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Backround This study investigated the respiratory function and mechanics of patients with orthopnea caused by acute left ventricular failure (ALVF). Methods The study comprised 40 patients with ALVF and 15 control subjects. All patients underwent lung function tests and impulse oscillometry in both sitting and supine positions. In a subgroup of 22 patients, isosorbide dinitrate was administered and impulse oscillometry was performed 15 minutes later in the supine position. Results No patient reported dyspnea while seated, and the orthopnea score was 2.9 ± 1.4. Left ventricular ejection fraction was 43% ± 10%. Patients demonstrated restrictive spirometric pattern in the sitting position, whereas functional residual capacity was comparable to that of the control group. In the supine position, all pulmonary volumes decreased, except inspiratory capacity which increased. Respiratory reactance (Xrs5) was higher in patients in both sitting (421.8 ± 630.6%pred vs 147.2 ± 72.8%pred, P = .01) and supine (699.8 ± 699.9%pred vs 251.2 ± 151.6%pred, P ≤ .001) positions. Respiratory resistance (Rrs5) (10.6% ± 17.8% mean decrease) and Xrs5 (17.2% ± 39.4% mean decrease) improved after nitrates administration. Orthopnea was better correlated with Xrs5%pred in the supine position ( r = .42, P = .007). Ejection fraction was positively correlated with inspiratory capacity %pred ( r = .42, P = .007) in the sitting position. Conclusion Patients with ALVF demonstrated increased respiratory reactance that correlated with orthopnea severity and improved after nitrates administration.

Background: Eosinophilic lung diseases comprise a group of heterogeneous pulmonary disorders linked by increased eosinophils in bronchoalveolar lavage fluid (BALF). There is supporting evidence that natural killer (NK) cells participate in the regulation of eosinophilic inflammation. Objective: Our aim was to investigate the relationship between eosinophils and NK cells in BALF in patients with different interstitial lung diseases (ILDs) focusing on eosinophilic pneumonias. Methods: Of 114 patients who presented with increased BALF eosinophils (>5%), 74 patients were classified into the following groups: 27 had eosinophilic pneumonia (EP), 17 had idiopathic pulmonary fibrosis (IPF), 16 had hypersensitivity pneumonitis (HSP) and 14 had cryptogenic organizing pneumonia (COP/BOOP). Total BALF cells, cell density and cell differential counts were assessed and lymphocyte subsets CD3+, CD4+, CD8+, CD19+, CD3–CD16/56+ (NK) and CD3+CD16/56+ (NKT) were determined by flow cytometry. Results: Significant differences were observed in the percentages of lymphocytes (p < 0.001) and CD3+CD16/56+ cells (p = 0.023) among patient groups. In patients with EP, the percentage of eosinophils correlated positively with the number of CD3–CD16/56+ cells (r = 0.522, p = 0.005), the percentage of CD3–CD16/56+ cells (r = 0.690, p < 0.001), and the absolute count of CD3+CD16/56+ absolute cells (r = 0.609, p = 0.001). However, in patients with IPF, HSP or COP/BOOP, no correlation between the percentage of eosinophils and CD3–CD16/56+ or CD3+CD16/56+ cells was observed. Conclusions: Eosinophil inflammation seems to develop through a different pathway in EP compared to other ILDs.

Background: Asbestos exposure is related to serious adverse health effects. However, there is disagreement about the relationship between chrysotile exposure and mesothelioma or lung cancer. Objectives: Our aim was to investigate the mortality rate among workers exposed to relatively pure chrysotile in an asbestos cement factory. Patients and Methods: In an asbestos cement plant opened in 1968, we prospectively studied all 317 workers. A quantity of 2,000 tons of chrysotile, with minimal amphibole contamination, was used annually until 1 January 2005. Asbestos fiber concentration was measured regularly. Date and cause of death were recorded among active and retired workers. Results: Asbestos fiber concentration was always below permissible levels. Fifty-two workers died during the study. The cause was cancer in 28 subjects; lung cancer was diagnosed in 16 of them. No case of mesothelioma was reported. Death was attributed to cardiovascular diseases in 23 subjects and to liver cirrhosis in 1. Overall mortality rate was significantly lower than that of the Greek general population, standardized mortality ratio (SMR) was 0.71 (95% CI 0.53–0.93). Mortality due to cancer was increased (SMR 1.15, 95% CI 0.77–1.67), mainly due to lung cancer mortality (SMR 1.71, 95% CI 0.98–2.78), but not significantly. Conclusions: Occupational exposure to relatively pure chrysotile within permissible levels was not associated with a significant increase in lung cancer or with mesothelioma. Decreased overall mortality of workers indicates a healthy worker effect, which – together with the relatively small cohort size – could have prevented small risks to be detected.

Background: Expiratory flow limitation (EFL) is one of the main mechanisms contributing to dyspnea in patients with chronic obstructive pulmonary disease but has not been explored in patients with pleural effusion. Objectives: It was the aim of this study to determine whether patients with pleural effusion exhibit EFL and to investigate the effect of therapeutic thoracentesis on EFL. Patients and Methods: The study was performed on 21 patients with pleural effusion who were subjected to thoracentesis and measurement of pleural pressure (PP). Spirometry and estimation of flow limitation by the negative expiratory pressure technique were performed before and after thoracentesis. Results: Statistically significant differences were observed in all spirometric parameters. No correlation between the increase in lung volumes and flows and any of the aspirated fluid parameters was observed. Before thoracentesis, 14 out of 21 patients were flow limited, compared with 7 patients after thoracentesis (χ2 = 6.151, p = 0.013). Mean values of flow limitation before and after thoracentesis differed significantly. The decrease in flow limitation did not correlate with the increase in the spirometric parameters, the aspirated fluid volume or PP decrease. Conclusions: In the majority of patients with pleural effusion, flow limitation improves after thoracentesis. Flow limitation may be a contributing factor to the sensation of dyspnea in these patients.

Background The type and mode of presentation of pulmonary sarcoidosis (radiologic stage, activity) influence alveolar lymphocyte number and subsets as well as other inflammatory cells. Aim To investigate the variations in alveolar cells, lymphocyte subsets and NK-cells in different radiological stages of active pulmonary sarcoidosis. Methods 85 untreated, newly diagnosed patients (32 male, 53 female), median age 47.2+/-14.7 years were investigated. Patients were classified into chest x-ray stages (33 stage I, 27 stage II, 14 stage III and 11 stage IV disease). Bronchoalveolar lavage was performed with 4 portions of 50 mL. Total cells and cell differentials were counted, while CD3+, CD4+, CD8+, CD19+, CD3-CD16/56+ (NK-cells) and CD3+CD16/56+ (NKT-cells) were determined by flow cytometry. Results Lymphocytosis was high in all stages. Significant differences were found in: a) CD4 between stages I and II and I and IV. b) CD8 between stages I and IV and c) NK and NKT cells between stages I and III. Conclusions Variations were observed in alveolar cells and lymphocyte subsets in different stages of pulmonary sarcoidosis. Cells exhibiting cytotoxic activity were increased with stage progression, CD8 from stage I to IV, NK and NKT cells from stage I to III. These cells may be involved in the inflammatory process regulating granuloma formation.

Introduction: About 5–25% of 16 000 athletes involved in preparation for the Athens 2004 Olympics may encounter respiratory allergy (asthma and rhinoconjunctivitis) triggered by exposure to aeroallergens (pollen and fungi spores). Aim: Provide information about circulating aeroallergens in three Olympic cities and ensure safety for the allergic athletes who will visit Greece from January to September 2004. Methods: Aeroallergens were recorded using a Burkard volumetric trap. The most frequently implicated pollen (cypress, hazel, wall pellitory, plane, olive, grasses, goosefoot and mugwort) and fungi spores (Alternaria spp., Cladosporium spp.) are presented. These data derive from a 15-year database created by the Pulmonary Department, Thessaloniki, a 2-year database (University of Heraklion-Crete) and a 6-year database by the Pediatric Department, Athens. The above data and the current aeroallergen counts will be continuously announced by the mass media and Internet during the Athens 2004 Olympics. Results: Are expressed as: (A) Presentation (Graphs, Tables) of the fluctuation of mean daily values of pollen grains or fungi spores/m3. (B) Presentation (Tables) of the start, peak and end time of aeroallergen circulation. Peak pollen concentrations were observed between March and May (athletes preparation time). During the 2004 Olympics (August–September) relatively high concentrations of goosefoot, mugwort, Alternaria and Cladosporium will be observed. Aeroallergens circulate in Athens 10–15 days earlier than in Thessaloniki and 10 days later than in Heraklion. Conclusions: The data presented in the study are expected to help allergic Olympic athletes achieve peak performance under prophylactic measures.

Weight loss has been recognized as a feature of advanced emphysema and a factor of poor prognosis, but its mechanisms remain obscure. Studies have demonstrated high serum concentrations of TNF-a (cachexin) in chronic obstructive pulmonary disease (COPD) patients with emphysema. Pink puffers (PP) COPD patients have worse tissue oxygenation when compared with blue bloaters (BB) COPD patients. Consequently, PP patients would become cachectic, whereas BB patients with better tissue oxygenation would not. The aim of this study is to test the hypothesis that malnutrition in emphysema is a cytokine-mediated marker of chronic progressive tissue hypoxia. Thirty male COPD patients, without clinical or laboratory evidence of infection and severe air way obstruction (FEV1 < 1.5 l) were allocated: 16 as pink puffers (PP) and 14 as blue bloaters (BB). Lung function measurements included FEV1, FVC, RV, TLC, DLCO and arterial blood gases on room air. TNF-a serum levels were measured by immunoenzymic method (ELISA). Tissue oxygenation was assessed from oxygen delivery (DO2), PvO2 and oxygen extraction ratio (O2ER) obtained after right heart catheterization with Swan Ganz catheter. PP patients demonstrated lower DLCO and higher TLC, FRC and PaO2 from BB. We found that oxygen delivery was better in our BB than in PP patients (CI 2.9 +/- 0.2 vs 2.5 +/- 0.4 l/min/m2--P < 0.01, DO2 16.1 +/- 2.1 vs 13.1 +/- 0.2 ml/min/kg--P < 0.001) and the same was found for tissue oxygenation (PvO2 34.6 +/- 2.9 vs 31.2 +/- 3.8 mmHg--P < 0.01, O2ER 0.27 +/- 0.02 vs 0.34 +/- 0.06%--P < 0.001). The TNF-a values were higher in PP (31.3 +/- 26 pg/ml vs 15.2 +/- 9.9 pg/ml--P < 0.05) and their percent fat-free mass (%FFM) was 49.6 +/- 11.5 vs 42 +/- 8%--P < 0.001. We found that COPD patients with lower DO2 had increased TNF-a levels; but the correlations between TNF-a serum levels and PvO2 or O2ER were not statistically significant. TNF-a levels were elevated in PP patients with tissue hypoxia and may be a factor contributing to the weight loss of these patients.

Background: It has been suggested that the Hering-Breuer reflex (HBR) is unimportant in adults during normal tidal breathing and that it is elicited only if tidal volume is increased above a certain critical threshold. Objective: The aim of this study was (1) to study the occurrence of the HBR in adults with normal pulmonary function and (2) to examine if changes in lung mechanics have any effect on the HBR. Methods: We examined 11 adults with normal pulmonary function, 8 patients with chronic destructive pulmonary disease (COPD) and 3 with interstitial fibrosis (IF). All subjects were lightly sedated with fentanyl, intubated and ventilated with a Servo-900 ventilator. Inspiratory and expiratory flow (and after integration, volume) and mouth pressure were recorded from the endotracheal tube with a pneumotachograph and a pressure transducer. Pressure support ventilation was applied in all patients and functional residual capacity (FRC) was measured with the N2 washout method. Mean (Temean) and maximal expiratory time (Temax) were determined for each individual for 20 breaths. Following several breaths to establish a stable baseline the airway was occluded at end inspiration by a shutter. A positive HBR was interpreted as longer Teocc than Temax (Teocc/Temax, %). Occlusion was maintained until negative airway pressure occurred and the occlusion time (Teocc) was measured. We attempted occlusions after the addition of 5 cm H2O positive end-expiratory pressure (PEEP) and subsequently with 10, 15 and 20 cm H2O PEEP. Teocc was measured of progressively larger lung volumes. To examine the HBR sensitivity in the three groups, we plotted the lung volumes of occlusion against the corresponding Teocc/Temax. Results: The ratio Teocc/Temax increased from 167.5 ± 82.5 at normal FRC to 474 ± 200.2 s (PEEP20). On the contrary, in patients with COPD, Teocc/Temax increased from 125.2 ± 34 to 193.7 ± 74.2 (p < 0.05). Conclusions: The HBR was positive in all subjects. COPD patients were found to be less sensitive to volume changes when compared with normal controls and with IF patients.

The respiratory response to CO2 during pressure-support ventilation (PSV) was studied in 16 conscious normal humans. The subjects breathed through a mouthpiece connected to a ventilator in PSV mode, with pressure set to the highest comfortable level for each subject (10.1 +/- 0.6 cm H2O, mean +/- SE). Compared with breathing spontaneously through the ventilator (CPAP mode with zero positive end-expiratory pressure), with PSV, tidal volume (VT) increased significantly (1.16 +/- 0.1 versus 0.85 +/- 0.04 L), whereas breathing frequency (f) remained stable (16.0 +/- 0.9 versus 15.6 +/- 1.1 breaths/min). As a result, the subjects hyperventilated, decreasing significantly end-tidal PCO2 (PETCO2, 23.5 +/- 1.2 versus 35.5 +/- 1.1 mm Hg). Fraction of inspired CO2 (FICO2) was then increased in steps, and changes in respiratory motor output were quantitated from changes in f, VT, ventilation (VI), peak inspiratory flow (Vpeak), and muscle pressure (Pmus). Pmus was calculated by the equation of motion, based on respiratory system mechanics, which were measured previously by airway occlusion at end-inspiration, VT, VI, and Pmus increased significantly with increasing PETCO2, and the response was detectable even below eupneic levels; f remained relatively stable over a wide range of PETCO2 (23 to 45 mm Hg) and increase significantly only when PETCO2 approached 50 mm Hg. These results indicate that in conscious normal humans during PSV, CO2 responsiveness extends well into hypocapnia and is expressed principally as an increase in intensity of respiratory motor output with little change in respiratory rate.

In normal conscious humans, when a brief hypoxic ventilatory stimulus is followed immediately by breathing 100% O2, ventilation during hyperoxia gradually declines to baseline prehypoxic levels without an undershoot. During the decline, ventilation is greater than baseline in the absence of hypoxia and hypercapnia. This has been interpreted as evidence of decay of short-term potentiation (STP) or afterdischarge. It is not known whether the intensity of the stimulus that activates STP influences the time course of its decay. Therefore we studied STP decay in nine normal adults after administration of placebo (P) and almitrine (A) in a single-blind manner on 2 separate days. On each day, three runs consisting of 45 s of isocapnic hypoxia (end-tidal PO2 = 55 mm Hg) followed by 2 min of hyperoxia were conducted while ventilation (VI) was measured breath by breath. Baseline VT did not differ between A and P, but at the end of hypoxia, VI with A was 169 +/- 14% (SE) of baseline while VI with P was 132 +/- 7% of baseline (p0.05). Immediately after hyperoxia was instituted, VI fell abruptly, the fall being 36% of baseline for A and 15% for P. This probably represented the withdrawal of peripheral chemoreceptor input. Thereafter, VI declined slowly toward baseline, and the time course of this decline did not differ between P and A. Our results indicate that within the limits we studied, the increase of the intensity of the discharge of the peripheral chemoreceptors during hypoxia does not influence STP decay.

Background: Pemphigus vulgaris belongs to a group of rare, autoimmune, blistering disorders, requiring intensive immunosuppressive therapy. Lung infections are common in patients with pemphigus vulgaris. Objective: To evaluate pulmonary function in patients with pemphigus vulgaris, in order to detect possible factors that might predispose PV patients to lung damage. Methods: Ten patients first diagnosed with severe pemphigus vulgaris and 10 healthy individuals, were included in the study. Pulmonary function testing, blood gas analysis and quantification of α1-antitrypsin serum levels were performed. Results: Mild reduction of CO diffusing capacity was recorded, compared to the mean predicted normal value. DLCOSB (single-breath carbon monoxide diffusing capacity test) values did not significantly differ between patients with pemphigus vulgaris and healthy controls, while differences regarding DLCO/VA (VA: Alveolar Volume) were statistically significant. Alpha 1-antitrypsin serum levels were decreased (

Buspirone is an anxiolytic agent that appears to have no sedative effects. The aim of this study was to assess the effects of buspirone on breathlessness and exercise tolerance in patients with chronic airway obstruction. Sixteen patients, age 56.9 +/- 17.0; forced expiratory volume in 1 s (FEV1) 1.15 +/- 0.42 l; FEV1/forced vital capacity (FVC) 50.7 +/- 15.0%; PaCO2 42.2 +/- 5.5 mm Hg; and PaO2 57.6 +/- 10 mm Hg, underwent a 6-min walking test, an incremental cycle ergometer test, an incremental treadmill walking test with self-assessment of dyspnea on Borg's scale during exercise and an assessment of respiratory drive (P 0.1), timing [inspiration time (TI)/total breathing time (Ttot)], PaO2, PaCO2, FVC, FEV1, following oral administration for 14 days of placebo or buspirone (20 mg daily) in a double-blind, cross-over randomized way. We also used the symptom check list-90-R for the assessment of subjective complaints and symptomatic behavior. A significant improvement in anxiety, depression and obsessive symptoms and complaints was noted after buspirone treatment. The P 0.1, TI/Ttot, arterial blood gases and respiratory mechanics did not change after drug treatment. There was an improvement in exercise tolerance and in the sensation of dyspnea during the buspirone period. Thus, as given in this study, oral buspirone has therapeutic potential in the treatment of dyspnea in patients with chronic lung disease.

A comparative analysis was made of 3 conventional tests for tuberculosis (TB) versus a DNA probe technique among suspected TB patients at a reference centre in Greece. During 2004, we tested 2961 biological specimens from 2234 patients with the following methods: Ziehl-Neelsen staining, LöwensteinOJensen culture, BACTEC mycobacteria growth indicator tubes (MGIT) and the Gen-Probe AMPLIFIED Mycobacterium tuberculosis direct test (MTD). Of a total of 136 TB patients diagnosed and under anti-TB treatment, 133 of them (98%) were positive by amplified MTD. There were 112 TB (82%) detected by the MGIT method, 102 (75%) by Löwenstein-Jensen culture and 75 (55%) by Ziehl-Neelsen staining. Using MTD the positive result is ready within hours compared with days or weeks.

The aim of pleurodesis in malignant pleural effusions is to prevent reaccumulation of the fluid, symptoms, and avoid the need for repeated hospitalization for thoracentesis. The purpose of this study was to evaluate the efficacy and safety of erythromycin as a pleural sclerosing agent.Over a 2-year period, 34 patients with a symptomatic, recurrent, malignant pleural effusion who referred for chest tube drainage and pleurodesis were included. They had not received prior intrapleural therapy and had predicted survival of at least 1 month. All underwent pleural drainage and chemical pleurodesis with erythromycin. Complications and response to pleurodesis, according to clinical and radiographic criteria after 90 days, were recorded.The overall response was 88.2%. Complete response (no reaccumulation of pleural fluid after 90 days) was observed in 27 patients (79.4%). Partial response (reaccumulation of fluid but without symptoms, not requiring drainage) was observed in 3 (8.8%). No response (symptomatic reaccumulation of fluid that required drainage) was observed in 4 (11.8%). All patients experienced pleurodynia that was treated with administration of paracetamol and/or dextropropoxyphene. Sinus tachycardia and concurrent mild systemic hypertension were observed 2 and 4 hours after pleurodesis. Both of them were attributed to pleurodynia as there was remission with analgesics.This study suggests that erythromycin is effective and safe as a sclerosing agent for pleurodesis in patients with recurrent malignant pleural effusions.

A major concern surrounding the use of tumor necrosis factor-alpha (TNF-alpha) inhibitors is their potential to increase the risk of opportunistic infections, particularly tuberculosis (TB).To estimate the incidence of active TB in patients with rheumatic diseases receiving anti-TNF drug therapy and to evaluate the effectiveness of an antituberculosis chemoprophylaxis regimen.Retrospective study of the files of 613 patients with rheumatic diseases who had received anti-TNF agent (etanercept, infliximab and adalimumab) therapy from July 2000 to June 2004 at the Aristotle University of Thessaloniki, Greece. All patients had a tuberculin skin test (TST) and a postero-anterior chest radiograph (CXR) prior to anti-TNF therapy. When indicated (TSTor =10 mm and/or fibrotic lesions on CXR), treatment for latent TB was established (6 months isoniazid [INH] or 3 months INH and rifampicin [RMP]). Anti-TNF agent therapy was started again 2 months later.Of 45 patients who fulfilled the criteria for chemoprophylaxis, only 36 were treated correctly. Eleven patients developed active TB 2-35 months after the beginning of anti-TNF therapy. Six patients developed pulmonary and five extra-pulmonary TB. Eight of these had received infliximab and three adalimumab.The incidence of active TB in this study population was estimated at 449 cases per 100,00 population annually. Anti-tuberculosis chemoprophylaxis was only of partial preventive success in these patients.

Background The progress of pleural plaques in persons exposed to environmental asbestos in Almopia, Greece were studied prospectively. Methods During a 15-year period, 198 individuals, in whom pleural plaques had been observed during the period 1988–1990 were followed. Respiratory function was initially evaluated in 23. All were inhabitants of seven villages of Northern Greece, where rocks with high concentration in asbestos fibers were used for whitewashing until 1935. Results Out of this population, 126 survived and underwent chest X-ray in 2003 while respiratory function was retested in 18. New radiological findings were compared to previous ones using digital technology. Furthermore, the cause of death of the remaining 72 was recorded. Deterioration of X-ray findings was observed in all survivors. Not only did the surface area of previous plaques increase (8.66 ± 12.6 cm2, mean value ± SD) but new ones also appeared. Total lung capacity decreased from 95.6 ± 14.8 in 1998 to 76.5 ± 9.3% predicted in 2003. It was found that out of 72 deaths, 11 people died of malignant lung neoplasm, and 4 of mesothelioma. Conclusions Radiological appearance of pleural plaques and respiratory function of people previously exposed to asbestos environmental pollution worsens over the years. Prevalence of mesothelioma was found to be higher than expected. Am. J. Ind. Med. 2006. © 2005 Wiley-Liss, Inc.

Visceral leishmaniasis (VL) is a severe disease that can develop in immunocompromised patients. Antitumor necrosis factor-alpha (TNF-alpha) treatment of rheumatoid arthritis can result in clinical benefits, but with an increased risk of opportunistic infections. Leishmania infection in patients treated with TNF-alpha antagonists is extremely rare; for this reason, we report a patient with VL after etanercept treatment who had an unfavorable outcome.

Oxidative processes, mediated by oxygen free radicals are recognized to contribute significantly to the inflammatory pathology of bronchial asthma. An imbalance between oxidants and antioxidants has also been proposed in this disease. This study examines the serum total antioxidant status (TAS) in asthmatic patients with severe exacerbation of their disease and the probable correlation with clinical or laboratory findings. The TAS was measured in 20 patients (10 men and 10 women, with a mean age of 41.95 +/- 20.75 years), using a colorimetric method. On the days of admission and discharge, the forced expiratory volume in 1 sec (FEV1), the partial arterial oxygen pressure (PaO2), and severity criteria were recorded and correlated with TAS at the same time. The TAS was also measured in 10 healthy subjects (8 men and 2 women, mean age of 39 +/- 9 years). A statistically significant decrease of TAS was observed on admission day compared to that on discharge day (0.98 +/- 0.08 vs. 1.12 +/- 0.17 mmol/L, p0.001, respectively, paired t-test) suggesting the presence of oxidative stress during an asthma attack. The TAS on admission was also statistically significantly decreased compared to that of normal subjects (0.98 +/- 0.08 vs. 1.19 +/- 0.09 mmo/L, p0.001, respectively, paired t-test). A statistically significant correlation was observed between FEV1 change and TAS change, from admission to discharge day (r = 0.58, p = 0.007, Pearson correlation). Finally, a statistically significant correlation was found between FEV1 change and TAS on discharge day (r = 0.65, p = 0.002). Decreased TAS was found during an asthma attack, probably as a consequence of increased oxidative stress. The TAS change was correlated with severity criteria, such as FEV1. Therefore, it seems that measurement of TAS could be a simple and useful tool in the evaluation of an asthma attack. The supplementary administration of antioxidants in future needs further clarification.

We investigated the efficacy of docetaxel (D) in combination with carboplatin (C) in the treatment of non-small cell lung cancer (NSCLC) patients. Since 1996, 123 with inoperable NSCLC were enrolled in the study; 120 (108 males, 12 females; mean age 58.0±8.3 years) were evaluated. Of those, 46 patients had squamous carcinoma, 44 adenocarcinoma, 11 large cell carcinoma and 19 undifferentiated tumours. Eligibility criteria included, documented inoperable NSCLC, WHO performance status (PS) 0–1, age up to 70 years, and normal renal and hepatic function. A total of 622 cycles of chemotherapy (CHT) (median 7 (95% CI 6.2–7.47), courses per patient) were administered. Each cycle consisted of 100 mg/m2 of docetaxel in a 2-h infusion with C at a dose of area under the curve (AUC) of 6 on day 1. This regimen was repeated every 28 days up to eight cycles. Of the patients, five (4%) achieved complete response, 49 (40%) partial response, 47 (39%) had stable disease and 19 (15%) had progressive disease. The median survival was 12 months for all patients, 12 for the four patients with stage IIb disease, 18 for the patients with stage IIIa disease, 20 for the 29 patients with stage IIIb disease, and 11 for the 65 stage IV patients. The median time to progression was 8 months (90 patients). Toxicity was, grade 3/4 neutropenia, 18 patients (15%); grade 3/4 anaemia, 6 patients (5%); and tolerable peripheral neuropathy, 16 patients (13.3%). Responders received radiotherapy (total dose, 50 Gy in 4 weeks) between the 6th and 8th cycle. Among responders with initial stage IIIb disease, 7 (5%) underwent surgical resection. Patients with early progression of the disease received the same dose of radiotherapy between 2nd and 3rd cycle. The study is ongoing, and six patients (5%) are still alive (after 3 years). Preliminary results indicate that the D/C combination is very active in the treatment of NSCLC with tolerable toxicity. It appears that this drug combination is also good as neoadjuvant therapy in inoperable NSCLC patients.

To examine the circulatory and respiratory effects of breathing pattern in patients with chronic obstructive pulmonary disease (COPD) and dynamic hyperinflation (DH) during controlled mechanical ventilation. Prospective, controlled, randomized, non-blinded study. Respiratory intensive care unit of a university hospital. Nine patients with acute respiratory failure and DH due to acute exacerbations of COPD. Keeping tidal volume and total breath duration (TTOT) constant, patients were ventilated at six different values of expiratory time (TE). TE changes were randomly induced by alterations of constant inspiratory flow $$\left( {\dot V_1 } \right)$$ and/or end-inspiratory pause (EIP). Patients were studied at three levels of $$\dot V_1 $$ (0.93±0.08, 0.72±0.06 and 0.55±0.04 l/s, mean ±SE), with and without EIP (10% of TTOT). Lung volumes, airflows, airways pressures, oxygenation indices and dead space were measured. Alveolar pressure and airway resistance (Rmin), as well as the additional resistance (δR) due to viscoelastic pressure dissipation and time-constant inequalities, were estimated by rapid airway occlusion during inflation. In seven out of nine patients, right-heart catheterization was performed and hemodynamic parameters were obtained at each value of TE. A significant decrease of intrinsic positive end-expiratory pressure (PEEPi), end-inspiratory static and mean (mPaw) airway pressures, end-expiratory lung volume above passive FRC (Vtrap), δR and venous admixture and a significant increase of peak airway pressure, Rmin, stroke volume index and mixed venous PO2 $$\left( {P\bar vO_2 } \right)$$ were observed when $$\dot V_1 $$ increased. At each $$\dot V_1 $$ , the addition of EIP significantly decreased iso-volume expiratory flows and $$P\bar vO_2 $$ and increased Vtrap and mPaw. We conclude that in mechanically ventilated patients with COPD, the pattern of lung inflation and TE alteration have a significant impact on respiratory system mechanics, gas exchange and hemodynamics. Addition of EIP in patients with COPD may be detrimental.

In normal humans when a brief hypoxic ventilatory stimulus is terminated abruptly by breathing 100% O2, ventilation during hyperoxia gradually declines to baseline prehypoxic levels without an undershoot. This has been interpreted as evidence of decay of short-term potentiation (STP), a mechanism located in the brainstem and not dependent upon higher center inputs. STP decay may be important in preventing periodic breathing by damping ventilatory responses to cyclic stimuli. Patients with brain damage commonly have periodic breathing that may be caused partly by impairment of STP activation. To test this 12 tracheostomized patients with severe brain damage (Glasgow score 9.9 +/- 0.6) were studied. Breathing stability was estimated by at least 6 h of capnography and from these records apnea index (AI, episodes/hour) and cyclic changes of end-tidal CO2 (c-PETCO2, cycles/hour) were derived. STP activation was examined by brief exposure to hypoxia (45 s, end-tidal O2 = 50 mm Hg) followed by hyperoxia. Forty-four hypoxic-hyperoxic runs were analyzed and compared with 19 normoxic-hyperoxic trials. At the end of the hypoxia ventilation (VI) increased 39.5 +/- 5.8% and PETCO2 decreased 2.7 +/- 0.6 mm Hg to 91.5 +/- 2.2% of baseline value. When hypoxia was terminated abruptly by hyperoxia VI dropped immediately to 63.2 +/- 7.2% of baseline, remaining for 35 s significantly lower than the corresponding values acquired during hyperoxia after normoxia. After hypoxia, apneas occurred in 19 of 44 hyperoxic runs. There was a negative relationship between nadir hyperoxic ventilation after hypoxia and both AI and c-PETCO2.(ABSTRACT TRUNCATED AT 250 WORDS)

In conscious normal humans after a brief hypoxic ventilatory stimulus, ventilation slowly decays to baseline and does not undershoot though the subjects are hyperoxic and hypocapnic. This phenomenon is attributed to short-term poststimulus potentiation (STP), which may be an important factor promoting ventilatory stability by preventing periodic breathing. It has been proposed that obstructive sleep apnea (OSA) is a variant of periodic breathing, with obstruction occurring when ventilatory drive is low. If this were the case, patients with OSA might have reduced STP. To test this, seven normal adults and 12 patients with OSA (mean apnea index, 52.4 +/- 6.9 SE events/h) were studied. Ventilation (VI) was measured in awake seated subjects during 30 to 45 s of exposure to hypoxia (end-tidal O2: 50 mm Hg) followed by hyperoxia. A total of 57 hypoxic-hyperoxic runs were analyzed (36 in the patients and 21 in the normal subjects). During hypoxia VI increased and end-tidal CO2 decreased by similar amounts in both groups. In normal subjects after hypoxia there was a gradual decay in VI to prehypoxic levels without an undershoot. In patients, there was on average a ventilatory undershoot at 35 s of hyperoxia, with a mean VI of 83% of baseline. The undershoot was due mainly to a decrease in tidal volume, which was significantly lower than that of the normal subjects for several seconds. These changes were particularly prominent in seven patients who were not different from the others in terms of baseline characteristics, hypoxic responses, and OSA severity.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary function has been studied extensively in patients with unilateral diaphragmatic paralysis (UDP), but there is scarce information regarding the respiratory function during sleep in this condition. We therefore studied pulmonary function in 12 patients with UDP when awake and when asleep. Diaphragmatic dysfunction was confirmed by the demonstration of low maximal transdiaphragmatic pressures in most of our patients; paradoxical gastric pressure swing was observed in 6 patients. There was a restrictive pattern in pulmonary function tests and resting arterial blood gases were rather well preserved (range SaO2 90-95%). Overnight sleep monitoring showed that the time spent in REM sleep and stage 3 and 4 sleep was reduced. The mean maximum decrease in SaO2 was 15.2 +/- 6.2% and the time with an SaO2 drop of more than 5% of the awake SaO2 was 25.4 +/- 22.8 min. None of our patients was in respiratory failure or had clinical evidence of cor pulmonale. We conclude that UDP leads to significant nocturnal hypoxemia but, in the absence of systemic lung disease, does not lead to chronic respiratory failure and cor pulmonale.

The effects of almitrine bismesylate and medroxyprogesterone acetate on oxygenation during wakefulness and sleep were compared in six patients with chronic obstructive lung disease and carbon dioxide retention. Patients received 1.5 mg/kg almitrine (a peripheral chemoreceptor stimulant), 100 mg of medroxyprogesterone (a central respiratory stimulant), or matched placebo daily for 15 days in random order in a crossover trial. When subjects were awake almitrine increased the ventilatory response to hypoxia and increased arterial oxygen tension (PaO2) to a greater extent than medroxyprogesterone, whereas medroxyprogesterone augmented the ventilatory response to hypercapnia and decreased arterial carbon dioxide tension (PaCO2) to a greater extent than almitrine. Neither drug influenced sleep architecture significantly, except that medroxyprogesterone increased the number of arousals. Almitrine had a more favourable effect than placebo on oxygenation as estimated from arterial oxygen saturation (SaO2) during the different stages of sleep, the number of episodes of hypoxaemia, and the amount of time that SaO2 was below 80%. The only change with medroxyprogesterone by comparison with placebo was a decrease in the number of hypoxaemic episodes. It is concluded that both active drugs improved blood gases during wakefulness, but that 1.5 mg/kg of almitrine is superior to 100 mg of medroxyprogesterone in improving SaO2 during sleep.

17102 Background: Patients with lung cancer account for approximately 50% of brain metastasis cases. On the other hand the majority of active cytotoxic agents (like taxanes) in lung cancer treatment, are unable to penetrate blood brain barrier (BBB) so the role of chemotherapy in management of brain metastasis from lung cancer remain controversial. To investigate predisposing factors (if any) of penetration of BBB from cytotoxic agents we measured concentation levels of Docetaxel in serum and cerebrospinal fluid (CSF) during first line chemotherapy. Methods: Twelve lung cancer patients receiving chemotherapy consisted of Docetaxel (100 mg/m2) and Carboplatin AUC 6 were included in this study. CSF and plasma samples were withdrawn half an hour after termination of chemotherapy infusion. Measurements were performed with high performance liquid chromatography and UV detection was at 227 nm. Results: Mean levels of docetaxel in blood was 2,5530 ± 0,53 mg/l and in CSF 0,7397 ± 0,22 mg/l. Three out of twelve patient had SCLC (2 with ED and 1 with LD) and 9 with NSCLC (2 stage IIIB and 7 stage IV). In three patients without metastasis no detectible level of docetaxel was measured. We were also unable to detect Docetaxel in CSF of the patient with NSCLC and metastasis in the ipsilateral lung. On the other hand in 9 patients with metastatic disease (4 brain metastasis 2 with bone metastasis 1 with metastasis in liver and adrenal and 2 with liver and bone metastasis) had detectable levels of docetaxel in CSF. There was not statistically significant correlation of docetaxel in plasma and CSF. Only one patient without any evidence of metastasis had a detectable level of Docetaxel in CSF (0,33229) but in 6 weeks a brain metastasis was apparent in brain MRI. Conclusions: Metastasis development seems to be associated with a modification of BBB penetration. If Docetaxel penetrates BBB (especially in the presence of brain metastasis) it would be probable to accelerate radiotherapy sensitivity of brain metastasis. No significant financial relationships to disclose.

A patient with a large hydatid cyst of the liver developed a positionally symptomatic right to left shunting across a patent foramen ovale with both platypnoea and orthodeoxia, despite normal pulmonary arterial pressures and normal pulmonary function tests. When the patient was in the supine position the calculated right to left shunt was 15.1% and 29.5% when seated. The shunt was attributed to the compression of the right atrium and ventricle by the cyst. Surgical evacuation of the cyst relieved the symptoms and the positionally induced shunting.

The purpose of the study was to examine the effects of chemical feedback on respiratory motor and ventilatory output in conscious subjects ventilated on various modes of assisted mechanical ventilation. Seven subjects were connected to a ventilator and randomly ventilated on assist-volume control (AVC), pressure support (PS) or proportional assist ventilation (PAV). On each mode, the assist level was set to the highest comfortable level. Airway and oesophageal (Poes) pressures, tidal volume, respiratory frequency (fR) and end-tidal carbon dioxide tension (PET,CO2) were measured breath-by-breath. When the subjects were stable on each mode, the fraction of inspired carbon dioxide (FI,CO2) was increased stepwise, and changes in minute ventilation (V'E) and respiratory motor output, estimated by the pressure-time product of all the respiratory muscles per breath (PTPrm) and per minute (PTPminute), were observed. At zero FI,CO2, PTPminute/PET,CO2 did not differ between modes, while V'E/ PTPminute was significantly lower with PAV than that with PS and AVC. As a result V'E/PET,CO2 was significantly lower with PAV, preventing, unlike AVC and PS, a significant drop in PET,CO2. With PAV, independent of CO2, V'E/PTPminute remained constant, while it decreased significantly with increasing CO2 stimulus with PS and AVC. At high PET,CO2 respiratory effort was significantly lower with PAV than that with PS and AVC. In conclusion, the mode of mechanical ventilation modifies the effects of chemical feedback on respiratory motor and ventilatory output. At all carbon dioxide stimulus levels neuroventilatory coupling was better preserved with proportional assist ventilation than with pressure support and assist-volume control ventilation.

Respiratory drive in a patient with central alveolar hypoventilation was assessed by mouth occlusion pressure method. Respiratory drive was almost abolished in this patient.

Vectorcardiograms in 34 patients with chronic obstructive pulmonary disease and 30 normal people were analyzed with the aim of developing sensitive criteria for the detection of pulmonary artery hypertension. The pulmonary artery pressure was correlated with the known vectorcardiographic measurements of the area of the QRS loop and with two new linear measurements which reflect the QRS loop displacement of the right ventricular hypertrophy. The proposed linear vector-cardiographic and the QRS loop area criteria provided a sensitive means for the noninvasive approximate estimation of mean pulmonary artery pressure in patients with chronic obstructive pulmonary disease. Their sensitivity and specificity were proved to be considerable.

The bronchodilator effect of salbutamol inhalation was compared with the oral administration of the drug in 10 patients with bronchial asthma. The study consisted of treating each patient for 4 consecutive days with: (1) a combined regimen consisting of a 2-mg tablet of salbutamol and 10 puffs of salbutamol inhalation (100 micrograms in each puff) given in pairs of two puffs every 20 min (regimen 1); (2) salbutamol inhalation (regimen 2); (3) salbutamol tablet (regimen 3), and (4) placebo, tablet and inhalation (regimen 4). The bronchodilator effect was assessed measuring the forced expiratory volume in 1 s, the forced vital capacity and the peak expiratory flow rate. The bronchodilator response was significantly greater on the inhalation alone and the combined regimen than on the oral and placebo regimens. The combined regimen showed a better although not significant bronchodilatory response than the inhalation regimen. We conclude that the inhalation treatment with salbutamol is superior to the oral route of administration in treating bronchial asthma and that the oral treatment has an added effect.

Baroreceptor sensitivity, reflected by the slope of the linear regression of the electrocardiographic R-R interval on the rise of systolic blood pressure after injection of phenylephrine, was significantly lower in 27 patients with chronic obstructive pulmonary disease (4.67 +/- 2.67) than in 10 normal subjects (12.07 +/- 3.3) of comparable age (p less than 0.001). In 20 patients in whom right heart catheterisation was performed, pulmonary artery pressure was inversely related to baroreflex sensitivity (r = - 0.603, p less than 0.01). Independent variables such as arterial Po2, Pco2, and mean pulmonary artery pressure were examined in order to assess their ability to predict baroreflex sensitivity. The independent variable that made the most significant contribution was mean pulmonary artery pressure. It seems that the attenuation of baroreflex response in patients with chronic obstructive pulmonary disease is caused mainly by pulmonary hypertension and partly by the central effects of hypoxia and hypercapnia.

Airway function was studied in 39 patients with stage I sarcoidosis and in 20 patients with stage II sarcoidosis. All of our patients were nonsmokers. Characteristic functional changes of restrictive lung disease was observed in 4 patients with stage II sarcoidosis. Specific airway conductance and % FEV1 were abnormal in 3 patients with stage II sarcoidosis. Abnormal small airway function was demonstrated in several patients with stage I and stage II sarcoidosis, always by multiple tests. Frequency dependence of dynamic compliance was demonstrated in 40% of stage I and 50% of stage II sarcoidosis. Maximal flow (Vmax50, Vmax25) was decreased respectively in 36 and 30% of patients of stage I sarcoidosis and in 56 and 62% of patients with stage II sarcoidosis. The ratio of closing volume to vital capacity was increased above corrected predictions in 30% of stage I and 44% of stage II sarcoidosis. delta Vmax25 decreased and Visov/VC (%) increased in more than 50% of patients. Upstream airway resistance was abnormally increased in 50% of patients with stage I and in 73% with stage II sarcoidosis. These results suggest that small airway dysfunction is common in early sarcoidosis without restrictive defect.

In patients with chronic obstructive pulmonary disease, respiratory drive as estimated from occlusion pressures (PO.1 and PO.1/PCO2, cm H2O/mm Hg) and respiratory timing (T1, T1/TTOT) were predicted accurately by multiple regression analysis from the respiratory parameters PO2, PCO2, and blood HCO3 in conjunction with estimates of cerebral blood flow. We used four linear models to obtain essentially the same multiple correlation coefficient, indicating that these independent variables are all important factors in controlling both the drive and timing of respiration.

Summary Ten patients with chronic obstructive pulmonary disease (COPD) with normal left ventricular function were given a single dose of captopril (0.25 mg/kg). Mean systemic arterial pressure, heart rate and coronary flow to the right ventricle were reduced significantly after captopril. In contrast captopril did not cause a significant fall in pulmonary arterial pressure or pulmonary vascular resistance. We conclude that captopril fails to produce haemodynamic benefits in such hypoxic patients and that angiotensin II is not playing a significant role in maintaining pulmonary vasoconstriction.

Respiratory drive (deltaP 0.1/deltaPCO2) and ventilatory response (deltaVE/deltaPCO2) to CO2 has been estimated in 20 normal subjects and 28 patients with chronic obstructive pulmonary disease (COPD). In patients with COPD, drive and ventilatory response to CO2 were diminished, but no statistical correlation with FEV1, MBC, TLC, FRC, RV/TLC was found. A statistically negative correlation was found between blood bicarbonate and drive or ventilatory response to CO2. Patients with emphysema and normal PaCO2 demonstrated normal deltaP 0.1/deltaPCO2. In contrast, patients with chronic bronchitis with the same pulmonary function abnormalities and hypercapnia had significant diminution of the deltaP 0.1/deltaPCO2. Therefore, we feel that pulmonary function abnormalities alone cannot explain the deltaP 0.1/deltaPCO2 decrease; in most cases there sould coexist a diminished respiratory sensitivity.

Ventilatory response to CO2 (delta VE/delta PCO2), respiratory drive (delta P0.1/delta PCO2), breath-holding time (BHT) on 100% O2 and log BHT/PCO2 slope during CO2 rebreathing was assessed, in 19 control subjects and in 22 patients with chronic obstructive pulmonary disease (COPD) with hypercapnia (PCO2 greater than 50 mm Hg). The log BHT/PCO2 slope was expressed as the PCO2 increment to half the BHT. We found no correlation between BHT on 100% O2 and delta VE/delta PCO2 or delta P0.1/delta PCO2 in controls and COPD subjects. delta PCO2 halving BHT had an inverse statistical significant correlation with delta VE/delta PCO2 and delta P0.1 delta PCO2 in controls and patients. In contrast to delta P0.1/delta PCO2, the delta PCO2 halving BHT increased in COPD patients and there are patients with normal respiratory drive but prolonged delta PCO2 halving BHT. The delta PCO2 halving BHT as delta VE/delta PCO2 cannot be substituted for delta P0.1/delta PCO2 in the clinical assessment of respiratory chemosensitivity in COPD patients.

In 11 patients with bronchial asthma and regular overnight falls in PEFR of greater than 15%, we demonstrated significant bronchodilation restricted only to large airways after the administration of a single dose of 10 mg of nifedipine. A statistically significant increase in PEFR, SGaw, and FEV1 was noticed at 1 and especially 2 hr after nifedipine administration. During 4 days of nifedipine treatment (10 mg t.i.d.), the overnight fall in mean PEFR was statistically significant (p less than 0.02) and less than the mean fall of PEFR during the 4 days of placebo treatment. Thus nifedipine does modify the basal bronchial tone of patients with asthma and diminishes the circadian swing of airway resistance.

We studied 18 asthmatic patients over an 8-week period. Each patient received for 4 weeks continuous and for 4 weeks intermittent salbutamol rotacaps (400 micrograms) using a double-crossover technique. No significant differences were found between the two treatment regimens as judged by daily card scores and daily PEFR (both a.m and p.m.). Lung Function tests performed monthly in the hospital showed no significant differences between two treatments or the development of bronchial beta-adrenoreceptor resistance.

In 11 asthmatic subjects the relative magnitude and the site of airway bronchoconstriction were compared after the oral administration of 40 mg of propranolol and 2.5 mg of pindolol and the magnitude and site of bronchodilation produced by 0.5 mg subcutaneous terbutaline were tested after pretreatment with propranolol and pindolol. Specific airway conductance (sGaw) and peak expiratory flow rate (PEFR), both believed to reflect changes in large airways, and capacity isoflow (Ciso-v) and delta Vmax50, both believed to reflect changes in small airways, were determined before and after administration of placebo, pindolol, and propranolol. Treatments were given double blind and in random order. After the administration of propranolol we noted a significant bronchoconstrictive effect in the large airways (mean values of PEFR and sGaw, expressed as percentages of control values, decreased by 87.4% +/- 13.2% and 43.3% +/- 8.9%) and in the small airways (mean value of Ciso-v increased by 20.6% +/- 4.7% and that of delta Vmax50 decreased by 50% +/- 11.9% of control). By contrast, pindolol produced no significant effect on sGaw or PEFR but the tests of small airway function showed significant bronchoconstriction (mean values of Ciso-v increased by 12.9% +/- 2.6% and those of delta Vmax50 decreased by 47.2% +/- 9.2%). This action makes pindolol potentially dangerous in asthmatic patients. The bronchodilator action of terbutaline on large airways is diminished after the use of both propranolol and pindolol.

The high incidence of right ventricular hypertrophy in patients with chronic obstructive pulmonary disease is a well-known fact. In clinical medicine according to our present status of thinking, severe impairment of ventilatory function and pulmonary hypertension are the two essential prerequisites for right ventricular involvement. To investigate this accepted assumption we studied 51 patients with chronic obstructive pulmonary disease, while they were in a remission period. The patients were subjected to clinical examination, chest roentgenography, spirometry, blood gas examination, electrocardiography, vectorcardiography, echocardiography, and right heart catheterization. The majority of the patients with significantly compromised ventilatory function and abnormal blood gases had right ventricular hypertrophy with elevation of the pulmonary artery pressure. Two subgroups of patients could be distinguished: One included 15 patients (29.4% of all patients) with normal pulmonary artery pressure and evidence of right ventricular hypertrophy. In this subgroup are included 10 patients (19.6% of all patients) showing mild ventilatory impairment and mild hypoxaemia. The second subgroup consisted of 5 patients (9.8% of all patients) with elevated mean pulmonary artery pressure at rest and right ventricular hypertrophy showing relatively mild ventilatory impairment and moderate hypoxaemia. Two conclusions could be drawn: (1) the pulmonary artery pressure at rest could be normal despite the evidence of right ventricular hypertrophy, and (2) a mild ventilatory impairment does not exclude an elevated pulmonary artery pressure or the development of right ventricular hypertrophy in patients with chronic obstructive pulmonary disease.

An echocardiographic (echo), vectorcardiographic (VCG) and electrocardiographic (ECG) study of the right ventricle was carried out in 27 patients with chronic obstructive pulmonary disease and cor pulmonale. The subxiphoid echocardiographic approach was applied in all patients. The right ventricular internal diameter index (RVIDd), anterior right ventricular wall thickness (RVWT) and the ratio (R) intraventricular septum thickness/anterior right ventricular wall thickness were statistically different in the 27 patients compared to the 33 normals. All 27 patients had a RVIDd greater than 1.33 cm while in only 17 (63%, P less than 0.01) of these was right ventricular hypertrophy (RVH) detected with VCG or ECg criteria. In 20 patients the RVWT was measured and in 19 of these the RVWT was greater than 0.56 cm. In only one patient was the RVWT less than 0.56 cm. VCG or ECG criteria showed RVH in only 14 (70%) of these patients. The R was measured in 18 patients. All patients had R less than 1.99 and in only 12 (67%, P less than 0.01) of these was RVH diagnosed with VCG or ECG criteria. It seems that the RVIDd, the RVWT and the R are useful indexes for the detection of right ventricular dilatation and hypertrophy. Therefore echocardiography is superior to the conventional ECG and VCG in the recognition of right ventricular hypertrophy and dilatation.