Inhaled and oral bronchodilator therapy in exercise induced asthma

Measurements of peak expiratory flow rate during serial exercise tests were used to assess the efficacy of the beta adrenergic stimulants oral terbutaline (5 mg) and fenoterol aerosol (400 micrograms), in preventing post-exercise bronchoconstriction in 18 asthmatic subjects. While both compounds significantly elevated resting levels of peak expiratory flow rate for at least four hours, there were qualitative and quantitative differences in the effects of the two drugs on exercise induced bronchoconstriction. Oral terbulation did not significantly alter the pattern of response to exercise. However, the peak expiratory flow rates before during and after exercise were significantly higher compared with placebo at two, four and six hours after the drug. The importance of examination of actual values for peak expiratory flow rates as well as percentage changes when testing oral bronchodilators is emphasised. Aerosol fenoterol completely blocked post-exercise bronchoconstriction immediately after inhalation and for up to four hours in most subjects. Bronchodilatation occurred in all subjects during exercise in the presence of both the active and placebo drugs. It is postulated that the superiority of the aerosol in blocking exercise induced bronchoconstriction may be function of its activity at the surface of the bronchial mucosa.     

Airway resistance and work of breathing in tracheostomy tubes

Recommendations for sizing of tracheostomy tubes are generally based on anatomic considerations with the largest fitting tube most commonly placed. Once in the tracheostomy site, the tube assumes the new role of the upper airway. Consideration of the airway resistance of each tracheostomy tube and change in work of breathing are important in maintaining the respiratory system homeostasis. The airflow dynamics of neonatal, pediatric, and adult tracheostomy tubes were studied. Flow rates were plotted against change in pressure for inspiratory and expiratory flows and resistances for each tube were calculated. The expiratory resistances were larger for the neonatal tubes and pediatric tubes 0 and 00, while inspiratory resistances were the limiting factor in the adult tubes and the larger pediatric tubes. Comparison of calculated resistances of the tracheostomy tubes was made with known physiologic airway resistances. Adult tubes 8 and 10 most closely simulated the upper airway resistance of adults and neonatal tube 0 appeared most appropriate for the newborn. Work of breathing was determined for each tracheostomy tube. Increasing tube diameter as well as decreasing tidal volume and respiratory rate decreased the amount of work required to maintain a given flow.     

Image analysis in the clinical laboratory: application of filtration cytometry to bacteriological screening of urine samples

The airway resistance (Raw) was determined with interruption technique for 327 normal old, middle-aged and young persons after exploration of the effect of forced respiration, lung volume and upper airway compliance on it. FVC, V75, V50 and V25 were also performed. The regression equations of expiratory and inspiratory resistances (R. R1) were built with age, height and FVC as independent variables. The results showed that both expiratory and inspiratory resistances had a tendency of increase with aging, and FVC, V75, V50, V25 were declined with aging. This reflected that various organs and tissues including respiratory organs gradually oldened with aging. The decrease of elastic recoil of lung and central airway can lead to an increase of airway resistance in various degrees or no change. The data and regression equations can be recommended for the application in public health and clinical care.     

Reconstruction of defects involving the upper one-third of the auricle

STUDY OBJECTIVES: The peak inspiratory flow rates (PIFRs) generated by cystic fibrosis (CF) and COPD patients through a range of clinically relevant resistances have not yet been reported (to our knowledge). The objectives of this study were to (1) explore a relevant range of resistive loads and address whether patients with stable CF and COPD can generate the PIFR sufficient to disperse dry-powder inhalants (DPI) and (2) determine whether the optimal inspiratory flow rate effective for delivery of aerosolized pharmacologic therapeutic agents can be attained with a comfort rating acceptable to subjects. DESIGN: Prospective, controlled, subject-blinded study. SETTING: Pulmonary function laboratory at the VA Palo Alto Health Care System. PATIENTS OR PARTICIPANTS: Thirty-six subjects, including 12 healthy volunteers, 12 subjects with CF, and 12 subjects with COPD were studied. MEASUREMENTS: Studies of dynamic lung function and PIFR without and with varying resistances were obtained at a single laboratory visit. RESULTS: Dynamic lung function and PIFR varied inversely with the resistive load for all patient groups and did not correlate with the disease severity, as indicated by FEV1 of percent predicted. The average subjective comfort rating for any given resistive load was similar for subjects with CF and COPD. CONCLUSIONS: These results support the conclusion that subjects with stable CF and COPD of varying severity can comfortably generate the necessary flow rates to operate new and currently available DPIs over a wide range of inspiratory resistances.     

A computer program for automatic measurement of respiratory mechanics in artificially ventilated patients

A program for automatic and periodic determination of respiratory mechanics in artificially ventilated patients is described. Airway pressure and flow signals are obtained from the ventilator in the controlled ventilation mode with constant flow inflation and end-inspiratory pause. Periodically, the program records both signals for a given time and it delimits a ventilatory cycle and its components out of this record. Then, four mechanical parameters of the respiratory system are calculated: (1) Rinit, the resistance obtained with the end-inflation occlusion technique; (2) Ers, the elastance (inspiratory) calculated from the slope of the airway pressure profile during inflation; (3) tau, the expiratory time constant; (4) PEEP, the global positive end expiratory pressure. All parameter measurements have been evaluated in experimental conditions, and are in good agreement with reference values. The complete software includes the display of the signals and of the trends together with automatic disk file backups. An additional program allows one to display the trends again and to create table text files containing all the recorded data for further analysis. The system proved to work in ICU and anaesthesia patients with various ventilators.     

Occlusion pressures in men rebreathing CO2 under methoxyflurane anesthesia

The effect of general anesthesia on control of breathing was studied by CO2 rebreathing and occlusion pressure measurements in six normal human subjects under methoxyflurane anesthesia. CO2 was found to increase the amplitude of the occlusion pressure wave without changing its shape, so that CO2 responses in terms of the occlusion pressure developed 100 ms after the onset of inspiration (Po/0.1) gave results equivalent to the responses in terms of Po/1.o or any other parameter of the pressure wave. Methoxyflurane depressed the ventilatory response to CO2 but not the occlusion pressure response, implying that the most important action of the anesthetic was to increase the effective elastance of the respiratory system rather than to depress the respiratory centers. The elastance was further increased by CO2, and this mechanical change had the effect of shifting the "apneic threshold" extrapolated from the ventilatory response curve to a lower PAco2. Frequency of breathing, inspiratory and expiratory times were not altered by CO2 in anesthetized subjects.     

Respiratory effort sensation during exercise with induced expiratory-flow limitation in healthy humans

Nine healthy subjects (age 31 +/- 4 yr) exercised with and without expiratory-flow limitation (maximal flow approximately 1 l/s). We monitored flow, end-tidal PCO2, esophageal (Pes) and gastric pressures, changes in end-expiratory lung volume, and perception (sensation) of difficulty in breathing. Subjects cycled at increasing intensity (+25 W/30 s) until symptom limitation. During the flow-limited run, exercise performance was limited in all subjects by maximum sensation. Sensation was equally determined by inspiratory and expiratory pressure changes. In both runs, 90% of the variance in sensation could be explained by the Pes swings (difference between peak inspiratory and peak expiratory Pes). End-tidal PCO2 did not explain any variance in sensation in the control run and added only 3% to the explained variance in the flow-limited run. We conclude that in healthy subjects, during normal as well as expiratory flow-limited exercise, the pleural pressure generation of the expiratory muscles is equally related to the perception of difficulty in breathing as that of the inspiratory muscles.     

Enhancement of exercise-induced asthma by cold air

To study the possibility that the inhalation of cold air accentuates the bronchoconstrictor response to exercise in asthma, eight subjects exercised while breathing air at ambient or subfreezing temperatures. On a separate day, cold air was breathed at rest so as to isolate the effects of this stimulus. Pulmonary mechanics were measured before and after each experiment. In all subjects acute bronchoconstriction followed the control exercise challenge. With cold-air breathing, however, the magnitude of the response was markedly enhanced. Residual volume increased 158 per cent more than it did previously, and specific conductance and one-second forced expiratory volumes changed an additional 85 and 100 per cent, respectively. The effects of cold air at rest were very small. The results demonstrate a positive interaction of two common naturally occurring stimuli in the induction of asthmatic attacks, and constitute objective verification of a frequent clinical complaint.     

Immediate response to inspiratory resistive loading in anesthetized patients with kyphoscoliosis: spirometric and neural effects

In kyphoscoliosis (KS), lung volumes are reduced, respiratory elastance and resistance are increased, and breathing pattern is rapid and shallow, attributes that may contribute to defense of tidal volume (VT) in the face of inspiratory resistive loading. The control of ventilation of 12 anesthetized patients about to undergo corrective spinal surgery was compared to that of 11 anesthetized patients free of cardiothoracic disease during quiet breathing and the first breath through one of three linear resistors. Mean forced vital capacity (FVC) of the KS group was 48% that of the controls (C). Passive elastance (Ers) and active elastance and resistance (E'rs and R'rs, respectively) were computed according to previously described techniques (Behrakis PK, Higgs BD, Baydur A, Zin WA, Milic-Emili J (1983) Active inspiratory impedance in halothane-anesthetized humans. J Appl Physiol 54: 1477-1481). Baseline tidal volume VT, inspiratory duration Tl, expiratory duration TE, duration of total breathing cycle TT, and inspiratory duty cycle TI/TT were significantly reduced, while VE was slightly decreased in the KS. Ers, E'rs, and R'rs, were, respectively, 72, 69, and 89% greater in the KS. Driving pressure (Pmus) was derived from the equation of motion, using active values of respiratory elastance. With resistive loading, there was greater prolongation of TI in the C, while percent reduction in VT and minute ventilation VE was less in KS. Compensation in both groups was achieved through three changes in the Pmus waveform. (1) Peak amplitude increased. (2) The duration of the rising phase increased. (3) The rising Pmus curve became more concave to the time axis. These changes were most marked with application of the highest resistance in both groups. Peak driving pressure and mean rate of rise of Pmus were greater in the KS. Increased intrinsic impedance, Pmus, and differences in changes in neural timing in anesthetized kyphoscoliotics contribute to modestly greater VT defense, compared to that of anesthetized subjects free of cardiorespiratory disease.     

On the causes of lung hyperinflation during bronchoconstriction

Airway obstruction in asthma and chronic obstructive pulmonary disease (COPD) is often associated with lung hyperinflation. In this review, we examine the mechanisms that may cause functional residual capacity (FRC), residual volume (RV) and total lung capacity (TLC) to increase during acute and chronic airway obstruction. Normally, FRC at rest is determined by the static characteristics of the lung and chest wall. When airways narrow, FRC may be also be determined by dynamic factors. There are data suggesting that expiratory flow limitation during tidal breathing represents the starting trigger for FRC to increase, in order to allow breathing at higher flows. Indeed, the increase in FRC during induced bronchoconstriction in asthma is closely associated with the occurrence of flow limitation, i.e. the achievement of maximum flow during tidal breathing. Conversely, the decrease in FRC following bronchodilatation in COPD is closely associated with flow limitation disappearing or occurring at lower lung volumes. In normal young people, RV is determined by the static characteristics of the chest wall. During bronchoconstriction RV may also be determined by dynamic factors; therefore, changes in flow or airway calibre at low lung volumes may modulate RV during bronchoconstriction. During acutely induced bronchoconstriction, RV achieved with an expiration from TLC is less than with an expiration from tidal breathing, and this effect appears to be linked to the bronchodilator effect of the deep inhalation. The reasons for the increase in TLC during airway narrowing are not clear, but the duration of the bronchoconstriction by itself may play a role.     

An accelerated increase of plasma adrenomedullin in acute asthma

A novel vasorelaxant peptide, adrenomedullin (AM), has been isolated from the acid extract of human pheochromocytoma. We have recently shown that AM inhibits histamine- and acetylcholine-induced bronchoconstriction in anesthetized guinea pigs in vivo, and this bronchodilatory effect is long-lasting. Here, we measured plasma AM concentrations in nine patients with an acute attack of bronchial asthma. The results were compared with values in 30 age-matched normal control subjects and seven age-matched stable asthmatic patients. The mean AM concentrations of patients with an acute asthma attack (98 +/- 22 pg/mL) were clearly higher than those of normal control subjects (18 +/- 2 pg/mL) and stable asthmatic patients (21 +/- 3 pg/mL). Reverse-phase high-performance liquid chromatography (HPLC) showed that the major component of plasma immunoreactive AM in patients with an asthma attack and in normal subjects equally corresponded to authentic human AM(1-52). Our results suggest that plasma AM is markedly increased in many of the patients during an acute attack of bronchial asthma, but it is not observed in stable asthmatic patients. Although this report is preliminary, the observed increase of circulating AM during an acute asthma attack may represent a compensatory mechanism against the bronchoconstriction, probably through its bronchodilatory action.     

Inhaled ICI 204,219 blocks antigen-induced bronchoconstriction in subjects with bronchial asthma

Three inhalation formulations of ICI 204,219 were compared for antagonism of antigen-induced bronchoconstriction in 16 subjects with asthma who demonstrated reproducible hypersensitivity to allergen during screening challenges. Each subject received a single 0.2-mg dose of each formulation and was challenged with ragweed 30 min after administration of ICI 204,219 until the forced expiratory volume in 1 s (FEV1) decreased by 20 percent or the maximum allergen concentration (100 micrograms/ml) was reached. The majority of subjects tolerated 100 micrograms/ml of allergen without a 20 percent decrease in FEV1. Inhalation formulations of ICI 204,219 successfully inhibited bronchoconstriction in subjects with reproducible sensitivity to ragweed challenges.     

Airway mechanics, gas exchange, and blood flow in a nonlinear model of the normal human lung

A model integrating airway/lung mechanics, pulmonary blood flow, and gas exchange for a normal human subject executing the forced vital capacity (FVC) maneuver is presented. It requires as input the intrapleural pressure measured during the maneuver. Selected model-generated output variables are compared against measured data (flow at the mouth, change in lung volume, and expired O2 and CO2 concentrations at the mouth). A nonlinear parameter-estimation algorithm is employed to vary selected sensitive model parameters to obtain reasonable least squares fits to the data. This study indicates that 1) all three components of the respiratory model are necessary to characterize the FVC maneuver; 2) changes in pulmonary blood flow rate are associated with changes in alveolar and intrapleural pressures and affect gas exchange and the time course of expired gas concentrations; and 3) a collapsible midairway segment must be included to match airflow during a forced expiration. Model simulations suggest that the resistances to airflow offered by the collapsible segment and the small airways are significant throughout forced expiration; their combined effect is needed to adequately match the inspiratory and expiratory flow-volume loops. Despite the limitations of this lumped single-compartment model, a remarkable agreement with airflow and expired gas concentration measurements is obtained for normal subjects. Furthermore, the model provides insight into the important dynamic interactions between ventilation and perfusion during the FVC maneuver.     

Endothelin-1 levels in induced sputum samples from asthmatic and normal subjects

BACKGROUND: Endothelin-1 (ET-1) is a potent bronchoconstrictor which may have a role in the pathogenesis of asthma. The levels of ET-1 in saliva, induced sputum, and plasma from asthmatic and non-asthmatic subjects were compared. METHODS: Sputum induction was performed on 28 asthmatic subjects and nine normal volunteers. ET-1 levels were measured in plasma, saliva, and sputum samples and reversed phase high performance liquid chromatography (RP-HPLC) was performed on saliva and sputum samples. RESULTS: ET-1 was present in the following order of concentration in both normal and asthmatic subjects: saliva > sputum > plasma (saliva, median 30.1 and 23.9 pg/ ml, respectively; sputum, median 15.5 and 11.2 pg/ml; plasma, median 3.1 and 3.6 pg/ ml). There were no differences between asthmatic and normal subjects in the levels of ET-1 in each fluid. The levels of ET-1 in asthmatic subjects were not influenced by whether or not they were taking inhaled steroids. RP-HPLC of sputum and saliva confirmed the presence of ET-1 in these fluids. CONCLUSIONS: Levels of ET-1 can be measured in saliva and sputum obtained by sputum induction in asthmatic and healthy subjects and, although no difference was found in basal levels of ET-1 in sputum, saliva and plasma between normal subjects and asthmatics without bronchoconstriction, it is apparent that ET-1 is produced or released locally within the respiratory tract in concentrations higher than those in plasma.     

Regulation of ventilatory capacity during exercise in asthmatics

In asthmatic and control subjects, we examined the changes in ventilatory capacity (VECap), end-expiratory lung volume (EELV), and degree of flow limitation during three types of exercise: 1) incremental, 2) constant load (50% of maximal exercise capacity; 36 min), and 3) interval (alternating between 60 and 40% of maximal exercise capacity; 6-min workloads for 36 min). The VECap and degree of flow limitation at rest and during the various stages of exercise were estimated by aligning the tidal breathing flow-volume (F-V) loops within the maximal expiratory F-V (MEFV) envelope using the measured EELV. In contrast to more usual estimates of VECap (i.e., maximal voluntary ventilation and forced expiratory volume in 1 s x 40), the calculated VECap depended on the existing bronchomotor tone, the lung volume at which the subjects breathed (i.e., EELV), and the tidal volume. During interval and constant-load exercise, asthmatic subjects experienced reduced ventilatory reserve, higher degrees of flow limitation, and had higher EELVs compared with nonasthmatic subjects. During interval exercise, the VECap of the asthmatic subjects increased and decreased with variations in minute ventilation, due in part to alterations in their MEFV curve as exercise intensity varied between 60 and 49% of maximal capacity. In conclusion, asthmatic subjects have a more variable VECap and reduced ventilatory reserve during exercise compared with nonasthmatic subjects. The variations in VECap are due in part to a more labile MEFV curve secondary to changes in bronchomotor tone. Asthmatics defend VECap and minimize flow limitation by increasing EELV.     

Effect of inhaled PGE2 on exercise-induced bronchoconstriction in asthmatic subjects

Previous studies have suggested that the endogenous release of inhibitory prostanoids limits the bronchoconstrictor response to repeated exercise. The aim of our study was to determine whether inhaled prostaglandin (PG)E2 attenuates exercise-induced bronchoconstriction or methacholine airway responsiveness in asthmatic subjects. Eight subjects with mild stable asthma and exercise bronchoconstriction were studied on 4 separate days, 48 h apart. Subjects inhaled PGE2 or placebo in a randomized, crossover, double-blind fashion, 30 min prior to an exercise challenge or a methacholine challenge. PGE2 inhalation significantly attenuated exercise bronchoconstriction. The mean maximal %fall in FEV1 after exercise was 26% (SEM 3.7%) after placebo, and was 9.7% (SEM 2.7%) after PGE2 (p < 0.001). PGE2 also significantly reduced the duration of exercise bronchoconstriction (p = 0.034). However, PGE2 did not significantly attenuate methacholine airway responsiveness. The geometric mean methacholine provocative concentration causing a 20% fall in FEV1 (PC20) was 0.77 (%SEM 1.48) after placebo day, and 1.41 (%SEM 2.20) after PGE2 (p = 0.30). These results demonstrate that inhaled PGE2 markedly attenuates exercise bronchoconstriction in asthmatic subjects and suggest that this effect is not occurring through functional antagonism of airway smooth muscle.     

Prescribing medications and malpractice suits: clear, consistent documentation is the key

BACKGROUND: Adenoid hyperplasia is one of the most common reasons for nasal obstruction in childhood. The consequences of a nasopharyngeal obstruction on the airflow in the nasal cavity and the epipharynx were investigated. MATERIALS AND METHODS: In a model of a nose we conducted experiments with adenoids of different size, documenting their influence on inspiratory and expiratory nasal flow. Rhinoresistometry was performed to obtain further information concerning resistance and turbulence. RESULTS: The flow experiments showed no alterations of the inspiratory nasal flow regardless of adenoid size. Instead the adenoid had a significant influence on the direction of the expiratory nasal flow in the cavity. Depending on the extension of the hyperplasia, parts of the nasal cavity were excluded from the flow. Rhinoresistometry showed that relation between nasopharyngeal obstruction and nasal resistance was nonlinear. CONCLUSION: Adenoid hyperplasia affects only expiratory nasal flow. In our model a critical mass seemed to be reached in case of more than 60% nasopharyngeal obstruction. A narrowing of the epipharynx up to 50% of its volume has no significant effects on nasal resistance.     

Elastase in hyperpnea-induced guinea pig airway constriction

Aerosolized elastase has been shown to produce airway constriction in guinea pigs. In this study, we examined whether endogenous elastase plays a role in isocapnic hyperpnea-induced airway constriction using an elastase inhibitor, eglin-c. The study was divided into three experiments. In the first experiment, we used an elastase inhibitor, eglin-c, to suppress hyperpnea-induced bronchoconstriction. Twenty-two young male Hartley guinea pigs were divided into three groups: control (n=8), eglin-c(1) (a lower dose of eglin-c, n=7), and eglin-c(2) (a higher dose of eglin-c, n=7). In the second experiment, we tested whether eglin-c affects pulmonary function following 15 min of normal air ventilation in two groups of animals: control (n=8) and eglin-c (n=8). In the third experiment, animals were divided into two groups: control (n=7) and compound 48/80 (a mast cell degranulating agent, n=7). Airway function was examined in the anesthetized-paralyzed animal. In the first and third experiments, 15 min of isocapnic hyperpnea caused marked decreases in dynamic respiratory compliance, forced expiratory flow at 0.1 s and maximal expiratory flow at 50% total lung capacity, demonstrating hyperpnea-induced airway constriction. This bronchoconstriction was significantly attenuated by eglin-c and by pretreatment with compound 48/80. In the second experiment, eglin-c did not significantly affect bronchial function following normal air ventilation. These data suggest that elastase released from mast cells directly or indirectly induces hyperpnea-induced bronchoconstriction.     

Density dependence of pulmonary resistance: correlation with small airway pathology

The density dependence of maximal expiratory flow is not an effective test of the site of airway narrowing in obstructive lung disease. We hypothesized that the density dependence of pulmonary resistance (DD,RL) would be more closely related to the degree of airway narrowing and peripheral airway pathology in smokers. We measured maximal expiratory flow at 50% vital capacity (V'max50) and lung resistance (RL) breathing air and 80% helium-20% oxygen, and calculated density dependence of V'max50 and RL in 40 patients who had moderate airflow obstruction and in 10 normal subjects. We compared the density dependence of RL and V'max50 with the degree of airway obstruction and bronchiolar pathology scores in 27 patients with resected lung specimens. There were no differences in DD of V'max50 or RL between normal subjects and patients, and no relationship between the degree of obstruction or the bronchiolar pathology score and the DD of these measurements. There were significant relationships between V'max50, RL and the bronchiolar pathology scores. In conclusion, lung resistance and maximal expiratory flow are related to the severity of peripheral airway pathology, but there is no relationship between the severity of obstruction or the severity of peripheral airway pathology and the density dependence of maximal expiratory flow or lung resistance.     

Inhaled furosemide prevents ultrasonically nebulized water bronchoconstriction in children with both atopic and nonatopic asthma

To determine whether inhaled furosemide can modify the bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) in children with both atopic and nonatopic asthma, a single-blind, randomized, placebo-controlled study was undertaken. The UNDW inhalation challenge was performed in 21 asthmatic children (atopic, 14; nonatopic, 7; mean +/- SEM age, 11.5 +/- 0.5 years), who had a fall in FEV1 of at least 20 percent after distilled water inhalation. On separate days, these subjects underwent UNDW challenge test after inhalation of furosemide (10 mg/body square meters) or placebo (saline solution). Inhaled furosemide exerted a protective effect against bronchoconstriction induced by UNDW in children with both atopic and nonatopic asthma (p < 0.01, p < 0.05, respectively). These results indicate that the protective action of furosemide against UNDW-induced bronchoconstriction may be independent of its direct inhibitory effect on airway mast cell activation.