Paradoxical Bronchoconstriction Research Articles

Paradoxical bronchoconstriction caused by β2-adrenoceptor agonists.

Salbutamol and terbutaline are short-acting β2 adrenergic agonists that produce bronchial smooth muscle relaxation and are widely used in obstructive pulmonary diseases. Nevertheless, their use has been the cause of a paradoxical bronchoconstriction, which is a rare and potentially serious adverse reaction. The aim of this study is to report a case of paradoxical bronchoconstriction caused by β2 adrenergic agonists. This case is about a 50-year-old asthmatic patient who describes a history of repeated acute asthma attacks after salbutamol inhalation or terbutaline nebulization. A double-blind crossover study was performed over 3 days, in order to compare the effects of each bronchodilator. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and maximal expiratory flow 25-75 (MEF25-75) were measured. On the first day, a bronchoconstriction caused by deep and repeated inhalations was eliminated. On the second day, an airway obstruction was confirmed by a decrease in FEV1 at 40% from baseline values after nebulization of a standard dose of terbutaline. On the third day, a spirometry was performed before and after nebulization of a standard dose of ipratropium bromide, and there were no significant changes in the spirometric parameters. Finally the patient was discharged with a written warning mentioning the danger of salbutamol and terbutaline use. Salbutamol and terbutaline are generally well-tolerated β2 adrenergic agonists. Nevertheless, in rare cases, these substances can cause a paradoxical bronchoconstriction. Doctors must therefore remain vigilant about its side effect and possibly investigate each case.

Prevalence of paradoxical bronchoconstriction after inhaled albuterol.

Paradoxical bronchoconstriction with resulting decreased airflow occurs in some patients after administration of bronchodilators. This study assessed the frequency of paradoxical bronchoconstriction in a real-life clinical setting at a large academic medical center. We analyzed data from 4593 patients who underwent pre- and post-bronchodilator spirometry testing. We assessed the forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) before and after the administration of an inhaled short-acting β2-agonist. Patients were categorized into 3 groups: bronchodilation, no significant change and paradoxical bronchoconstriction. When assessing response to bronchodilators, 201 (4.4%) patients demonstrated significant bronchoconstriction, whereas 849 (18.5%) showed bronchodilation. The majority (3543 or 77.1%) had no significant change. There were no significant relationships noted between paradoxical bronchoconstriction and sex, race/ethnicity or body mass index. A significant subset of patients experience paradoxical bronchoconstriction after albuterol administration. Further research to better understand the clinical implications of paradoxical acute bronchoconstriction is needed.

Transient paradoxical bronchospasm associated with inhalation of the LAMA AZD9164: analysis of two Phase I, randomised, double-blind, placebo-controlled studies

BackgroundAZD9164 has demonstrated potential as an inhaled, long-acting, muscarinic antagonist (LAMA) bronchodilator. However, in patients with COPD, but not in healthy subjects, a transient initial drop in FEV1 was observed following inhalation of nebulised doses of AZD9164 in citrate buffer.Two additional studies were conducted to further assess the safety and tolerability of multiple ascending doses of AZD9164 in 27 white and 18 Japanese healthy subjects and in 4 patients with COPD. In these studies, AZD9164 was inhaled via Turbuhaler™.MethodsThese were Phase I, randomised, double-blind, placebo-controlled, multiple ascending dose (MAD) studies conducted in Sweden and UK. Healthy subjects (mean age 25.9 yrs) and patients with COPD (mean age 66 yrs, mean post-bronchodilator FEV1 60.1% predicted normal value) were randomised 2:1 to active treatment (400, 1000 or 2800 μg delivered doses of AZD9164) or placebo.ResultsNo safety or tolerability concerns were identified in the healthy subjects at doses up to and including 2800 μg and both studies confirmed the bronchodilator effect of AZD9164. However, the first 3 patients in the COPD cohort who received AZD9164 (1000 μg) experienced a transient fall in FEV1 5 to 15 minutes after inhalation of AZD9164 while the patient receiving placebo did not. The study safety review process then resulted in cessation of further activities on AZD9164. Retrospective analysis showed that two healthy subjects had also had transient falls in FEV1 shortly after inhalation of AZD9164 400 and 2800 μg respectively, although neither reported any related respiratory symptoms or other AEs.ConclusionsThese results show that transient paradoxical bronchoconstriction can occur in some healthy subjects, in addition to patients with COPD, following inhalation of AZD9164 and that the citrate buffer used in the nebulised formulation cannot have been the only cause of the drop in FEV1 in previous studies. As preclinical data do not provide an explanation, the reasons for this brief post-dose drop in FEV1 remain unclear. However, these results highlight the importance of monitoring lung function immediately post-dose when investigating novel inhaled treatments, even when a rapid onset of effect is not expected.Trial registrationClinicaltrials.gov NCT01016951 and NCT01096563.

Paradoxical bronchoconstriction occurs in 5% of COPD patients treated with beta-2-agonists

Paradoxical bronchoconstriction occurs in 5% of COPD patients treated with beta-2-agonists

Lack of paradoxical bronchoconstriction after administration of tiotropium via Respimat® Soft Mist™ Inhaler in COPD

Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat® Soft Mist™ Inhaler (SMI). We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks’ treatment with once-daily tiotropium (5 or 10 μg) or placebo inhaled via Respimat® SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3%) reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1%) reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in forced expiratory volume in one second (FEV1) of ≥15% were recorded on all test days, with no change in incidence over time, and affected 8.2% of those in the tiotropium groups and 14.5% of those on placebo. In COPD patients receiving long-term treatment with tiotropium 5 or 10 μg via Respimat® SMI, no bronchospasm was recorded, and the number of events possibly indicative of paradoxical bronchoconstriction was very low.

Anaphylaxis with use of eye‐drops containing benzalkonium chloride preservative

Benzalkonium chloride (BAC) is a bactericidal preservative found commonly in cosmetics, disinfectants, nebuliser solutions, spermicides and eye-drops. BAC is reported as the most commonly used quaternary ammonium compound. Numerous cases of contact sensitivity have been reported, including alarming cases of paradoxical bronchoconstriction and anaphylaxis (an acute multi-system and very severe Type I hypersensitivity reaction) with BAC in nebuliser solutions. In 1997, Chiambaretta, Pouliquen and Rigal reported two cases of contact sensitivity and a third case of immediate hypersensitivity involving chemosis and angioneurotic oedema. Chemosis and angioneurotic oedema are associated with anaphylaxis but differ from our case because the patient had established anaphylaxis to another member of Figure 1. Skin testing to epinastine ophthalmic drops. Prick testing done on the left of the arm, while intradermal testing was done on the right. Results show wheal/flare in mm for each component and control: Histamine (H)prick 13/36, intradermal not performed; Saline and BAC (SB)prick 3/14, intradermal 15/>45; Epinastine ophthalmic (contains BAC) (EB)prick 0/0, intradermal not performed; Control (C)prick 0/0, intradermal 7/0. C L I N I C A L A N D E X P E R I M E N T A L

Potential Adverse Effects of Bronchodilators in the Treatment of Airways Obstruction in Older People

Asthma and chronic obstructive pulmonary disease (COPD) are common disorders that are associated with increasing morbidity and mortality in older people. Bronchodilators are used widely in patients with these conditions, but even when used in inhaled form can have systemic as well as local effects. Older people experience more adverse drug effects because of pharmacodynamic and pharmacokinetic changes and particularly drug-drug and drug-disease interactions. Cardiovascular disease is common in older people and beta-adrenoceptor agonists (beta-agonists) have inotropic and chronotropic effects that can increase arrhythmias and cardiomyopathy. They can also worsen or induce myocardial ischaemia and cause electrolyte disturbances that contribute to arrhythmias. Tremor is a well known distressing adverse effect of beta-agonist administration. Long-term beta-agonist use can be associated with tolerance, poor disease control, sudden life-threatening exacerbations and asthma-related deaths. Functional beta2-adrenoceptors are present in osteoblasts, and chronic use of beta-agonists has been implicated in osteoporosis. Inhaled anticholinergics are usually well tolerated but may cause dry mouth, which can be troublesome in older people. Pupillary dilatation, blurred vision and acute glaucoma can occur from escape of droplets from loosely fitting nebulizer masks. Although ECG changes have not been seen in randomized controlled trials of long-acting inhaled anticholinergics, supraventricular tachycardias have been observed in a 5-year randomized controlled trial of ipratropium bromide. Paradoxical bronchoconstriction can occur with inhaled anticholinergics as well as with beta-agonists, but tolerance has not been reported with anticholinergics. Anticholinergic drugs also cause central effects, most notably impairment of cognitive function, and these effects have been noted with inhaled agents. Use of theophylline is limited by its adverse effects, which range from commonly occurring gastrointestinal symptoms to palpitations, arrhythmias and reports of myocardial infarction. Seizures have been reported, but are rare. Theophylline is metabolized primarily by the liver, and commonly interacts with other medications. Its concentration in plasma should be monitored closely, especially in older people. Although many clinical trials have been conducted on bronchodilators in obstructive airways disease, the results of these clinical trials need to be interpreted with caution as older people are often under-represented and subjects with co-morbidities actively excluded from these trials.

Acute Local Tolerability of Acidic Aqueous Vehicles Delivered via Respimat® Soft Mist™ Inhaler in Hyperreactive Asthma Patients

Background:Acidic inhalers can be associated with increased adverse reactions. Objectives: This study aimed to determine the acute local tolerability of acidic aqueous placebo formulations delivered via Respimat® Soft Mist™ Inhaler (SMI) and placebo chlorofluorocarbon metered dose inhaler (CFC-MDI).Methods: A single-dose (four inhalations), randomized, double-blind within Respimat SMI device, four-way crossover study in asthma patients with documented bronchial hyperresponsiveness was used. Patients received acidic placebo solutions [pH 2.7, 3.4 or 7.0 (neutral)], delivered via Respimat SMI or placebo CFC-MDI. The primary endpoint was the largest decrease in forced expiratory volume in 1 s (FEV₁) from baseline to 0–30 min after dosing. Secondary endpoints included spirometry, paradoxical bronchoconstriction (defined as a fall in FEV₁ ≧15% below baseline within 30 min of dosing), cough episodes and adverse events.Results: Thirty-two patients were included in the per-protocol population (mean age 27 years, 62.5% males). The mean percentage decrease in FEV₁ was comparable between treatment groups: –1.6% (Respimat SMI pH 2.7), –1.8% (Respimat SMI pH 7.0), –1.9% (CFC-MDI), and –2.3% (Respimat SMI pH 3.4); no patient experienced paradoxical bronchoconstriction. The mean number of cough episodes was significantly lower in the Respimat SMI pH 2.7 group versus CFC-MDI (p = 0.0165). No patient used rescue medication. Only 3 patients experienced at least one adverse event. Conclusions: The Respimat SMI pH 2.7 placebo solution does not induce adverse events in these patients. Compared with the CFC-MDI placebo suspension, Respimat SMI is a well-tolerated inhaled medication delivery system that can accommodate medication formulations with a wide range of pH solutions.

Inhaled Ethanolic and Aqueous Solutions via Respimat Soft Mist Inhaler Are Well-Tolerated in Asthma Patients

Background: Respimat^® Soft Mist^™ Inhaler (SMI) is a new-generation inhaler offering improved lung deposition compared with other devices. Bronchodilators administered via Respimat SMI are preserved and stabilized with benzalkonium chloride (BAC) and ethylene diamine tetra-acetic acid (EDTA); both have been reported to cause paradoxical bronchoconstriction if a threshold dose is exceeded. Objective: The aim of this randomized, double-blind, three-period, crossover study was to establish that the safety of inhaled ethanolic and aqueous placebo solutions (containing BAC and EDTA) is equivalent to that of inhaled normal saline solution when administered to asthma patients via Respimat SMI. Methods: Thirty-seven asthma patients with airway hyper-reactivity were randomized to receive four actuations of each of the following three treatments via Respimat SMI, one on each of 3 study days: ethanolic placebo (12 µl 96% ethanol + 0.13 µg EDTA/actuation), aqueous placebo (12 µl water + 5.5 µg EDTA + 1.1 µg BAC/actuation), and normal saline (12 µl 0.9% sodium chloride/actuation). Pulmonary function tests were performed at baseline and at 5, 15, 30, 60, 120 and 180 min after inhalation; the primary endpoint was the lowest FEV₁ recorded between 0 and 30 min. Results: The mean lowest FEV₁ recorded between 0 and 30 min after inhalation minus the study day baseline was –0.090 litres for ethanolic placebo, –0.121 litres for aqueous placebo and –0.094 litres for normal saline (SEM 0.034 litres for all). The mean treatment differences were: ethanolic placebo versus normal saline 0.004 litres (90% CI –0.075–0.083 litres, p = 0.002), and aqueous placebo versus normal saline –0.028 litres (90% CI –0.107–0.052 litres, p = 0.006). Since both 90% CIs fell within the pre-determined equivalence region of ±0.15 litres, both treatments were considered equivalent to normal saline. Conclusion: Ethanolic and aqueous solutions administered via Respimat SMI are safe with regard to paradoxical bronchoconstriction in asthma patients with airway hyper-reactivity.

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Paradoxical Bronchoconstriction with Albuterol Administered by Metered-Dose Inhaler and Nebulizer Solution

To report a case of a patient who experienced bronchoconstriction following both a single dose of albuterol via metered-dose inhaler and a subsequent rechallenge with nebulized albuterol and review previously published case reports of albuterol-induced paradoxical bronchoconstriction. A 92-year-old white man with a history of chronic obstructive pulmonary disease was prescribed an albuterol inhaler for treatment of cold symptoms. Within 30 minutes of his first inhalation, he became short of breath and had difficulty speaking. During emergency department examination for the initial event, the bronchospasm improved with administration of oxygen 15 L/min via a non-rebreather mask. Two hours later, the patient received albuterol via nebulizer and experienced stridor, shortness of breath, and severe bronchospasm. He was admitted, treated with methylprednisolone, and discharged the following day. Paradoxical bronchoconstriction is a rare complication of bronchodilator therapy. Although theories have been proposed about components of albuterol solutions and preservatives as causative agents, the true mechanism of the phenomenon remains unknown. Several previous case reports described bronchospasm with albuterol given via tablet, inhaler, and nebulizer. In 2 of these cases, symptoms recurred upon rechallenge; however, none of these cases demonstrates rechallenge using albuterol as both the index and challenge agent. In our patient, paradoxical bronchoconstriction was considered to be probable according to the Naranjo probability scale. beta(2)-Agonists are generally well-tolerated medications. However, clinicians should remain vigilant in their monitoring of adverse effects so they will be able to provide immediate care and minimize the chance of an unfavorable outcome.

Low incidence of paradoxical bronchoconstriction in asthma and COPD patients during chronic use of Respimat ® soft mist™ inhaler

Respimat Soft Mist Inhaler (SMI) is a new-generation inhaler that offers improved lung deposition compared with chlorofluorocarbon metered dose inhalers (CFC-MDIs). Bronchodilators administered via Respimat SMI are preserved and stabilised with low concentrations of benzalkonium chloride and ethylene diamine tetra-acetic acid, both of which have been reported to cause dose-related paradoxical bronchoconstriction. The aim of this analysis was to compare the incidence of paradoxical bronchoconstriction after chronic use of bronchodilators via Respimat SMI and CFC-MDI. Data from three clinical trials, in which patients with asthma or chronic obstructive pulmonary disease (COPD) received ipratropium bromide alone or in combination with fenoterol hydrobromide, or placebo via Respimat SMI or CFC-MDI for 12 weeks, were included in the analysis. In order to evaluate the risk of paradoxical bronchoconstriction, we identified four respiratory events that might have occurred within 30 min of inhalation on four test days; these were: 'bronchospasm', 'other respiratory adverse events', 'rescue medication use' and 'asymptomatic drop in FEV(1) 15% from baseline'. In total, 631 asthma and 1538 COPD patients participated in the three studies. No occurrences of bronchospasm were reported with Respimat SMI on any test day. Overall, the incidence of respiratory events possibly indicative of paradoxical bronchoconstriction was low and similar for both devices. There was no increase in the incidence of events during 12 weeks' treatment. Delivery of bronchodilators by Respimat SMI is safe with regard to paradoxical bronchoconstriction during chronic use in patients with asthma or COPD.

Call for worldwide withdrawal of benzalkonium chloride from nebulizer solutions

Call for worldwide withdrawal of benzalkonium chloride from nebulizer solutions

Laryngospasm and Paradoxical Bronchoconstriction After Repeated Doses of β 2- Agonists Containing Edetate Disodium

A 22-year-old woman with mild intermittent asthma, who had no previous history of an adverse reaction to an albuterol metered-dose inhaler, developed paradoxical bronchoconstriction after inhalation of the fourth dose of an albuterol nebulizer solution. She experienced the same symptoms and laryngospasm with repeated inhalations of albuterol and metaproterenol nebulizer solutions that contained edetate disodium. Each episode responded to racemic and subcutaneously administered epinephrine. To our knowledge, this is the first report of paradoxical bronchoconstriction and laryngospasm due to repeated doses of beta 2-agonist solutions with edetate disodium.

Preliminary Data from Phase II Studies with Respimat, a Propellant-Free Soft Mist Inhaler

Inhalation is regarded as the most effective treatment for respiratory disorders. Boehringer Ingelheim (Ingelheim am Rhein, Germany) has developed Respimat, a soft mist inhaler that delivers a metered dose of drug solution as an aerosol with a high "fine particle fraction" approximately five times slower than aerosols from chlorofluorocarbon-driven metered dose inhalers (CFC-MDIs). These characteristics have led to improved drug deposition in the lungs. In scintigraphic studies using fenoterol and flunisolide, mean drug delivery to the lungs was 31.1 to 44.6% of the dose delivered using Respimat compared with less than 20% using a CFC-MDI. Clinical studies in asthmatic patients using inhaled fenoterol alone (Berotec; Boehringer Ingelheim) or combined with ipratropium bromide (Berodual; Boehringer Ingelheim) confirmed the hypothesis that lower doses administered using Respimat should produce bronchodilator effects similar to those obtained with standard doses administered via a CFC-MDI. For Berotec, 12.5 or 25 micrograms administered by Respimat was therapeutically equivalent to either 100 or 200 micrograms administered by a CFC-MDI. For Berodual, bronchodilatory effects of 25/10- or 50/20-microgram doses using Respimat tended to be close or slightly superior to those of 100/40 micrograms using a CFC-MDI. Safety profiles did not differ between Respimat and CFC-MDI administration in either trial. Patients with airway hyperreactivity who inhaled placebo or drug solutions containing different preservatives and stabilizers had low incidences of paradoxical bronchoconstriction or asymptomatic decreases in lung function, which were similar with Respimat and a CFC-MDI. Furthermore, facial deposition data suggest a low risk of untoward effects even in potential misuse situations. Thus, Respimat promises to be a valuable alternative to conventional CFC-MDIs, with the additional benefit of improved drug targeting to the lungs.

Lung Deposition of Fenoterol and Flunisolide Delivered Using a Novel Device for Inhaled Medicines: Comparison of RESPIMAT With Conventional Metered-Dose Inhalers With and Without Spacer Devices

To compare lung deposition of fenoterol or flunisolide administered from a novel, multidose inhalation device delivering liquid droplets (RESPIMAT; Boehringer Ingelheim Ltd; Bracknell, UK) or from conventional metered-dose inhalers (MDIs) with and without spacers. Two randomized, three-way crossover studies. Clinical research laboratory. Healthy, nonsmoking volunteers. In one study, radiolabeled aerosols of fenoterol from the RESPIMAT device and from a conventional MDI with or without an Aerochamber spacer (Trudell Medical; London, Ontario Canada). In the second study, radiolabeled aerosols of flunisolide from a RESPIMAT device, from a RESPIMAT device modified by inclusion of a baffle/impactor in the mouthpiece, and from a conventional MDI with an Inhacort spacer (Boehringer Ingelheim; Ingelheim, Germany). Assessment of the deposition of fenoterol or flunisolide in the lung and oropharynx using gamma scintigraphy. Safety was assessed based on reported adverse effects and spirometry (FEV1, FVC, and peak expiratory flow rate) to detect any paradoxical bronchoconstriction. The RESPIMAT device delivered significantly more fenoterol to the lungs than either an MDI alone or an MDI with Aerochamber (39.2% vs 11.0% and 9.9% of metered dose, respectively; p<0.01). Oropharyngeal deposition of fenoterol from the new device was lower than that from the MDI (37.1% vs 71.7%, respectively; p<0.01). The RESPIMAT device deposited significantly more flunisolide in the lungs compared with MDI plus spacer (44.6% vs 26.4%, respectively; p<0.01), while resulting in similar oropharyngeal deposition (26.2% vs 31.2%, respectively). Introduction of a baffle into the RESPIMAT system reduced lung deposition of flunisolide to 29.5%, and oropharyngeal deposition to 7.8% (p<0.01). The RESPIMAT device may prove to be an effective alternative to MDIs for the administration of inhaled bronchodilators and corticosteroids. The high lung deposition and low oropharyngeal deposition may lead to improved efficacy and tolerability of inhaled medications, especially corticosteroids.

In vitro assessment of drug delivery through an endotracheal tube using a dry powder inhaler delivery system.

Jet nubulisers and metered dose inhalers are widely used to deliver aerosolised drugs to the lungs of intubated patients in adult intensive care units. Drug delivery using these systems has been shown to be inefficient and both forms of delivery have the potential to induce paradoxical bronchoconstriction in patients with reactive airways disease. Experiments were carried out to determine whether it was possible to deliver drug from a dry powder delivery system through an endotracheal tube. A 200 micrograms budesonide Turbohaler was enclosed in a chamber which allowed it to be inserted into a ventilator circuit. Experiments were performed with a multistage liquid impinger in which drug was drawn through the Turbohaler and endotracheal tube at 60 l/min providing an index of the maximum drug delivery achievable via this route. A second series of experiments was performed in which the Turbohaler was placed in a ventilator circuit using a Servo 900C volume cycled ventilator. Drug delivered from the Turbohaler during the inspiratory phase was collected on a filter placed between the end of a 9 mm endotracheal tube and a model lung. A tidal volume of 500 ml and inspiratory time of 0.5 seconds was used. Budesonide was assayed using an ultraviolet spectrophotometric assay. Thirty percent of the nominal dose passed through the endotracheal tube and was collected in the multistage liquid impinger. Mean drug delivery to the filter in the ventilator circuit was 20%. This in vitro study indicates that drugs from dry powder inhalers (in this case the Turbohaler) can be satisfactorily delivered through endotracheal tubes and that clinical evaluation of this technique is now indicated.

PARADOXICAL BRONCHOCONSTRICTION WITH NEBULIZED ALBUTEROL BUT NOT WITH TERBUTALINE

Paradoxical bronchoconstriction to β-agonists has been reported previously, and has been attributed to hypotonicity or acidity of solution or to preservatives such as benzalkonium chloride. As both solutions studied were isotonic, of like acidity, and preservative- and additive-free, these factors were not likely to be contributing to the results observed. Paradoxical bronchocontriction to β-agonists is not necessarily a class effect, but can attributed to treatment with one specific agent while not observed with other agents in the class.

A combined respiratory and cutaneous hypersensitivity syndrome induced by work exposure to quaternary amines

The quaternary amine, benzalkonium chloride, has been associated with cutaneous and mucosal delayed hypersensitivity reactions and with paradoxical bronchoconstriction after use of aerosolized asthma medications. Until now, quaternary amines have not been reported to cause occupational asthma. We describe a case of occupational asthma caused by prolonged exposure to a cleaning solution containing benzalkonium chloride in the workplace. Single-blind, placebo-controlled, open-room challenges were performed to determine the specific agent responsible for the patient's symptoms. Pulmonary function and epicutaneous challenge tests were also performed. The patient had positive responses to challenges with a liquid toilet bowl cleaner containing benzalkonium chloride but was unreactive to other agents tested. Removal from the workplace resulted in complete resolution of symptoms. The exact mechanisms responsible for occupational asthma induced by quaternary amines remain unknown; however, this case emphasizes the importance of recognizing reactive chemicals as possible causes. (J ALLERGYCLINIMMUNOL1994;94:257-9.)

Paradoxical bronchoconstriction in wheezing infants after nebulised ipratropium bromide: Authors' reply

Paradoxical bronchoconstriction in wheezing infants after nebulised ipratropium bromide: Authors' reply