Antenatal exposure to fenoterol is not associated with the development of retinopathy of prematurity in infants born before 32 weeks of gestation.

PURPOSE: Despite safety concerns, ß2-sympathomimetics are still widely used as tocolytic agents. ß-Blockers in turn are used to treat vasculo-proliferative diseases of the newborn such as retinopathy of prematurity (ROP), which may lead to visual impairment and blindness. The scope of this study was to investigate whether antenatal exposure to the ß2-sympathomimetic fenoterol contributes to the development of ROP. METHODS: For this single-center retrospective case-control study of prospectively collected clinical data, all infants born before 32 weeks of gestation between 2001 and 2012 were included. The association of prenatal exposure to fenoterol and the development of ROP were analyzed by multivariate logistic regression. RESULTS: n = 1134 infants < 32 weeks of gestation were screened for eligibility, out of which n = 722 met the inclusion criteria. Exposure to fenoterol (n = 505) was not associated with a higher rate of ROP (OR 0.721, 95% CI 0.463-1.122). Further, duration of exposure (days) did not alter the incidence of ROP (OR 1.001, 95% CI 0.986-1.016). Frequency distribution of different ROP stages and the need for therapeutic intervention was also not affected by prenatal exposure to fenoterol. Risk factors for the development of ROP like low birth weight, low gestational age, prolonged respiratory support and multiple gestation were confirmed in our large study cohort. CONCLUSION: ß2-Sympathomimetic tocolysis does not increase the rate of ROP in premature infants born < 32 weeks of gestation. Our results render fenoterol a safe tocolytic agent regarding neonatal ROP development.

The T/QRS ratio values in pregnancies complicated by threatened preterm labour treated with intravenous infusions of fenoterol.

AIMS: To evaluate values of foetal T/QRS ratios in pregnancies complicated by threatened preterm labour treated with intravenous infusions of fenoterol using non-invasive methods with transabdominal electrodes. MATERIALS AND METHODS: The study group consisted of 451 Caucasian women (63 preterm pregnancies and 327 healthy controls) whose pregnancies ranged from 28 to 37 gestational weeks. Foetal electrocardiograms were recorded and T/QRS ratios were calculated by KOMPOREL software (ITAM, Zabrze, Poland). The first recording was performed 30 min after the start of fenoterol infusion and the second 2 days after finishing tocolysis. T/QRS ratio variables were calculated. One-way analysis of variance was carried out. RESULTS: Significantly higher mean values of the T/QRS ratio were observed in pregnancies during tocolytic treatment in comparison to controls and pregnancies after tocolysis (P=0.0158 and P=0.0071, respectively). The T/QRS ratio values fall again shortly after finishing intravenous tocolysis. CONCLUSIONS: The T/QRS ratio is one of the methods used for non-invasive foetal distress assessment that can be used in antepartum foetal monitoring in complicated pregnancies. Raised values of the T/QRS ratio in the foetus during tocolysis with fenoterol and next its fall to values observed in physiological pregnancies may indicate transient worsening of fetal well-being, however, additional research is required.

[Tocolysis in preterm labour--current recommendations]. / Tokoliza w porodzie przedwczesnym--aktualne wytyczne.

Common use of tocolytic drugs in preterm labor has not been shown to reduce the rate of neonatal mortality and morbidity Currently tocolytics should be administered in the course of a 48-h administration of antepartum glucocorticoids and/or transfer of the gravida to a center with neonatal intensive care unit. Only oxytocin receptor antagonist--atosiban and short-acting beta-agonists--fenoterol are licensed to reduce preterm uterine activity Owing to its safety and efficacy atosiban should be the first-choice tocolytic, especially in women with other diseases or multiple gestations.

[Right ventricular hypertrophic cardiomyopathy in the fetus --may it be caused by chronic oral tocolysis with fenoterol?]. / Kardiomiopatia przerostowa prawej komory u plodu--czy przewlekla doustna tokoliza fenoterolem moze byc jej przyczyna?

The use of fenoterol in the treatment of preterm labor is associated with the risk of many complications in the mother and the fetus. We present a case of a multipara treated with oral fenoterol due to threatening preterm labor 14 weeks. At 35 weeks of gestation the fetus was diagnosed with hypertrophic cardiomyopathy with severe impairment of the right ventricle. The only factor that might have caused such a state of the fetal circulatory system was fenoterol, used from 21 weeks of gestation. After the withdrawal of the fenoterol the fetal right ventricular function improved gradually. However fetal cardiac hypertrophy persisted until the birth at 39 weeks of gestation. Concentric hypertrophy of the right ventricular wall and interventricular septum were confirmed in the newborn.

beta2-Agonist modulates epithelial gene expression involved in the T- and B-cell chemotaxis and induces airway sensitization in human isolated bronchi.

Regular use of beta(2)-adrenoceptor agonists may enhance non-specific airway responsiveness and inflammation. In earlier experimental studies, we showed that prolonged in vitro fenoterol exposure induced airway sensitization via perturbed epithelial regulation of bronchoconstriction. The aim of the present work was to examine the involvement of inflammatory mediator genes and proinflammatory cells and to investigate the role of the bronchial epithelium in these untoward effects. Bronchial tissues were surgically removed from 17 ex-smokers. Bronchial rings and primary cultures of bronchial epithelial cells were incubated with 0.1microM fenoterol for 15h. Levels of mRNA-expression were analyzed using a real-time quantitative reverse transcription-polymerase chain reaction array. Bronchial rings were contracted with endothelin-1 and immune cell infiltration was assessed by immunohistochemistry. Compared to paired controls, fenoterol up-regulated the mRNAs of cytokines/proteins implicated in the recruitment of T and B cells or the activation and proliferation of bronchial epithelial cells (CCL20/MIP-3alpha, FOXA2, PPAR-gamma) in isolated bronchi and in cultured epithelial cells. Fenoterol exposure significantly enhanced CD8(+)-T and differentiated CD138(+)-B-cells infiltration into the bronchi, especially the subepithelial area. Increase in CD8 or CD138 labeling-intensity strongly correlated with rise in maximal contraction to endothelin-1 induced by fenoterol exposure. In summary, our results show that fenoterol modulates the T and B cells chemotaxis possibly via the epithelial chemokine secretion in isolated bronchi from ex-smokers. They also suggest that the infiltration of resident T and B cells into the subepithelial area is associated with an increase in airway responsiveness due to fenoterol exposure.

Neonatal exposure to fenoterol and betamethasone: effects on the behavioral development in the rat.

We investigated longitudinally the behavioral development in the rat following exposure to beta-agonists and glucocorticoids (GC). Neonatal rats received either 1 mg/kg fenoterol (FEN), 0.3 mg/kg betamethasone (BET), or saline (SAL). Weanling and young adult rats were tested in the open field, the elevated-plus maze, and the water maze. FEN-treated as well as BET-treated animals displayed increased anxiety-like behavior. Furthermore, BET-treated adult animals showed a reduced locomotor activity. An enhanced 24-h memory in the water maze in both treatment groups may be facilitated by emotional arousal due to the increased anxiety levels. The possible neurobiological underpinnings are discussed in detail.

[Effectiveness and safety of atosiban vs. pulsatile administration of fenoterol in the treatment of preterm labour]. / Wirksamkeit und Sicherheit von Atosiban vs. pulsatiler Applikation von Fenoterol bei der Behandlung vorzeitiger Wehen.

BACKGROUND: The aim of this study was to compare the efficacy and side effects of atosiban with those of fenoterol (pulsatile administration) for acute tocolysis. METHODS: A prospective, open-label, randomised controlled trial was performed. Patients in preterm labour at 24+0 to 33+6 weeks of gestation were randomised to receive atosiban (A) or fenoterol (F) pulsatile administration. Primary outcome was the arrest of preterm labour. RESULTS: The proportion of woman remaining undelivered at 48 hours (86.3% atosiban group and 79.6% fenoterol group) and at 7 days (78.4% vs. 66.7%) was comparable. The incidence of maternal cardiovascular side effects was lower in the atosiban group (4% vs. 78%, p=0.0). Tocolysis was terminated as a result of maternal adverse effects in the fenoterol group (9%). Fetal tachycardia was lower in the atosiban group (2% vs. 22%). The mean duration of tocolytic administration was lower in the atosiban group (19 h vs. 24.5 h, p<0.05). DISCUSSION: The adverse effects in the pulsatile administration of fenoterol for short duration were only dependent on the initial dosage for the arrest of preterm labour. Neonatal outcome were similar between the treatment groups and were rather related to the gestational age not to the tocolytic agent. CONCLUSIONS: Atosiban was comparable in clinical effectiveness and was associated with fewer maternal and fetal adverse effects, so that fenoterol cannot be recommended. Completion of tocolytic therapy 12 hours after arrest of preterm labour is effective and associated with a short mean duration.

Diagnosis, treatment, observation and outcome of fetal supraventricular tachycardia in a twin pregnancy.

BACKGROUND: Magnetocardiography and M-mode fetal echocardiography are non-invasive techniques capable of identifying fetal arrhythmias. The STAN-fetal scalp electrode system can record the fetal echocardiogram in labor. CASE: A patient was admitted to hospital with preterm contractions and cervical insufficiency at 28 weeks of gestation. After treatment with a beta-sympathomimetic drug (Partusisten) one fetus developed supraventricular tachycardia. After terminating the Partusisten medication, there was no effect on the fetal arrhythmia and flecainide therapy was initiated. Maintenance dosages controlled the condition thereafter. Cardiac time intervals of a fetus in labor can be presented, which did not change significantly throughout the first stage of labor. CONCLUSION: Flecainide is an effective therapy for supraventricular tachycardias in a twin pregnancy. Analyzing the cardiac time intervals during pregnancy can improve perinatal outcome.

Myoclonus induced by salbutamol: A case report

Salbutamol is a ß2 adrenergic agonist widely prescribed in patients with obstructive and restrictive lung diseases. The main side effects associated with its use are tachycardia and tremor. Myoclonus is an involuntary, irregular, abrupt, brief and sudden muscular contraction, which can be generalized, focal or multifocal. We report the case of a 61-year-old patient presenting with myoclonus difficult to treat who showed improvement only after the definitive discontinuation of the ß2 adrenergic agonist. We describe the clinical findings, the interventions, and the outcomes related to the onset of myoclonus secondary to the use of salbutamol, as well as the possible genesis and importance of this adverse effect. We used the CARE guidelines to delineate the clinical case. Although myoclonus secondary to the use of different drugs has been described in the literature, as far as we know this is the fourth report of salbutamol-induced myoclonus to date.

Increased Systemic Exposure and Stronger Cardiovascular and Metabolic Adverse Reactions to Fenoterol in Individuals with Heritable OCT1 Deficiency.

Fenoterol is a widely used anti-asthmatic and tocolytic agent, but high plasma concentrations of fenoterol may lead to severe and even fatal adverse reactions. We studied whether heritable deficiency of the liver organic cation transporter 1 (OCT1), a trait observed in 3% of Europeans and white Americans, affects fenoterol plasma concentrations and toxicity. OCT1 transported fenoterol with high affinity, and OCT1 inhibition in human hepatocytes reduced fenoterol uptake threefold. After administration of 180 µg of fenoterol to 39 healthy individuals, the OCT1-deficient individuals (zero active OCT1 alleles; n = 5) showed 1.9-fold greater systemic fenoterol exposure (P = 4.0 × 10-5 ) and 1.7-fold lower volume of distribution (P = 8.0 × 10-5 ). Correspondingly, the OCT1-deficient individuals had a 1.5-fold stronger increase in heart rate (P = 0.002), a 3.4-fold greater increase in blood glucose (P = 3.0 × 10-5 ), and significantly lower serum potassium levels. In conclusion, heritable OCT1 deficiency significantly increases plasma concentrations of fenoterol and may be an important factor underlying the excess mortality associated with fenoterol.

Short-acting inhaled beta-2-agonists increased the mortality from chronic obstructive pulmonary disease in observational designs.

OBJECTIVE: The effect of short-acting inhaled beta(2)-agonists on mortality from chronic obstructive pulmonary disease (COPD) is controversial. Different observational designs were used to investigate about this topic. STUDY DESIGN AND SETTING: A population-based case-control design was performed, by linking automated health databases from the Varese Province of Italy. Deaths of COPD generated from the cohort of 135,871 patients for whom at least one prescription for drugs used to treat COPD had been dispensed between 1997 and 1999 entered into the study as cases. Up to 20 controls were randomly selected for each case from the cohort after matching on gender, age, and date of cohort entry. Risk ratios were estimated using the case-control, case-crossover, and case-time-control approaches. RESULTS: A total of 222 cases and 3022 controls met the inclusion criteria. Odds ratios (and corresponding 95% confidence intervals) corresponding to more than 0.5 defined-daily-doses were 2.6 (1.7, 4.0), 1.9 (1.1, 3.3), 2.1 (1.1, 4.0), and 2.3 (1.2, 4.6) by using crude and adjusted case-control, case-crossover, and case-time-control estimates, respectively. CONCLUSION: Evidence that higher doses of short-acting inhaled beta(2)-agonists are associated with higher mortality from COPD was consistently supplied by three observational approaches.

Myocardial ischemia induced by nebulized fenoterol for severe childhood asthma.

We examined for myocardial ischemia induced by continuous inhalation of fenoterol in children with severe acute asthma. Thirty children with severe acute asthma were evaluated for signs of myocardial ischemia when treated with 0.5 mg kg dose (maximum 15 mg) of inhaled fenoterol for one hour. The heart rate was measured before and after inhalation. Cardiac enzymes (creatine kinase, creatine kinase MB fraction and troponin levels) were measured at admission and 12 hours later. An EKG was recorded before inhalation was started and immediately after its completion to detect the presence of any evidence of myocardial ischemia. All patients developed significant increase in heart rate. Six patients showed EKG changes compatible with myocardial ischemia, despite normal enzyme levels. Patients with severe acute asthma show tachycardia and may show EKG changes of myocardial ischemia.

Aerosol fenoterol by intermittent positive pressure breathing in asthmatic patients.

Ten subjects with mild to moderately severe asthma participated in a study of the bronchodilator activity and incidence of side effects of fenoterol aerosol administered by intermittent positive pressure breathing (IPPB). The doses of fenoterol used in the Bird micronebulizer were 0, 0.25 mg, 0.5 mg, 1.0 mg, and 2.5 mg, and these were administered in a randomized, double-blind fashion. The bronchodilator response, assessed by the area under the FEV1 curve, showed mean (+/- SE) values of 1.44 +/- 0.53 1 hr for 0.25 mg of fenoterol to 1.66 +/- 0.56 1 hr for 2.5 mg of fenoterol (p greater than 0.05), longer (p less than 0.01) than the mean placebo response of 0.06 +/- 0.38 1 hr. A dose-dependent increase in tremor was observed for each of the doses of fenoterol. The 0.25-mg dose of fenoterol solution is an appropriate starting dose for the treatment of moderately severe asthma.

The pulmonary and extrapulmonary effects of inhaled beta-agonists in patients with asthma.

The cardiovascular, respiratory, and hypokalemic effects of repeated inhalation of fenoterol, albuterol, and isoproterenol were compared in 12 subjects with stable asthma according to a double-blind, crossover design. Ipratropium bromide served as a control providing bronchodilatation without extrapulmonary effects. Subjects inhaled the beta-agonists on an equal-weight basis (400 micrograms) at 0, 30, 40, and 45 minutes. Measurements of heart rate, blood pressure, total electromechanical systole (measure of inotropic activity), preejection period, QTc interval, plasma potassium levels, and forced expiratory volume in 1 second were made 5 minutes after each dose and again at 60 and 75 minutes. There were no differences in the bronchodilating effect between the beta-agonists. However, both fenoterol and isoproterenol resulted in greater positive inotropic stimulation than did albuterol, and fenoterol caused a greater fall in plasma potassium levels than did the other beta-agonists.

Comparison of the effects of inhaled SCH 1000 and fenoterol on exercise-induced bronchospasm in children.

The effect of 40 microgram of SCH 1000 (ipratropium bromide, an anticholinergic agent) on bronchodilation and suppression of exercise-induced bronchospasm (EIB) was compared with 400 microgram of fenoterol and a placebo in a single-blind controlled study. Twenty-seven randomly selected asthmatic children performed a standardized treadmill exercise challenge and the 17 children who were shown to have EIB continued in the study. Pulmonary function was evaluated before and after drug administration and exercise. When individual results were analyzed and grouped according to the responsiveness of EIB to the drugs, two patterns emerged: (1) the EIB was more severe in those (6/17) children who did not respond to either drug than in the rest of children; (2) the resting pulmonary function was significantly better in the children (4/17) who responded to both drugs than in those (7/17) who responded to fenoterol alone. In conclusion SCH 1000 was shown to be an effective bronchodilator comparable to, but no better than, fenoterol. It had minimal side effects. As an EIB inhibitor it depended on relatively normal base line pulmonary function and only a moderate deterioration following exercise, whereas fenoterol depended on the exercise response alone. Although anticholinergic drugs are not very extensively used, SCH 1000 may be useful in some patients where the beta 2 adrenergic drugs cause signficant side effects or are contraindicated.

An evaluation of the initial treatment of acute asthma.

Two treatment regimens for the initial treatment of acute asthma in 50 patients between the ages of 12 and 20 years seen in the emergency room were evaluated. The treatments were randomized such that 26 patients received 2.5 mg of the beta 2-agonist fenoterol by nebulizer and 24 patients received 0.3 mg of epinephrine followed by 0.75 mg of Sus-Phrine. Clinical assessment and spirometry were performed over a two-hour period. Both groups responded within ten minutes and peak improvement was reached within one hour. Peak expiratory flow and clinical score were better following fenoterol treatment in the first hour (P less than .05). The one-second forced expiratory volume and the forced expiratory flow in the middle half of the vital capacity were greater at 20 minutes with fenoterol (P less than .05). Those with more severe obstruction (forced expiratory volume less than 30%) receiving aerosol therapy also had significantly greater improvement in the first 20 minutes compared with those who received injections. Four patients failed to respond to epinephrine whereas all patients showed improvement with fenoterol (P less than .05). These results demonstrated that an inhaled beta 2-agonist is effective in the initial treatment of acute asthma in children, regardless of severity, and avoids the need for injections.

A review of ipratropium bromide/fenoterol hydrobromide (Berodual) delivered via Respimat Soft Mist Inhaler in patients with asthma and chronic obstructive pulmonary disease.

Asthma and chronic obstructive pulmonary disease (COPD) can be effectively treated by the use of bronchodilator therapies delivered by inhalation. Berodual is a fixed combination of the anticholinergic agent ipratropium bromide (IB) and the beta2-adrenergic agonist fenoterol hydrobromide (FEN). IB/FEN has been available for the treatment of asthma and COPD in a pressurised metered dose inhaler (MDI) [pMDI] formulation for many years. The pMDI is the most widely used device for the delivery of inhaled medications, such as IB/FEN. However, most conventional pMDIs contain chlorofluorocarbon (CFC) propellants, which are currently being withdrawn because of their detrimental effects on the environment. This has resulted in alternative methods of drug delivery being developed. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that generates a fine, slow-moving cloud (the Soft Mist) which can be easily inhaled. Scintigraphic studies have shown that this improves deposition of drugs in the lung and results in less oropharyngeal deposition than the CFC-MDI. A clinical development programme has been conducted to compare the efficacy and safety of IB/FEN delivered via Respimat SMI with that of IB/FEN via CFC-MDI in the treatment of patients with asthma or COPD. Five clinical studies (two phase II and three phase III) investigated dosages of IB/FEN 5/12.5 microg to 320/800 microg via Respimat SMI in single and multiple dose administration regimens. Four of the trials were conducted in patients with asthma (three in adults and one in children), while one phase III trial was conducted in patients with COPD. In phase III, 2058 patients participated, with a total of 1112 patients treated with IB/FEN via Respimat SMI. In the phase III studies, each dose from Respimat SMI was given in one actuation compared with two actuations with the CFC-MDI. In the paediatric asthma phase III study, all CFC-MDI doses were delivered via a spacer device. The results of the trials demonstrated that IB/FEN via Respimat SMI allows a reduction in the nominal dose of IB/FEN, while offering similar therapeutic efficacy and safety to a CFC-MDI. In children, Respimat SMI obviates the need for a spacer.

Fenoterol: a review of its pharmacological properties and therapeutic efficacy in asthma.

Fenoterol, the 4-hydroxyphenyl derivative of orciprenaline, is a resorcinol derivative with relatively high selectivity for beta2-adrenoceptors. It is active in man after inhalation or oral administration and is indicated in the treatment of bronchospasm associated with asthma, bronchitis and other obstructive airway diseases. Clinical experience has shown that fenoterol is an effective bronchodilator with negligible effects on the cardiovascular system following aerosol administration of usual therapeutic doses. In children, inhaled fenoterol is effective in preventing exercise-induced asthma and administration of the aerosol in young children has been successfully used to terminate acute asthma attacks. In trials in adults, inhaled fenoterol was superior to placebo. In other controlled studies, it showed a tendency to cause a slightly greater maximum improvement in airway function as assessed spirometrically, and to have a longer duration of action than inhaled orciprenaline, salbutamol or terbutaline, although in these trials statistically significant differences were often not found. The onset of maximum effect is less rapid than with isoprenaline but is longer lasting. About 60% of the eventual maximum response to fenoterol is reached in the first few minutes after inhalation. Oral fenoterol is more effective than placebo, ephedrine or orciprenaline, and probably similar to salbutamol and terbutaline. Following usual aerosol doses, side-effects are minimal. Oral administration is associated with a higher incidence of side-effects than inhalation, including fine muscle tremor and tachycardia.

Optical illusions from visual data analysis: example of the New Zealand asthma mortality epidemic.

The abundance of health-related statistics routinely collected worldwide invites their misuse from haphazard associations between secular trends of these data. This misuse is often compounded by assessing these associations simply on the basis of a visual inspection of the data. The visual approach to data analysis, known to have several pitfalls, is particularly tempting in the context of asthma where it has often been used. For example, the epidemic of asthma deaths that occurred in New Zealand during the last two decades has been imputed to fenoterol, a medication for asthma, on the basis of a visual assessment of ecological data. The simultaneity of time trends in the asthma death rate and fenoterol market share in that country formed an important part of the statistical basis of the evidence. We verified whether the results of such visual analyses are corroborated by more objective quantitative statistical methods of analysis. We reanalyzed these same data, namely the time trend data of New Zealand asthma death rates, fenoterol market share, sales of beta-agonists and inhaled corticosteroids, measured yearly for the 16-year span 1976-1991, using Poisson weighted loglinear regression. We found that the protective effect of inhaled corticosteroids (rate ratio 0.5 per canister per month; 95% confidence interval 0.4 to 0.7; p = 0.0001) was more closely associated with changes in asthma mortality than either fenoterol (RR 2.7 per canister per month; 95% CI: 0.9 to 7.5; p = 0.06) or all beta-agonists combined (RR 1.6; 95% CI: 0.8 to 3.0; p = .19). We conclude from this quantitative analysis that these ecological asthma mortality data provide evidence of a stronger association with inhaled corticosteroids, little used in New Zealand at the onset of the epidemic but used abundantly at its termination, than with fenoterol. This conclusion is diametrically opposite to that found by the visual approach. The quantitative analysis demonstrates that the visual approach to the analysis of ecological data, although seemingly convincing, can be misleading by creating an optical illusion. This purely visual approach to data analysis may thus have serious implications when the resulting scientific information is used to make vital public health and policy decisions.

International trends in sales of inhaled fenoterol, all inhaled beta-agonists, and asthma mortality, 1970-1992.

To evaluate the hypothesis that fenoterol or all inhaled beta-agonists caused an epidemic of asthma mortality in New Zealand from the late 1970s to the mid-1980s, we examined trends from 1970 to 1992 in per capita sales of inhaled fenoterol, inhaled beta-agonists, and asthma mortality in New Zealand and nine other countries that marketed fenoterol. During the last two decades, there has been a large and widespread increase in sales of inhaled beta-agonists, including fenoterol. Asthma mortality in most countries, however, has been relatively stable. Only New Zealand experienced an epidemic of asthma mortality. In addition, sales rates of fenoterol similar in magnitude to those in New Zealand near the peak of the epidemic also occurred in Belgium, Austria, and Germany, while asthma mortality in these countries remained low. Also, sales rates of all beta-agonists in Australia were similar to those in New Zealand, but no epidemic of asthma mortality occurred in Australia. Therefore, the difference between asthma mortality rates in New Zealand and other countries is not explained by differences in per capita sales of fenoterol or all beta-agonists. Within New Zealand, the beginning and end of the epidemic correlated with a rise and fall in sales of all beta-agonists, including fenoterol. From 1980 to 1989, however, sales of fenoterol and all beta-agonists doubled in New Zealand while asthma mortality declined by 40%. International data on medication sales and asthma mortality, therefore, do not point to a relation between asthma mortality and beta-agonists in general nor fenoterol in particular.