Long-term effect of inhaled corticosteroids on growth rate in adolescents with asthma.

BACKGROUND: Growth in stature in asthmatic adolescents may be delayed compared to normals as a result of treatment with inhaled corticosteroids (CS) or because of a delay in puberty. However, growth rates in asthmatic children have never been studied when treatment with CS was randomized and when growth was compared with that of matched healthy control subjects. OBJECTIVE: To assess the long-term effect of CS treatment on growth rates in asthmatic adolescents. METHODS: Participants were 40 asthmatic teenagers (mean age 12.8 years) who received randomized treatment with 0.2 mg of albuterol (salbutamol) with either placebo three times a day (BA + PL) or 0.2 mg of budesonide three times a day (BA + CS) for a median period of 22 months in a double-blind controlled study. Growth rates were compared with those of 80 control subjects who were matched for sex, age, height, and duration of follow-up. RESULTS: Growth rates in male patients, but not in female patients, were significantly less than in control subjects (P < .05), a finding consistent with a delay of puberty due to asthma. The mean difference (95% confidence interval) in growth rates between patients treated with BA+PL and their controls was -0.70 (-1.62, 0.22) cm/y; that between patients treated with BA + CS and their controls was -0.44 (-1.25, 0.37) cm/y. The observed mean (SEM) case-control difference between treatment groups was +0.27 (0.58) cm/y in favor of BA + CS. CONCLUSION: Growth retardation observed in adolescents with asthma may be due to a delay in puberty but not to the prescription of 0.6 mg of budesonide daily.

Effects of hyperosmolarity on human isolated central airways.

1. We studied the effect of hyperosmolarity on human isolated airways because a better understanding of the effect of hyperosmolarity on the human airway wall may improve insight into the pathophysiology of hyperosmolarity-induced bronchoconstriction in asthma. 2. In cartilaginous bronchial rings dissected from fresh human lung tissue, hyperosmolar krebs-Henseleit buffer (450 mosM, extra sodium chloride added) evoked a biphasic response: a rapid relaxation phase (peak after 5.0 +/- 0.3 min) followed by a slow contraction phase (peak after 25.4 +/- 0.8 min). 3. With the histamine (H1) receptor antagonist mepyramine, the contraction phase was reduced to 41.2% of the control value (P less than 0.001), with atropine to 50.0% (P less than 0.01), with the local anaesthetic lignocaine to 48.7% (P less than 0.05) and with mepyramine together with atropine to 19.2% (P less than 0.001). 4. With the inhibitor of neutral metalloendopeptidase, phosphoramidon, the contraction phase increased to 128.0% of the control value (P less than 0.05) and after removal of the epithelium to 131.8% (P less than 0.05). 5. Indomethacin, the leukotriene C4/D4 (LTC4/D4) antagonist FPL 55712 or the blocker of nerve conduction, tetrodotoxin, had no effect on the contractile phase. 6. The relaxation phase was not altered by any of these drugs nor by epithelial denudation. The relaxation phase was also unchanged in the presence of alpha-chymotrypsin, which degrades muscle relaxing peptides such as vasoactive intestinal peptide. 7. Hyperosmolar buffer slightly increased the sensitivity and maximal response to methacholine as well as the cholinergic twitch to electric field stimulation. 8. We conclude that hyperosmolarity releases acetylcholine, histamine and neuropeptides in the human airway wall in sufficient quantities to contract airway smooth muscle. This release itself or its effect on airway muscle is modulated by the airway epithelium. The mechanism of the relaxation phase may be an unknown smooth muscle relaxing substance or a direct effect on the airway muscle, related to ion fluxes.

Pharmacokinetics of antimicrobial drugs in cystic fibrosis. Aminoglycoside antibiotics.

Patients with cystic fibrosis (CF) show abnormal aminoglycoside pharmacokinetics. After a conventional dose, the serum concentrations in CF patients are lower than those in nonCF patients. The lower serum concentrations in CF might be explained by increased total body clearance and/or a larger volume of distribution. The therapeutic range of aminoglycosides is narrow due to oto- and nephrotoxicity. The changed pharmacokinetics and the narrow therapeutic range make it difficult to ensure that patients with CF are adequately and safely treated with aminoglycosides. The mode of administration of aminoglycosides influences the antibacterial effect of these agents on Pseudomonas aeruginosa and the development of possible side effects. The therapeutic implications of these facts are discussed.

Pharmacokinetics of tobramycin in patients with cystic fibrosis. Implications for the dosing interval.

The pharmacokinetics of tobramycin were evaluated in 15 patients (8 to 22 years of age) with cystic fibrosis (CF). A dose of 3.0 to 3.3 mg/kg of body weight was given intravenously over 20 minutes, and concentrations in serum were followed up to eight hours after initiation of the infusion. In the calculation of pharmacokinetic parameters, a two-compartment open model was used. The elimination half-life of the drug was highly inversely correlated with age (p less than 0.0004), and body weight (p less than 0.00002). Total body clearance (TBC), and volume of distribution at steady state (VDSS) were directly correlated with age and body weight. However, when TBC and VDSS were corrected for BSA, no correlation could be demonstrated. The mean one-hour and eight-hour serum concentrations of tobramycin were 5.40 and 0.45 microgram X ml-1, respectively. Between patients, considerable differences were found in the time after administration at which the serum concentration decreased below 1 microgram X ml-1. This interpatient variation has clinical implications for tobramycin therapy in CF, in particular for the dosing interval.

Tobramycin in patients with cystic fibrosis. Adjustment in dosing interval for effective treatment.

The efficacy of the dosing regimen of tobramycin was investigated in 28 patients with cystic fibrosis who had an acute exacerbation of chronic pulmonary infection with Pseudomonas aeruginosa. The initial dose of tobramycin was 3.3 mg/kg of body weight three times daily (ie, 10 mg/kg/day). A highly significant relationship was found between the serum concentration of tobramycin before the dose and the change in the forced expiratory volume in one second (FEV1), both measured on the tenth day of treatment (rs = 0.75; p less than 0.001). In nine of the 16 patients who had a six-hour serum concentration of 1 mg/L or less on the tenth day of treatment, the eight-hour dosing interval of tobramycin was shortened to achieve a serum concentration of tobramycin of about 1 mg/L before the dose. In the other seven patients, the dosage of tobramycin was not changed. On the 20th day, seven of the nine patients in whom the dosing interval was shortened exhibited an increase in FEV1 of 20 percent or more. Such an increase was observed only in one of the seven patients in whom the dosing interval was not reduced (p less than 0.05). We conclude that individualizing the dosage of tobramycin in patients with cystic fibrosis results in a better clinical outcome.

Nonneural components in the response of fresh human airways to electric field stimulation.

Fresh human bronchi, obtained at thoracotomy and maintained at 37 degrees C, were studied in vitro to investigate their response to electric field stimulation (EFS). We found complex responses that were not only composed of a rapid initial nerve-mediated cholinergic contraction and a non-adrenergic nerve-mediated relaxation, but, in 80% of preparations, also of a tonic contraction with a sustained time course. This sustained phase was not blocked by the nervous conductance blocker tetrodotoxin (TTX) and was therefore not neurally mediated. Controlled transient cooling to 4 degrees C in the organ bath reduced this sustained phase selectively for several hours. The leukotriene (LT) antagonist FPL 55712, dexamethasone, which inhibits phospholipase A2, and the antiasthmatic drug cromolyn all reduced the sustained phase significantly. In 20% of strips, an additional TTX-resistant contraction was seen directly after the cholinergic phase. This contraction could be inhibited by indomethacin. A similar small peak sometimes appeared after selective blocking of either the cholinergic or the sustained phases. Experiments in which the epithelium was removed from the strips suggested that this indomethacin-sensitive response, but not the sustained phase, was dependent on the presence of epithelium. These results show that EFS of fresh human bronchi stimulated cholinergic and nonadrenergic inhibitory nerves and gave rise to a partly epithelium-dependent synthesis of arachidonic acid metabolites, which caused contractile responses that interfered with the neurally mediated responses.

Effects of changes in osmolarity on isolated human airways.

The effects of hypo- and hyperosmolarity on the function of isolated human airways were studied. Changes in osmolarity induced an increasing bronchoconstriction that was proportional to the magnitude of the change in osmolarity. Hypertonicity-induced airway narrowing resulted when buffer was made hypertonic with sodium chloride or mannitol but not with urea. The airways showed no tachyphylaxis to repetitive exposure to hypo- and hypertonic buffer of 200 and 600 mosM, respectively. The bronchoconstriction was not secondary to stimulation of H1 or leukotriene C4/D4 receptors or the release of prostaglandins in the preparation. The bronchoconstriction in hypotonic buffer was totally dependent on extracellular calcium, whereas in hypertonic buffer the bronchoconstriction seemed partially dependent on intracellular calcium release. Isoprenaline prevented the bronchoconstriction in hyper- or hypotonic buffer of 450 and 250 mosM but not in buffer of 600 and 150 mosM. It is concluded that hypo- and hypertonic buffers lead to bronchoconstriction via different mechanisms, which relate to influx of extracellular calcium in hyposmolar buffer and probably to release of calcium from intracellular stores in hypertonic buffer. In strongly hypertonic buffer, part of the bronchoconstriction may be due to osmotic shrinkage. The relevance of our data for the mechanism of bronchoconstriction after inhalation of hypo- or hypertonic saline depends on whether changes in osmolarity around the airway smooth muscle occur in asthmatics but not in normal subjects, and this has not yet been established.

Wave-speed-determined flow limitation at peak flow in normal and asthmatic subjects.

The purpose of this study was to examine whether peak expiratory flow is determined by the wave-speed flow-limiting mechanism. We examined 17 healthy subjects and 11 subjects with stable asthma, the latter treated with inhaled bronchodilators and corticosteroids. We used an esophageal balloon and a Pitot-static probe positioned at five locations between the right lower lobe and midtrachea to obtain dynamic area-transmural pressure (A-Ptm) curves as described (O. F. Pedersen, B. Thiessen, and S. Lyager. J. Appl. Physiol. 52: 357-369, 1982). From these curves we obtained cross-sectional area (A) and airway compliance (Caw = dA/dPtm) at PEF, calculated flow at wave speed (Vws = A[A/(Caw*rho)0.5], where rho is density) and speed index is (SI = V/Vws). In 13 of 15 healthy and in 4 of 10 asthmatic subjects, who could produce satisfactory curves, SI at PEF was > 0.9 at one or more measured positions. Alveolar pressure continued to increase after PEF was achieved, suggesting flow limitation somewhere in the airway in all of these subjects. We conclude that wave speed is reached in central airways at PEF in most subjects, but it cannot be excluded that wave speed is also reached in more peripheral airways.

Growth of airways and air spaces in teenagers is related to sex but not to symptoms.

To determine growth patterns of the lung and airways in adolescents, we analyzed maximal expiratory flow-volume curves, closing capacity, and residual volume. They were obtained every 6 mo for up to 7 yr in 430 boys and 125 girls (11-19 yr), of whom 143 boys and 36 girls were classified as symptomatic; symptoms were most often minor and limited to childhood. Development of flows vs. volumes was used to investigate growth of the airways relative to lung size. A model of isotropic growth of the airways and air spaces (J. Appl. Physiol. 65: 822-828, 1988) was modified for increasing elastic recoil pressure with growth. Growth of airways relative to volume occurred faster in teenage boys than in teenage girls and was compatible with isotropic growth in 92% of asymptomatic boys and in 44% of asymptomatic girls: dysanaptic growth in teenage girls seems to be a normal phenomenon and not a unique characteristic of symptomatic subjects. Subjects with respiratory symptoms in childhood and/or adolescence have lower flows for a given lung size and airway closure at a greater lung volume when they enter adulthood. However, no difference in patterns of lung growth was observed in association with the presence of respiratory symptoms.

Ecology of Pseudomonas aeruginosa in patients with cystic fibrosis.

The occurrence of various Pseudomonas aeruginosa strains in the sputum of 15 patients with cystic fibrosis (CF) was monitored over periods ranging from 2 to 60 months. Isolates of P. aeruginosa were typed by four different techniques, namely serotyping, active and passive pyocin typing, and phage typing. The maximum number of different serotypes found in the patients was three (one serotype in nine patients; two serotypes in five patients; three serotypes in one patient). Pyocin and phage typing showed no marked differences between strains of the same serotype in individual patients. Exacerbations of chronic respiratory infection were not associated with changes in the sputum flora, the composition of P. aeruginosa strains in which remains constant over long periods in patients with CF.

Leukotriene generation and small airway smooth muscle responsiveness in human lung.

The hypothesis was tested that endogenous leukotriene (LT) production in the lung causes desensitisation of airway smooth muscle to LT. The synthesis of LTB4, C4, D4 and E4 by human lung tissue, obtained at thoracotomies, after stimulation with Ca-ionophore was assessed by HPLC. Functional studies of small airway smooth muscle from the same tissue specimens were carried out using LTC4 and methacholine as the contracting agents. Generation of LTB4, C4, D4 and E4 was 453 +/- 82, 84 +/- 15, 71 +/- 27 and 40 +/- 16 pmol/g fresh tissue respectively (mean +/- S.E.M., n = 10). All airway smooth muscle preparations responded to LTC4 in a concentration dependent way with a -log EC20 of 8.56 +/- 0.13, a -log EC50 of 7.95 +/- 0.08 and a Tmax of 82 +/- 11 mg force/mg tissue weight, corresponding to 79 +/- 4% of the maximal response to methacholine (mean +/- S.E.M.; 27 preparations from 10 patients). No correlations were found between any of the functional parameters (-logEC20, -logEC50, Tmax to LTC4 and methacholine) and the amounts of LT's generated by the lung tissue. Furthermore airway smooth muscle contractility was not significantly reduced after repeated exposure of bronchiolar strips to LTC4 in vitro. These findings suggest that the responsiveness of human peripheral airway smooth muscle to LT is not related to the capacity of the lung tissue to synthetize LT.

Antibacterial therapy in cystic fibrosis.

Bacterial lung infections determine the prognosis for most cystic fibrosis patients. The antibacterial therapy is difficult because of the host-bacterium interaction and altered pharmacokinetics. The new insights in the working mechanisms of antibiotics that may lead to better treatment results have been discussed, and guidelines for treatment of lung infections in cystic fibrosis patients were given.

The perfused human bronchiolar tube characteristics of a new model.

Strips or rings of airway tissue are often used to study contractile responses of human airways in vitro. These preparations have the disadvantage that it is impossible to deliver stimuli selectively to the mucosal or serosal surface. Hence, they allow only for a limited evaluation of the modulatory role of the airway epithelium. We developed an in vitro model that allows independent stimulation from either the serosal or the mucosal side of human peripheral airways. Segments of human peripheral airways were perfused with a Krebs solution at a constant pressure, and responsiveness was measured as a change in flow rate. Pressure/flow relationships indicated laminar flow over a wide pressure range, and a working pressure of 6 cm H2O was chosen because this is a physiological transpulmonary pressure. When stepwise stretching the airway to 180% of its length, we noted an increase in baseline flow and a decrease in flow reduction after methacholine 10(-5) M. At 140% of the length, accurate and reproducible measurements of the sensitivity (EC50) to methacholine were obtained, and airway closure did not occur. A one-way analysis of variance (ANOVA) revealed that the between-patients differences accounted for 91% of the total variability for -log EC50. We conclude that this in vitro model offers interesting possibilities for evaluating the modulatory effects of the human airway epithelium. In addition, the model provides the opportunity to study human small-airway mechanical properties and secretory functions.

Effects of beta 2-receptor agonists on airway responsiveness.

Airway hyper-responsiveness is one of the characteristics of asthma. It may be distinguished by airway hyper-sensitivity and an increase of the maximal response plateau. Short-acting beta 2-agonists have an acute protective effect on airway sensitivity, which is shorter in duration than the bronchodilating effect, without affecting the maximal response plateau. Long-term treatment has no beneficial effect on airway responsiveness. A diminishment of the protection against metacholine- and histamine-induced airway obstruction and a rebound increase of this after cessation of continuous treatment have been reported. Single doses of long-acting beta 2-agonists give a prolonged protection against methacholine- and histamine-induced airway sensitivity of at least 12 hours. A small decrease in the maximal response plateau has been noted. Currently, there is little data on long-term treatment. One study has described the development of tolerance to the protecting effect on methacholine-induced airway sensitivity after 2 months treatment. However, a protection by 1.0 doubling dose remained and the bronchodilating effect was not influenced. So far, no rebound increase in airway sensitivity has been reported after cessation of continuous treatment.

What limits endurance in normal children?

We have compared the results of a standard progressive maximal exercise test to those of an endurance exercise test in 22 healthy school children (13 girls, 9 boys, mean age 14.8 years) in order to examine whether it is possible to extrapolate results from a maximal test to predict their endurance capacity. All children performed a standard progressive maximal exercise test (15 W increments every minute until exhaustion) and an endurance test (individually calculated loads to mimic cycling at 20 km/h against a windforce 5 of Beaufort for 30 minutes) on 2 separate days. In both tests metabolic [oxygen uptake (VO2), CO2 production, blood lactate accumulation], ventilatory [minute ventilation (VE)], and circulatory variables were measured. From the maximal test the threshold of lactate accumulation (LT) was determined. Thirteen children were capable of enduring the 30 minute exercise (Group 1), and 9 could not complete the endurance test (Group 2). These two groups were comparable with respect to age, height, and baseline lung function. Children in Group 2 had a higher mean weight (P < 0.005) than those in Group 1. Eight of the 9 children in Group 2 were girls, whereas Group 1 consisted of 5 girls and 8 boys. There was no significant difference between Group 1 and 2 in the mean values of VO2 max, maximal respiratory exchange ratio (R max), VEmax, LT, oxygen pulse, and other variables obtained during the maximal exercise tests. Lactate accumulation during the endurance test in Group 2 was larger than in Group 1 (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of FEV1 and transcutaneous oxygen tension in the measurement of airway responsiveness to methacholine.

The measurement of airway responsiveness in preschool children is hampered by the fact that most tests of airway caliber are difficult to carry out at a young age. Patient cooperation is only needed to a limited extent when transcutaneous oxygen tension (PtcO2) is used as an indicator of airway obstruction following bronchial provocation. In 51 children, aged 6-14 years with asthma we have measured PtcO2 and forced expiratory volume in 1 second (FEV1) concurrently after bronchial provocation, using increasing doses of methacholine administered with a De Villbiss 646 nebulizer and a French-Rosenthal dosimeter. The shapes of the dose-response curves to PtcO2 and FEV1 show a close similarity. After methacholine challenge, the decrease in PtcO2 correlates highly with the decrease in FEV1. We conclude that in children a 20% decrease in PtcO2 can be used as a sensitive indicator of airway narrowing after methacholine challenge.

Lung function and bronchial responsiveness in children who had infantile bronchiolitis.

A number of studies have shown that children who had infantile bronchiolitis are at increased risk of recurrent episodes of wheezing. A genetic predisposition to atopy is mentioned in some studies and is contested by others. Lung function abnormalities and increased bronchial responsiveness (BR) have been described after infantile bronchiolitis. We investigated children who had had the clinical syndrome of bronchiolitis during infancy and compared them with asthmatic and healthy children of the same age regarding bronchial caliber, smooth muscle tone, and responsiveness to histamine. Lung function was measured by forced oscillometry. We found that most children with current symptoms had either decreased baseline bronchial caliber, increased bronchial smooth muscle tone, or increased BR. These patients are comparable to mild asthmatics. The children without current symptoms are comparable to healthy children in these respects. Recurrent respiratory symptoms after bronchiolitis should be regarded as mild asthma and treated as such.

Measurement of bronchial responsiveness in young children: comparison of transcutaneous oxygen tension and functional residual capacity during induced bronchoconstriction and -dilatation.

Demonstration of an increased bronchial responsiveness in preschool children may support the diagnosis of asthma. Most young children cannot perform routine lung function tests. Transcutaneous PO2 (PtcO2) measurement has been applied successfully in young children, and changes in PtcO2 have been shown to correlate well with changes in forced expiratory volume in 1 second (FEV1) during bronchoprovocation testing with methacholine. PtcO2 is, however, an indirect measure of the effect of inhaled spasmogens. As functional residual capacity (FRC) can also be measured by helium dilution spirometry in preschool children, we compared PtcO2 and FRC during methacholine inhalation challenges and after inhaled terbutaline, in order to determine whether FRC is useful as a more direct measure of induced bronchoconstriction and -dilatation than PtcO2. We studied 41 allergic asthmatic children (mean age, 5.2 years) who underwent a methacholine bronchoprovocation test; 38 children received terbutaline 1 h after the final methacholine dose. The provocative concentration of methacholine that caused a 20% decrease of PtcO2 was determined, and changes in FRC and PtcO2 after each methacholine dose step were compared. Similarly, changes in PtcO2 and FRC before, and 15 and 30 min after, terbutaline were compared. All children had a drop in PtcO2 after increasing doses of methacholine; a 20% change was reached in 38 patients. Mean FRC values increased significantly but variably with increasing doses of methacholine, and changes in PtcO2 and FRC did not correlate. After terbutaline, PtcO2 increased slightly but significantly, and FRC again varied unpredictably. In a separate group of 11 children, the effect of terbutaline was assessed directly after the final methacholine dose, when significant bronchoconstriction was still present.(ABSTRACT TRUNCATED AT 250 WORDS)

[Consensus asthma in children]. / Consensus astma bij kinderen.

The conclusions are presented of a consensus meeting of the Central Advisory Committee for Peer Review concerning detection and treatment of asthma in children. The aims of the management of asthmatic patients are maximal control of symptoms and optimal long-term evolution. Asthma was defined as a disease characterized by reversible bronchial obstruction and bronchial hyperreactivity (i.e. increased sensitivity of the respiratory tract to aerogenic stimuli with the symptoms of dyspnoea, cough and/or wheezing owing to increased sensitivity of the respiratory tract to allergenic and non-allergenic stimuli with as the pathological substrate a chronic inflammatory reaction. The working hypothesis was that early recognition of asthma and adequate treatment can prevent or reduce respiratory problems at later ages. For the diagnosis, the follow-up of the disease and monitoring of the treatment, a few simple lung function tests suffice: determination of the expiratory peak flow and of the forced expiratory one-second volume. If the symptoms recur or are of a permanent nature, allergological examination is indicated. Basic elements of intervention are preventive measures, including cleaning up the living environment, drug treatment, attention for the experience of the disease and information. A specific recommendation is made for drug treatment, in the form of a step-by-step approach based on a division of the severity of the disease into four categories.

[Inhalation therapy in children with asthma]. / Inhalatietherapie bij kinderen met astma.

Inhalation therapy for childhood asthma is safe and effective. It has the advantages of a low dose, a rapid effect and a wide therapeutic range. For the majority of children the available medications make it possible now to treat asthma optimally, provided that special care is taken to select the appropriate inhalation devices, and repeated practical instructions are given.