 was (8.5 +/- 1.3)% of the total. The total chest-wall contribution of Xe-133 was (27 +/- 8)% of the total count rate.

The circadian variation of spirometry and blood gases was studied in eight male, normoxemic, patients with chronic air flow obstruction and complaints of early morning dyspnea. The patients were selected for a high amplitude in circadian variation of PEFR. They were treated for eight days with placebo and slow-release terbutaline tablets (5 mg at 8 am and 10 mg at 8 pm). Thereafter, arterial blood gas levels were measured at four-hour intervals over 24 hours. Just after blood sampling, FEV1 measurements were performed. The results on placebo therapy were compared with results in eight healthy volunteers matched for age, sex, and smoking habits. The circadian rhythms of FEV1, PaO2, and SaO2 in these patients showed a higher amplitude than in normal subjects. The decrease of FEV1 in the patient group at 8 am coincided with the decrease in PaO2 and SaO2. In normal subjects no significant nocturnal fall in FEV1, PaO2, or SaO2 occurred. Administration of slow-release terbutaline tablets for eight days, providing comparable diurnal and nocturnal serum levels, prevented the nocturnal decrease of FEV1, PaO2, and SaO2. The increase of the FEV1 at all hours of observation showed a significant correlation with the increase of the PaO2.

The mean airway pressure difference within a respiratory cycle at end-inspiration was measured at different tidal volumes (VT) in 59 patients treated with mechanical ventilation, and plotted in a pressure-volume (P-V) diagram. Regression analysis revealed three types of regression lines which were clearly correlated with clinical pulmonary condition and outcome. The slope of such regression lines may be a more realistic representation of lung elasticity than conventional total static compliance, which is measured at only one VT, and the intercept of these lines may be a more appropriate reflection of operating lung volume than functional residual capacity. Ventilator settings should put the patient's lungs on the steepest part of the P-V curve with the smallest intercept, while maintaining acceptable arterial blood gas tensions.

We have studied the pharmacokinetics of theophylline and enprofylline in patients with liver cirrhosis, patients with chronic renal failure, and healthy subjects, and have assessed the predictive value of routine tests of liver function and renal function (creatinine clearance) for theophylline and enprofylline total body clearances. Theophylline clearance was significantly decreased in the patients with liver cirrhosis compared with both the patients with renal failure and the healthy subjects (the mean values in the three groups were 24, 47, and 46 ml.h-1.kg-1 respectively. Enprofylline clearance was significantly decreased in the patients with chronic renal failure, compared with both the patients with liver cirrhosis and the healthy subjects (the values in the three groups were 64, 250, and 289 ml.h-1.kg-1 respectively. There was a strong correlation between creatinine clearance and enprofylline clearance, while there was only a poor correlation between the liver function tests and theophylline clearance. It appears that in various clinical situations enprofylline elimination can be predicted more precisely than theophylline elimination, which may make the drug safer in clinical practice.

Forty-eight patients with a history of exercise-induced asthma were exercised on ambient breathing (T = 18-20 degrees C, relative humidity = 45-55%). There were 19 responders and 29 non-responders according to post-exercise spirometry. During the first minutes of exercise at a workload of 25-50 W, the functional residual capacity (FRC) was measured by a rebreathing technique. There was a significant increase in FRC in responders (p less than 0.025). A loose though significant correlation was found between the rise in FRC during exercise and the fall in forced expiratory volume in one second (FEV1) after exercise (r = -0.429, p less than 0.005). The effects of a sympathomimetic drug were studied in five responders submitted to a second exercise test 4 h after the first one. Spirometry returned to normal but FRC remained high between both tests. During the second test neither spirometry nor FRC changed. The results suggest that different mechanisms may be responsible for changes in FRC and in maximal expiratory flow in exercise-induced broncho constriction.

A method is described for analysis of xenon-133 washin and washout curves, in the presence of a slowly varying background. The method uses least-squares fitting of a single exponential together with a quadratic function to correct for the background. The method has been applied both to simulated data and to data from 25 patients. The accuracy in the relevant lung parameters was 5% over a wide range of the specific ventilation. A comparison is made with other methods in use to measure regional lung-function parameters. Our method produces reliable results even when specific ventilation is low, which can occur in patients with chronic airflow obstruction, where other methods may incur errors of more than 45%.