Different Relationships between FENO and COPD Characteristics in Smokers and Ex-Smokers.

Exhaled nitric oxide (FENO) is a marker of type-2 inflammation in asthma and is used in its management. However, smokers and ex-smokers have lower FENO values, and the clinical use of FENO values in COPD patients is unclear. Therefore, we investigated if FENO had a relationship to different COPD characteristics in smoking and ex-smoking subjects. Patients with COPD (n = 533, 58% females) were investigated while in stable condition. Measurements of FENO50, blood cell counts, IgE sensitisation and lung function were performed. Medication reconciliation was used to establish medication usage. Smokers (n = 150) had lower FENO50 9 (8, 10) ppb (geometric mean, 95% confidence interval) than ex-smokers did (n = 383) 15 (14, 16) ppb, p < 0.001. FENO50 was not associated with blood eosinophil or neutrophil levels in smokers, but in ex-smokers significant associations were found (r = 0.23, p < 0.001) and (r = -0.18, p = 0.001), respectively. Lower FENO values were associated with lower FEV1% predicted in both smokers (r = 0.17, p = 0.040) and ex-smokers (r = 0.20, p < 0.001). Neither the smokers nor ex-smokers with reported asthma or IgE sensitisation were linked to an increase in FENO50. Ex-smokers treated with inhaled corticosteroids (ICS) had lower FENO50 14 (13, 15) ppb than non-treated ex-smokers 17 (15, 19) ppb, p = 0.024. This was not found in smokers (p = 0.325). FENO is associated with eosinophil inflammation and the use of ICS in ex-smoking COPD subjects, but not in smoking subjects suggesting that the value of FENO as an inflammatory marker is more limited in smoking subjects. The association found between low FENO values and low lung function requires further investigation.

Cardiac function after hematopoietic cell transplantation: an echocardiographic cross-sectional study in young adults treated in childhood.

BACKGROUND: Hematopoietic cell transplantation (HCT) including preparative regimens with chemotherapy and total body irradiation (TBI) is an accepted treatment for many malignant disorders but may have side-effects for several organs, including the cardiovascular system. The aim of this study was to study very long-term consequences on cardiac function after childhood HCT. PROCEDURE: Cardiac function was evaluated using echocardiography and levels of NT-proBNP and growth hormone (GHmax) in 18 patients, at a median of 18 years after HCT including TBI, and in 18 matched controls. RESULTS: Patients after HCT had cardiac dimensions, volumes, and left ventricular ejection fractions within normal range after correction for body size. However, compared with the control group, patients after HCT had significantly lower E/A ratio, as a measure of left ventricular diastolic function, significantly lower fractional shortening and mitral annular plane systolic excursion, as measures of left ventricular systolic function, significantly lower tricuspid annular plane systolic excursion, as a measure of right ventricular function, and significantly higher NT-proBNP, as a measure of total cardiac function. Also, pulmonary flow acceleration time was shorter in the group after HCT, indicating possible pulmonary involvement. Heart rate was significantly higher and GHmax significantly lower in patients after HCT. CONCLUSIONS: Almost two decades after HCT, including preparative regimens with TBI, cardiac function in patients was found to be within normal range. However, when compared with a healthy control group, patients after HCT showed lower systolic and diastolic left ventricular function as well as lower right ventricular function.

Commonly used reference values underestimate oxygen uptake in healthy, 50-year-old Swedish women.

Cardiopulmonary exercise testing (CPET) is the gold standard among clinical exercise tests. It combines a conventional stress test with measurement of oxygen uptake (VO2 ) and CO2 production. No validated Swedish reference values exist, and reference values in women are generally understudied. Moreover, the importance of achieved respiratory exchange ratio (RER) and the significance of breathing reserve (BR) at peak exercise in healthy individuals are poorly understood. We compared VO2 at maximal load (peakVO2 ) and anaerobic threshold (VO2@AT ) in healthy Swedish individuals with commonly used reference values, taking gender into account. Further, we analysed maximal workload and peakVO2 with regard to peak RER and BR. In all, 181 healthy, 50-year-old individuals (91 women) performed CPET. PeakVO2 was best predicted using Jones et al. (100·5%), while SHIP reference values underestimated peakVO2 most: 112·5%. Furthermore, underestimation of peakVO2 in women was found for all studied reference values (P<0·001) and was largest for SHIP: women had 128% of predicted peakVO2 , while men had 104%. PeakVO2 was similar in subjects with peak RER of 1-1·1 and RER > 1·1 (2 328·7 versus 2 176·7 ml min-1 , P = 0·11). Lower BR (≤30%) related to significantly higher peakVO2 (P<0·001). In conclusion, peakVO2 was best predicted by Jones. All studied reference values underestimated oxygen uptake in women. No evidence for demanding RER > 1·1 in healthy individuals was found. A lowered BR is probably a normal response to higher workloads in healthy individuals.

Large Buffering Effect of the Duodenal Bulb in Duodenal Switch: a Wireless pH-Metric Study.

INTRODUCTION: Bariatric procedures result in massive weight loss, however, not without side effects. Gastric acid is known to cause marginal ulcers, situated in the small bowel just distal to the upper anastomosis. We have used the wireless BRAVO™ system to study the buffering effect of the duodenal bulb in duodenal switch (DS), a procedure in which the gastric sleeve produces a substantial amount of acid. METHODS: We placed a pre- and a postpyloric pH capsule in 15 DS-patients (seven men, 44 years, BMI 33) under endoscopic guidance and verified the correct location by fluoroscopy. Patients were asked to eat and drink at their leisure, and to register their meals for the next 24 h. RESULTS: All capsules but one could be successfully placed, without complications. Total registration time was 17.2 (1.3-24) hours prepyloric and 23.1 (1.2-24) hours postpyloric, with a corresponding pH of 2.66 (1.74-5.81) and 5.79 (4.75-7.58), p < 0.01. The difference in pH between the two locations was reduced from 3.55 before meals to 1.82 during meals, p < 0.01. Percentage of time with pH < 4 was 70.0 (19.9-92.0) and 13.0 (0.0-34.6) pre and postpylorically, demonstrating a large buffering effect. CONCLUSION: By this wireless pH-metric technique, we could demonstrate that the duodenal bulb had a large buffering effect, thus counteracting the large amount of gastric acid passing into the small bowel after duodenal switch. This physiologic effect could explain the low incidence of stomal ulcers.

Intragastric pH after oral administration of single doses of ranitidine effervescent tablets, omeprazole capsules and famotidine fast-dissolving tablets to fasting healthy volunteers.

BACKGROUND: The therapeutic effect of drugs inhibiting acid production on acid-related discomforts is related to both the onset and duration of action of the drug. The effects on gastric pH by single oral doses of some acid-inhibiting drugs were investigated by measuring daytime (morning to lunch) intragastric pH in healthy volunteers. METHODS: This randomized, single-dose, 4-way crossover study included 15 healthy fasting subjects. Effervescent ranitidine tablets 150 and 300 mg, fast-dissolving famotidine tablets 20 mg and capsules of omeprazole 20 mg were administered. Measurements of intragastric pH were performed every 4 s for 10 min prior to drug administration and during the following 4 h. RESULTS: The effervescent ranitidine tablets (150 or 300 mg) produced similar changes in intragastric pH: following an immediate increase to about pH 5, intragastric pH decreased slightly over the next 10-20 min. Thereafter pH increased steadily, reaching pH 4 after 20-40 min and pH 6 after about 70 min. After famotidine, pH 4 was reached after 80 min, significantly slower than ranitidine. After omeprazole, pH 3 was never reached. Ranitidine 150 and 300 mg showed significantly larger integrated pH responses over the 4-h observation period, compared to famotidine (P = 0.0288 and 0.0074) or omeprazole (P < 0.001). CONCLUSIONS: After single-dose administration to healthy fasting volunteers), ranitidine effervescent tablets showed a significantly more rapid onset of action and a significantly larger integrated pH response compared to either famotidine 20 mg fast-dissolving tablets or omeprazole 20 mg capsules.

Rapid onset of action of inhaled formoterol in asthmatic patients.

Twelve patients with stable asthma (mean age, 39 years; asthma duration, 11 years; mean forced expiratory volume in 1 s, 65 percent of predicted; and reversibility, 31 percent) were studied in a double-blind crossover trial. The patients were studied during three test days. Airway resistance and specific airway conductance (Raw and SGaw) were measured using a body plethysmograph and pulse rate, blood pressure, tremor, and subjective effects were recorded before and 1, 3, 5, 10, 15, 30, 60, and 120 min after the test doses. A baseline Raw variability of +/- 20 percent was allowed between the test days. Formoterol 12 micrograms, 24 micrograms, and terbutaline 500 micrograms were given in a spacer (Nebulator) in a randomized double-blind crossover manner as two puffs with a 30-s interval in between. The effect of formoterol 12 micrograms on Raw was significantly better than terbutaline after 3, 5, 10, 60, and 120 min. Formoterol 24 micrograms was significantly better than terbutaline as soon as 3 min after inhalation and at every point in time after that. Formoterol 24 micrograms tended to be better than formoterol 12 micrograms but the differences were not significant at any point in time. All three treatments were well-tolerated. No differences were observed for pulse rate, blood pressure, tremor, or palpitations. The overall onset of bronchodilatation after formoterol 12 and 24 micrograms was faster than after terbutaline 500 micrograms. The tolerability of formoterol was good.

The bronchial response, but not the pulmonary response to inhaled methacholine is dependent on the aerosol deposition pattern.

The clinical effect of inhaled radio-labeled (Technetium-99m diethylenetriamine-pentaacetic acid) methacholine was studied in two separate experiments performed in eight symptom-free asthmatics with bronchial hyperresponsiveness. Aerosols were formed by two different nebulizers, producing either mainly small aerosol particles (2-microns mass median aerodynamic diameter [MMAD]) for peripheral, or mainly large aerosol particles (9-microns MMAD) for large airway deposition. The intended site of deposition was confirmed by gamma camera recordings. Changes in specific airway conductance (sGaw) were set as an index of central airway constriction, and functional alterations in the gas exchanging parts of the lung were estimated by multiple inert gas elimination technique (MIGET) and arterial blood gas analyses. The main finding was that the responses, as measured by the changes in arterial blood gases and by MIGET, were similar in the two experiments, while the fall in sGaw was significantly larger after deposition in the main bronchi than in the peripheral airways (p < 0.05). The time courses of the abnormalities in the gas exchanging elements were much longer than those of the responses of the central airways, and the abnormalities were recorded still at the end of the experiment 2 h after challenge in most patients. A discrepancy in dose dependency and time courses suggests differences in mechanism and/or dynamics of the responses exerted by the various target organs. Interaction in the process of clearance from the lung of inhaled methacholine by the bronchial circulation may have contributed to the observed discrepancies.

Large emphysematous bullae. Successful treatment with thoracoscopic technique using fibrin glue in poor-risk patients.

Five patients with poor lung function (FEV1, 0.8 to 1.0 L; MVV, 27 to 36 L/min) and large emphysematous bullae were operated on. Fibrin glue was introduced into the bullae through a thoracoscope. The results have been excellent and no serious perioperative or postoperative complications have occurred. The patients have all improved clinically and are very satisfied with the results. Postoperatively, FEV1 was between 1.0 and 1.2, and MVV was 30 to 52 L. The clinical improvement was, however, larger than these figures illustrate. Our preliminary experience using this technique suggests that it can be used in patients with very low lung function with a minimal risk. We propose that all patients with severe emphysema should be screened for bullous components because improvement might be possible by operation with this minimally traumatizing technique.

Investigation of the excluded stomach after Roux-en-Y gastric bypass.

BACKGROUND: One problem with Roux-en-Y gastric bypass (RYGBP) is that it leaves the bypassed segment not readily available for endoscopic or radiographic examinations. MATERIALS AND METHODS: Three males, 50, 54 and 64 years old, suffered from repeated, gastrointestinal bleeding of unknown origin requiring transfusion 1/2, 1 and 7 years after RYGBP. Access to the stomach was obtained by an ultrasound-guided percutaneous gastrostomy. RESULTS: We could perform endoscopy, barium studies and gastric acid output measurements through the gastrostomy. Histological gastritis, low acid output and absence of H. pylori infection were found. CONCLUSION: We were able to exclude severe gastric disease in our patients.

Pulmonary function after autologous bone marrow transplantation in children: a long-term prospective study.

We performed serial pulmonary function tests (PFTs) consisting of spirometry and diffusing capacity in 26 children after BMT. The median follow-up was 10 years. The influence of total body irradiation (TBI) on long-term pulmonary function was of particular interest. In the 20 children who had received TBI, after an initial decrease the PFTs showed recovery, but the mean lung volumes were still significantly decreased 5 years after BMT at 10% below baseline. The proportions of children with restrictive impairment 5 and 10 years after BMT were 20 and 21%, respectively. Only one child was diagnosed with obstructive impairment. The proportions of children with isolated diffusing impairment at 5 and 10 years were 7/20 (35%) and 7/13 (54%), respectively. Six children had received chemotherapy only and showed isolated diffusing impairment as the only long-term sequela in 4/5 and 1/3 at 5 and 10 years. Our main finding was that there was little change in PFTs 1-10 years after BMT. TBI was associated with persistently decreased lung volumes in a proportion of patients, whereas chemotherapy also might have been of importance for the development of impaired gas exchange.

Extended NO analysis applied to patients with COPD, allergic asthma and allergic rhinitis.

The recommended method to measure exhaled nitric oxide (NO) cannot reveal the source of NO production. We applied a model based on the classical Fick's first law of diffusion to partition NO in the lungs. The aim was to develop a simple and robust solution algorithm with a data quality control feature, and apply it to patients with known alterations in exhaled NO. Subjects with allergic rhinitis, allergic asthma, chronic obstructive pulmonary disease (COPD) smokers and controls were investigated. NO was measured at three expiratory flow rates. An iteration method was developed to partition NO. The airway tissue content of NO was increased in asthma, 144 +/- 80 ppb (P = 0.04) and decreased in smokers, 56 +/- 36 ppb (P = 0.02). There was no difference between subjects with rhinitis, 98 +/- 40 ppb and controls, 98 +/- 44 ppb. The airway transfer rate was increased in allergic asthma and allergic rhinitis, 12 +/- 4 vs. 12 +/- 5 ml sec(-1), compared to controls, 8 +/- 2 ml sec(-1) (P < 0.001). The alveolar levels were no different from controls, 2 +/- 1 ppb. In COPD the alveolar levels were increased, 4 +/- 2 ppb (P < 0.001). Extended NO analysis reveals from where in the respiratory system NO is generated. Hence, this new test can be added to the tools the physician has for the diagnosis and treatment of patients with respiratory disorders.

Exhaled nitric oxide and its relationship to airway responsiveness and atopy in asthma. BHR-Study Group.

Exhaled nitric oxide (NO) has attracted increasing interest as a non-invasive marker of airway inflammation. The purpose of this study was to determine whether exhaled nitric oxide in subjects with asthma varied according to their atopic status and to examine its correlation with airway hyperresponsiveness and lung function measurements. Forty patients with asthma and 13 controls participated in the study. Nitric oxide was measured on three occasions with intervals of at least 3 days, using a chemiluminescence method. Airway responsiveness was assessed with methacholine challenge and lung function measurements were made. All subjects recorded peak expiratory flow and kept a symptom diary during a 17-day period. There was no significant difference in lung function measurements, peak expiratory flow or symptom score between the two asthma groups. Atopic patients with asthma had a significantly higher mean amount of exhaled NO than non-atopic subjects with asthma (162 +/- 68 vs. 113 +/- 55 nl min-1; P = 0.03) and the control group (88 +/- 52 nl min-1; P = 0.004). No significant difference was found in the amount of exhaled NO between non-atopic patients with asthma and the controls. In atopic subjects with asthma the mean exhaled NO was significantly correlated to the dose-response slope for methacholine (r = -0.52; P = 0.02), while no such correlation was found in the non-atopic group. In conclusion; in this study, atopic subjects with asthma had higher levels of exhaled NO than non-atopic subjects. Atopic status should be taken into account when measuring levels of exhaled NO in subjects with asthma.

Lack of correlation between the grade of methacholine-induced bronchial hyperreactivity and ipratropium bronchodilation in asthmatics.

In 46 never-smoking randomly chosen patients with non-allergic asthma, 40 to 60 years old, a methacholine hyperreactivity test and lung function tests were performed after inhalation of different doses of ipratropium bromide (IB). The grade of hyperreactivity was measured as the cumulative dose of methacholine necessary to produce a decrease in the forced expiratory volume in one second of 20% of the lowest post-NaCl value (PD20). The following lung function tests were carried out: Lung volumes, ventilatory capacity including flow-volume curves, airway resistance and nitrogen single-breath wash-out test. The bronchodilator effect, measured as a change in the different lung function tests for different doses of IB given (0.08 mg, 0.15 mg and 0.25 mg), was correlated to the grade of hyperreactivity (PD20 dose). No or only a slight correlation was found between the grade of methacholine-induced hyperreactivity and the bronchodilator effects of the different doses of IB. These results indicate a lack of correlation between an anticholinergic bronchodilator effect and the grade of methacholine-induced bronchial hyperreactivity, or possibly an insensitivity of the above-mentioned methacholine test.

Reference values for lung function tests in men: regression equations with smoking variables.

Prediction formulas for static and dynamic spirometry, gas distribution, static lung mechanics and the transfer test were derived from measurements in healthy men. The measurements included total lung capacity, residual volume, airways resistance, static elastic recoil pressure of the lung, static compliance, closing volume, slope of the alveolar plateau (phase III), flow-volume variables (including mean transit time) during breathing of air or a helium/oxygen mixture, and conventional spirometric indices. The results from 146 smokers and 124 never-smokers were evaluated separately and combined. For all lung function tests a single regression equation was obtained. The prediction formulas included time-related smoking variables and were valid for both smokers and never-smokers. For many lung function tests, a nonlinear age coefficient resulted in a significant reduction in variance compared with simple linear models. Heavy tobacco smoking influenced most lung function tests less than ageing from 20 to 70 years, but for airways resistance, transfer factor and phase III the opposite was found.

Exercise-induced dyspnea is a problem among the general adolescent population.

RATIONALE: Respiratory symptoms during exercise are common and might limit adolescents' ability to take part in physical activity. OBJECTIVE: To estimate the prevalence, determinants and consequences of exercise-induced dyspnea (EID) on daily life in a general population of 12-13 year old adolescents. METHODS: A letter was sent to the parents of all 12-13 year old adolescents in the city of Uppsala (n = 3838). Parents were asked to complete a questionnaire together with their child on EID, asthma and allergy, consequences for daily life (wheeze, day time- and nocturnal dyspnea) and physical activity. The response rate was 60% (n = 2309). RESULTS: Fourteen percent (n = 330) reported EID, i.e. had experienced an attack of shortness of breath that occurred after strenuous activity within the last 12 months. Female gender, ever-asthma and rhinitis were independently associated with an increased risk of EID. Ever-asthma was reported by 14.6% (n = 338), and 5.4% (n = 128) had both EID and ever-asthma. Sixty-one percent (n = 202) of the participants with EID did not have a diagnosis of asthma. In addition to rhinitis, participants with EID reported current wheeze and day-time as well as nocturnal dyspnea more often than the group without EID. No difference was found in the level of physical activity between participants with and without EID. CONCLUSION: Adolescents with undiagnosed exercise-induced dyspnea have respiratory symptoms and are affected in daily life but have the same level of physical activity as adolescents without exercise-induced respiratory symptoms.

Utility of relating pulmonary airflow measures to total lung capacity.

Among healthy never-smokers, forced expiratory volume in one second (FEV1) and maximal voluntary ventilation (40 breaths per minute, MVV40) divided by total lung capacity (TLC) showed less interindividual variability than FEV1 and MVV40, whereas the interindividual variability of other flow variables increased after division by TLC. FEV1, MVV40 and peak expiratory flow (PEF) divided by TLC had higher Student's t-values than FEV1, MVV40 or PEF in comparisons between 224 smokers and 232 never-smokers or between 137 asthmatic patients and 456 reference subjects. Thus these airflow variables corrected for lung size appear to be generally useful indicators of airflow limitation. In these comparisons, the variables were adjusted for body size. All t-test comparisons were based on an equal number of tests. Forced expiratory flow at 70% of TLC (MEF70%TLC) and the area of the expiratory part of the flow-volume curve had the highest t-values when comparing airflow before and after bronchodilatation in 70 asthmatic subjects, except in subjects with more advanced bronchoconstriction in whom MVV40 ranked highest. For the computation of MEF70%TLC, measured TLC could be substituted with predicted TLC with little loss of discriminatory capacity. Reference equations for forced expiratory flow at different TLC fractions and for FEV1/TLC are given.

Effect of nebulized ipratropium bromide on lung function in nonallergic bronchial asthma.

The present investigation was performed on 64 randomly chosen never-smoking patients, 40-60 years old, with nonallergic bronchial asthma with an average FEV1 of 69-73% of predicted, a positive methacholine test, a normal serum IgE level, and a negative RAST or skin test to common allergens and not receiving oral steroid treatment. Sensitive spirometric tests were used to evaluate the dose-response effect of inhalation of 0.08, 0.15 or 0.25 mg of ipratropium bromide. The drug caused bronchodilatation with a nearly linear dose-response relationship for static lung volumes, while the total lung capacity was unchanged after this inhalation. Airway resistance decreased and specific airway conductance increased after all doses. Ventilation and flows were better after doses of 0.15 and 0.25 mg than after 0.08 mg. The intrapulmonary gas distribution improved only after inhalation of 0.25 and 0.15 mg. The currently recommended dose of 0.08 mg seems to be suboptimal for dilatation of both small and large airways.

Optimal combinations of lung function tests in the detection of various types of early lung disease.

The ability to detect early lung disease with different combinations of lung function tests was assessed by discriminant analysis. A number of lung function tests were performed in 224 never-smokers, 232 smokers, 111 pneumoconiotic subjects and 137 asthmatic patients. The discriminatory capacities of different combinations of test variables are presented. For detecting lung damage induced by tobacco smoke, a combination of the transfer factor and the slope of the alveolar plateau (phase III) increased the sensitivity from 18% to 32% at a specificity of 95%, compared with phase III alone. Dynamic spirometry did not add to the discriminatory capacity. Patients with asthma could be separated from reference subjects by airway resistance, Phase III or a combination of variables in dynamic spirometry. Pneumoconiotic subjects were best identified by a combination of the transfer factor, volumic compliance and phase III. Closing capacity divided by total lung capacity (TLC) and FEV1/TLC further improved the discrimination between different subgroups.

Learning effects, variation during office hours and reproducibility of static and dynamic spirometry.

Static and dynamic spirometric tests were performed in 21 healthy subjects (21-61 years old, 8 smokers and 9 ex-smokers) on 3 different days within 2 weeks. The design of the study allowed separation of the influence of learning and diurnal changes between 09.00 and 17.00 h. In addition, the reproducibility of the tests and the effect of inhalation of 2.5 mg of terbutaline sulphate were studied. No learning effect was observed. There were slight, but statistically significant differences between morning, noon and afternoon measurements. Thus, the residual volume and flow in the early phase of forced expiration were highest in the afternoon, while maximal voluntary ventilation was lower at noon than in the afternoon or morning. The intraindividual variabilities (defined as standard deviation of difference between first and second measurement) of total lung capacity, vital capacity and forced expiratory volume in 1 s (FEV1) were about 3% of the predicted values. The ratio of intra- to interindividual variability was 0.2-0.3. The remaining tests showed higher variability and a higher intra- to interindividual variability ratio. Terbutaline inhalation caused a significant increase in most forced expiratory flow variables. A 10% increase in FEV1 corresponded to a 50-60% increase in endexpiratory flow. In spite of this, the endexpiratory flow and mean transit time were better discriminators of the effects of bronchodilation in normal subjects.

Reference values for lung function tests in females. Regression equations with smoking variables.

Prediction formulas for static and dynamic spirometry, gas distribution, static lung mechanics and transfer test were derived from measurements in healthy females. The measurements included total lung capacity, residual volume, airway resistance, static elastic recoil pressure of the lung, static compliance, closing volume, slope of the alveolar plateau (phase III), flow-volume variables (including mean transit time) during breathing of air or a helium/oxygen mixture, and conventional spirometric indices. The results from 86 smokers and 100 never-smokers were evaluated separately and combined. For all lung function tests, a single regression equation including time-related smoking variables, valid for both smokers and never-smokers, was obtained. For many lung function tests, a nonlinear age coefficient resulted in a significant reduction in variance compared with simple linear models. Heavy tobacco smoking influenced most lung function tests less than ageing from 20 to 70 years, but for airway resistance, volumic airway conductance, closing volume, phase III, FEV1/VC, volume of isoflow and mean transit time the opposite was found.