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Original Research: Asthma |

Adverse Respiratory Effect of Acute β-Blocker Exposure in AsthmaAcute 03B2-Blockade in Asthma: A Meta-analysis: A Systematic Review and Meta-analysis of Randomized Controlled Trials FREE TO VIEW

Daniel R. Morales, MBChB; Cathy Jackson, MD; Brian J. Lipworth, MD; Peter T. Donnan, PhD; Bruce Guthrie, PhD
Author and Funding Information

From the Quality, Safety, and Informatics Group (Drs Morales and Guthrie), Asthma and Allergy Research Group (Dr Lipworth), and Dundee Epidemiology and Biostatistics Unit (Dr Donnan), Medical Research Institute, University of Dundee, Dundee; and the Bute Medical School (Dr Jackson), University of St Andrews, Fife, Scotland.

Correspondence to: Daniel R. Morales, MBChB, Quality, Safety, and Informatics Group, Medical Research Institute, University of Dundee, Mackenzie Bldg, Dundee, DD2 4BF, Scotland; e-mail: danielmorales@nhs.net


Funding/Support: This study was funded by a Scottish Government Chief Scientist Office Clinical Academic Fellowship, which provided research costs and support for Dr Morales [Grant CAF/11/07].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(4):779-786. doi:10.1378/chest.13-1235
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Background:  β-Blockers are avoided in asthma over concerns regarding acute bronchoconstriction. Risk is greatest following acute exposure, including the potential for antagonism of β2-agonist rescue therapy.

Methods:  A systematic review of databases was performed to identify all randomized, blinded, placebo-controlled clinical trials evaluating acute β-blocker exposure in asthma. Effect estimates for changes in respiratory function, symptoms, and β2-agonist response were pooled using random effects meta-analysis with heterogeneity investigated.

Results:  Acute selective β-blockers in the doses given caused a mean change in FEV1 of −6.9% (95% CI, −8.5 to −5.2), a fall in FEV1 of ≥ 20% in one in eight patients (P = .03), symptoms affecting one in 33 patients (P = .18), and attenuation of concomitant β2-agonist response of −10.2% (95% CI, −14.0 to −6.4). Corresponding values for acute nonselective β-blockers in the doses given were −10.2% (95% CI, −14.7 to −5.6), one in nine patients (P = .02), one in 13 patients (P = .14), and −20.0% (95% CI, −29.4 to −10.7). Following investigation of heterogeneity, clear differences were found for celiprolol and labetalol. A dose-response relationship was demonstrated for selective β-blockers.

Conclusions:  Selective β-blockers are better tolerated but not completely risk-free. Risk from acute exposure may be mitigated using the smallest dose possible and β-blockers with greater β1-selectivity. β-Blocker-induced bronchospasm responded partially to β2-agonists in the doses given with response blunted more by nonselective β-blockers than selective β-blockers. Use of β-blockers in asthma could possibly be based upon a risk assessment on an individual patient basis.

Figures in this Article

Guidelines recommend avoiding β-blockade in patients with asthma because of concerns regarding the potential for acute bronchoconstriction.1 This is caused by catecholamine antagonism at the pulmonary β2-adrenocepter, which may uncover unopposed increased cholinergic tone resulting in airway constriction.2 These concerns may largely relate to adverse events occurring in patients with uncontrolled asthma before widespread use of inhaled corticosteroids. As such, β-blockers are withheld from patients with asthma despite strong clinical indications.

Only selective β-blockers have previously been systematically evaluated in patients with reversible airways disease (asthma and COPD), where single-dose exposure reportedly caused a mean fall in FEV1 of 7.46% with no change in symptoms.3 However, β-blockers vary according to β1-adrenoceptor selectivity and partial agonist and α-blocking activity. The effects of selective β-blockers may also vary by dose and individual susceptibility, in which case use of mean values alone may mask a clinically significant risk in a small proportion of patients. β-Blocker exposure is not uncommon in asthma, with 2.2% of patients prescribed β-blockers each year, so their risk needs to be properly evaluated.4 Nonselective β-blockers have not been systematically evaluated, although they are widely used in clinical practice, including labetalol, used first-line for the treatment of pregnancy-induced hypertension, and topical agents used in glaucoma. Nonselective β-blockers such as nadolol and propranolol have been investigated for their paradoxical potential to reduce airway hyperresponsiveness and inflammation in asthma.5 These benefits may only be seen following chronic exposure, and in this sense patients must first be able to tolerate acute exposure. Additionally, β2-agonists are first-line rescue therapy for acute bronchoconstriction, and, in theory, their efficacy could be reduced when given to patients receiving β-blockers. The aim of this meta-analysis is to systematically evaluate changes in respiratory function and β2-agonist efficacy following acute β-blockade.

A systematic review of MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was performed using a prespecified protocol and search strategy (e-Tables 1, 2) to identify all randomized, blinded, placebo-controlled clinical trials published on or before January 20, 2013, evaluating acute β-blocker exposure (up to 7 days) in asthma. References and full texts were independently screened by a minimum of two reviewers, with agreement based on consensus. References of included studies were searched to identify additional trials. Only English language publications and published data were included. Methodological quality and risk of bias were evaluated for each trial using the Cochrane collaboration tool for assessing risk of bias. Publication bias was examined using funnel plots looking for asymmetry and performing the Egger test. The systematic review was reported according to PRISMA (Preferred Reporting Items for Systematic Reviews) requirements.

Statistical Analysis

Mean percentage change in FEV1 was calculated and presented as the mean absolute percentage difference in FEV1. A fall in FEV1 of ≥ 20% and development of symptoms was presented as the risk difference. A fall in FEV1 of ≥ 20% was defined to better assess individual response. β2-Agonist responsiveness was calculated as mean percentage change in FEV1 and presented as the mean absolute difference compared with placebo. All measures of FEV1 were calculated relative to original baseline FEV1 values. Heterogeneity was assessed using the I2 statistic. Subgroup analysis was used to evaluate if individual drug-level effects and dose-response relationships were feasible. A generic inverse variance method of analysis was used for continuous outcomes, and a Mantel-Haenszel method of analysis was used for dichotomous outcomes. A random-effects method was performed because heterogeneity was detected. Random-effects metaregression was used to evaluate group baseline FEV1 and effect of steroid exposure categorized for each study as no exposure, mixed exposure, and exposed. Metaregression was performed in STATAv11 (SAS Institute Inc) and meta-analysis in Review Manager (RevMan) v5.1 (The Cochrane Collaboration).

Sensitivity Analyses

Only patients with asthma were included. Sensitivity analysis was performed according to whether trials reported a definition of asthma according to American Thoracic Society or British Thoracic Society guidelines, reversibility in FEV1 of ≥ 15% in response to β2-agonist, or response to methacholine/histamine provocation challenges. Sensitivity analysis was also performed according to whether trials explicitly reported withholding β2-agonists for at least 8 h. Missing SDs were calculated using individual patient data and from P values as described.6 For remaining missing values, the median P value was imputed and sensitivity analyses performed using the minimum and maximum P values to ensure conclusions remained unaltered.

Of 1,989 references screened, 32 studies were included (Fig 1, e-Table 3741). A total of 16 studies evaluated selective β-blockers, six studies evaluated nonselective β-blockers, and 10 studies evaluated both. No randomized blinded placebo-controlled trials evaluating topical β-blockers in unselected patients were found. For selective β-blockers, 23 studies provided data on mean absolute percentage change in FEV1, 13 on symptoms, and five on fall in FEV1 of ≥ 20%. For nonselective β-blockers, 14 studies provided data on mean absolute percentage change in FEV1, six on symptoms, and three on fall in FEV1 of ≥ 20%.

Figure Jump LinkFigure 1. PRISMA (Preferred Reporting Items for Systematic Reviews) flow diagram for study selection.Grahic Jump Location

The most common β-blockers studied were atenolol, metoprolol, and propranolol (e-Tables 3, 4). A total of 600 acute selective β-blocker exposures were evaluated in 330 patients with asthma (mean age, 46 years; 67.5% men). A total of 301 acute nonselective β-blocker exposures were evaluated in 218 patients with asthma (mean age, 40.5 years; 68.9% men). Mean baseline FEV1 for selective and nonselective patients were 2.28 L and 2.50 L, respectively. In total, 28 trials (88%) were single-dose studies (e-Table 3), with respiratory measurements taken on average 108 min postdose.

Acute Selective β-Blockade

Compared with placebo, acute selective β-blockade caused a mean absolute fall in FEV1 of −6.9% (95% CI, −8.5 to −5.2; P < .001) (Fig 2). The risk difference for fall in FEV1 of ≥ 20% was 0.13 (95% CI, 0.01-0.24; P = .03) (Fig 3), equating to a number needed to treat of eight. The risk difference for symptoms was 0.03 (95% CI, −0.01 to 0.06; P = .18) (e-Fig 1) equating to a number needed to treat of 33, which was not statistically significant.

Figure Jump LinkFigure 2. Mean change in FEV1 following acute selective β-blocker exposure. df = degrees of freedom.Grahic Jump Location
Figure Jump LinkFigure 3. Fall in FEV1 of ≥ 20% following acute selective β-blocker exposure. M-H = Mantel-Haenszel. See Figure 2 legend for expansion of other abbreviation.Grahic Jump Location
Acute Nonselective β-Blockade

Compared with placebo, acute nonselective β-blockade caused a mean absolute fall in FEV1 of −10.2% (95% CI, −14.7 to −5.6; P < .001) (Fig 4). The risk difference for fall in FEV1 of ≥ 20% was 0.11 (95% CI, −0.04 to 0.26; P = .14) (e-Fig 2), equating to a number needed to treat of nine, which was not statistically significant. The risk difference for symptoms was 0.08 (95% CI, 0.01-0.15; P = .02) (Fig 5), equating to a number needed to treat of 13.

Figure Jump LinkFigure 4. Mean change in FEV1 following acute nonselective β-blocker exposure. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5. Symptoms following acute nonselective β-blocker exposure. See Figure 2 and 3 legends for expansion of abbreviations.Grahic Jump Location
β2-Agonist Response Following Acute β-Blockade

Of studies evaluating selective and nonselective β-blockers, 17 (74%) and nine (64%) included data on β2-agonist response, respectively (e-Table 3). Relative to original baseline values, the crude mean FEV1 response to β2-agonists was +22.7% for placebo, +16.0% for selective β-blockade, and −0.7% for nonselective β-blockade (Fig 6). Following meta-analysis, the absolute mean difference in FEV1 response to β2-agonists relative to placebo was −10.2% (95% CI, −14.0 to −6.4; P < .001) (e-Fig 3) for selective β-blockade and −20.0% (95% CI, −29.4 to −10.7; P < .001) (e-Fig 4) for nonselective β-blockade.

Figure Jump LinkFigure 6. Mean change in FEV1 and response to β2-agonist by class of β-blocker. Mean FEV1 response to β2-agonists was +22.7% for placebo, +16.0% for selective β-blockade, and −0.7% for nonselective β-blockade. Following meta-analysis, absolute mean difference in FEV1 between placebo was −10.2% and −20.0% for selective and nonselective β-blockers, respectively, suggesting the placebo β2-agonist response is partially blunted by selective and completely blunted by nonselective β-blockade. Baseline represented by the dotted horizontal line. Unweighted 95% CIs calculated from pooling mean percentage change in FEV1 from all studies.Grahic Jump Location
Subgroup Analysis
Individual β-Blocker Comparison:

Selective β-blockers varied in relation to the degree of fall in FEV1 following acute exposure (Fig 7). Compared with placebo, celiprolol did not cause a statistically significant mean change in FEV1 (difference, 1.8%; 95% CI, −2.3 to 5.8; P = .39) (e-Fig 5), whereas metoprolol (difference, −9.3%; 95% CI, −12.0 to −6.6; P < .001) (e-Fig 6) and atenolol (difference, −10.2%; 95% CI, −12.6 to −7.8; P < .001) (e-Fig 7) did.

Figure Jump LinkFigure 7. Mean change in FEV1 for individual selective β-blockers. Baseline represented by dotted horizontal line. dose = mean dose; n = number of patients.Grahic Jump Location

Nonselective β-blockers also varied in relation to mean change in FEV1 following acute exposure (Fig 8). Compared with placebo, labetalol did not cause a statistically significant mean change in FEV1 (difference, −2.7%; 95% CI, −9.6 to 4.1; P = .43) (e-Fig 8), whereas propranolol did (difference, −17.0%; 95% CI, −21.4 to −12.6; P < .001) (e-Fig 9).

Figure Jump LinkFigure 8. Mean change in FEV1 for individual nonselective β-blockers. Baseline represented by dotted horizontal line. See Figure 7 legend for expansion of abbreviations.Grahic Jump Location
Dose-Response Relationship:

An increasing dose-response relationship was demonstrated following acute exposure to metoprolol, atenolol, and bisoprolol (e-Figs 10-12). Mean change in FEV1 following acute exposure to 50 mg, 100 mg, and 200 mg of metoprolol was −6.0%, −8.9%, and −13.0%, respectively. Mean change in FEV1 following acute exposure to 50 mg, 100 mg, and 200 mg of atenolol was −5.4%, −11.4%, and −10.9%, respectively. Mean change in FEV1 following acute exposure to 10 mg and 20 mg of bisoprolol was −5.8% and −7.5%, respectively.

Baseline FEV1 and Steroid Exposure:

Meta-regression analyses are presented in e-Table 5. There was little evidence to suggest steroid exposure influenced mean change in FEV1 following either acute selective (3.9%; 95% CI, −7.2 to 15.0 for exposed vs unexposed; P = .469) or nonselective β-blocker exposure (5.8%; 95% CI, −25.3 to 36.8, for exposed vs unexposed; P = .688). Mean baseline FEV1 did not influence mean change in FEV1 following either selective (−1.9%; 95% CI, −5.5 to 1.7; P = .272) or nonselective β-blocker exposure (−1.0%; 95% CI, −11.1 to 9.0; P = .829).

Risk of Bias and Sensitivity Analyses

Many methodological qualities had an unclear risk of bias, as studies did not provide explicit detail to make an informed judgment (e-Fig 13). For studies evaluating mean change in FEV1, funnel plot asymmetry was observed for selective β-blockers (P value 0.005) (e-Fig 14) but not for nonselective β-blockers (P = 0.111). Results from sensitivity analyses were consistent with the main findings.

Acute selective β-blockade in the doses given caused statistically significant mean reductions in FEV1, nonsignificant increases in symptoms, and significant absolute falls in FEV1 of ≥ 20% (affecting 13% of subjects). For mean changes in FEV1 and symptoms, findings were similar to a previous meta-analysis, which evaluated selective β-blockers only and did not include fall in FEV1 of ≥ 20% as an outcome.3 Our findings suggest that, although the mean effects of acute selective β-blockade are relatively small, it may cause clinically significant events in a minority of susceptible patients who have exaggerated cholinergic tone. The β2-agonist response after selective β-blockade was partially attenuated relative to placebo. However, blunting of this magnitude is possibly of limited clinical significance, as pulmonary function typically increased well beyond original baseline FEV1.

Acute nonselective β-blockade in the doses given caused larger mean falls in FEV1, a significant increase in symptoms (affecting 8%), and similar but nonsignificant falls in FEV1 of ≥ 20%. As expected, nonselective β-blockade completely attenuated β2-agonist response relative to placebo, with post β2-agonist FEV1 values approximately returning to baseline. In other studies involving patients with nonselective β-blockade, β2-agonists completely reversed histamine and methacholine challenge following acute and chronic β-blockade.4244 These studies differ because bronchoconstriction was experimentally induced to more closely mimic what happens during acute asthma or titrated exposure.

Falls in FEV1 of ≥ 20% may represent patients who are more susceptible to β-blockade, in which use of mean values alone may underestimate risk. It remains possible that other factors are important to trigger clinically significant exacerbations, including uncontrolled airway inflammation or genetic factors such as the arginine-16 β2-adrenoceptor polymorphism. Approximately 15% of white patients with asthma are homozygous for arginine-16 β2-adrenoceptor polymorphism, which predisposes to asthma exacerbations in patients using salmeterol with inhaled corticosteroids.45 The lack of data on topical β-blockers is important, as deaths following oral and topical exposures have occurred. Two studies were excluded because patients were selected on the basis of prior timolol exposure. From these, timolol and betaxolol caused mean falls in FEV1 of 14.2% and 9.6%, respectively.46,47 It is plausible that topical exposure is riskier than oral because rapid absorption into the systemic circulation occurs without first-pass metabolism, and topical agents have similar effects to IV administration in terms of β2-adrenoceptor occupancy and cardiopulmonary effects.48

Heterogeneity in Treatment Effect

A dose-response relationship was seen with selective β-blockers in keeping with loss of β1-adrenoceptor selectivity at higher doses. Although not demonstrated here, low-dose nonselective β-blockade can be tolerated.5,42,44 Subgroup analysis suggests differences in treatment effect within class, particularly among celiprolol and labetalol. β1-adrenoceptor selectivity varies, with β1-/β2-affinity ratios ranging from 13.5 for bisoprolol to 4.7 for atenolol and 2.3 for metoprolol.49,50 Celiprolol is a β-blocker with partial agonist activity and greater selectivity than atenolol or bisoprolol, which may explain better tolerability.51 However, labetalol is nonselective with α-blocking properties, and, therefore, selectivity cannot not be the only reason for better tolerability. α-Blockade is not therapeutic in asthma, but nonselective α-blockade may protect against bronchoconstriction in patients with asthma with β-blockade, suggesting a protective action only when sympathetic activity is blocked.5254 Although labetalol caused nonsignificant falls in FEV1, heterogeneity remained, and other outcome data are lacking to comprehensively evaluate its safety for use in asthma.

Mean baseline FEV1 or steroid exposure did not appear to influence treatment effect. This was done because individuals with lower baseline FEV1 may be at higher risk where even small changes in FEV1 are of clinical significance. It was not possible to evaluate baseline hyperresponsiveness. Increased methacholine sensitivity may occur following β-blockade but remains unaffected in many patients following acute or chronic exposure.10,14,44 One study evaluated exhaled nitric oxide and reported no significant variation following nebivolol in steroid-naive patients, a finding also seen with propranolol in steroid-treated patients.13,44 Although meta-regression explores statistical heterogeneity with different study characteristics, it can suffer from confounding, lack of power, and aggregation bias. In many instances reporting of steroid exposure was limited, and we cannot be certain steroid exposure does not attenuate β-blocker response.

Limitations and Strengths

In general, moderate to high β-blocker doses were administered acutely, and no studies titrated exposure. Most patients had mild to moderate asthma, and results may not be applicable to patients with severe or unstable asthma. However, most studies included patients with 15% reversibility to β2-agonists that could be more sensitive to β-blockers. The degree of bronchomotor tone regulated by sympathetic and parasympathetic drive also probably determines susceptibility to acute β-blockade, as will transient heightened airway hyperresponsiveness, which may follow respiratory tract infections. Respiratory function was evaluated using FEV1, which may be less sensitive than other methods.55 Studies often failed to describe aspects of study design, and it is possible that some heterogeneity may be due to bias. However, only randomized blinded placebo-controlled trials were included, which are considered the gold standard for clinical research.

Implications for Clinical Practice

The principal indication for β-blockers in asthma is for cardiovascular comorbidities. Although reasonably well tolerated by the majority, acute selective β-blockade may cause detrimental changes in lung function in susceptible patients with asthma. However, risk from acute exposure in patients with controlled asthma may be mitigated by commencing the lowest dose possible and using a highly selective agent, with reassurance that any bronchoconstriction responds reasonably well to β2-agonists. As such, it may be possible to consider their use in asthma on an individual basis following a risk assessment in patients with well-controlled asthma. Although many patients with asthma tolerated exposure to nonselective β-blockade, acute risk is greater, which could possibly be mitigated through gradual dose titration and initial concomitant cover with a long-acting muscarinic antagonist, to prevent unopposed increased cholinergic tone uncovered by acute β-blockade.44 Irrespective of which β-blocker is contemplated, acute exposure appears to have the greatest risk, which may attenuate upon chronic exposure.5,44

Although bronchospasm induced by moderate- to high-dose β-blockade appears to respond reasonably well to conventional doses of β2-agonists, partial blunting may occur that is greater when nonselective β-blockers are given compared with selective β-blockers. In this regard, higher doses of β2-agonists are probably required to achieve sufficient β2-receptor occupancy with concomitant β-blockade, as demonstrated.5,44 The acute and chronic dosing effects of selective and nonselective β-blockade on long-acting β2-agonist response in patients taking combination therapy requires further prospective evaluation.

Author contributions: Dr Morales is guarantor of the data.

Dr Morales: contributed to conceiving the idea, study design, interpretation of the findings, data analysis, drafting of the manuscript, and approving the final draft.

Dr Jackson: contributed to conceiving the idea, study design, interpretation of the findings, drafting of the manuscript, and approving the final draft.

Dr Lipworth: contributed to study design, interpretation of the findings, drafting of the manuscript, and approving the final draft.

Dr Donnan: contributed to conceiving the idea, study design, interpretation of the findings, data analysis, drafting of the manuscript, and approving the final draft.

Dr Guthrie: contributed to conceiving the idea, study design, interpretation of the findings, drafting of the manuscript, and approving the final draft.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Lipworth has received fees for speaking, consulting and advisory boards from Teva Pharmaceuticals USA, Chiesi Ltd, Sandoz, Cipla, Synexus, Tridas, Genkyotex S.A., and Nycomed. The Asthma and Allergy Research Group has received unrestricted grant support from Teva Pharmaceuticals USA, Chiesi Ltd, and Almirall S.A. and other funding for multicenter trials from RocheGenentech, Janssen Pharmaceuticals, Inc, AstraZeneca, and Teva Pharmaceuticals USA. Dr Donnan has received fees for consulting from the Scottish Medicines Consortium and grant support from GlaxoSmithKline plc, Otsuka America Pharmaceutical, Inc and Amgen Inc. Drs Morales, Jackson, and Guthrie have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Additional information: The e-Figures and e-Tables can be found in the “Supplemental Materials” area of the online article.

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Repsher LH, Vincent ME, Medakovic M. The effect of single doses of labetalol, metoprolol and placebo on ventilatory function in patients with bronchial asthma. J Hypertens. 1986;4(suppl 5):S510-S512.
 
Skinner C, Gaddie J, Palmer KN. Comparison of intravenous AH 5158 (ibidomide) and propranolol in asthma. BMJ. 1975;2(5962):59-61. [CrossRef]
 
Sue DY, Hansen JE, Wasserman K. The value of exercise in testing beta blockade and airway reactivity in asthmatic patients. Am Heart J. 1982;104(2 pt 2):442-445. [CrossRef]
 
Suzuki S, Mue S, Ohmi T. Effect of atenolol on pulmonary function in asthma. Acta Ther. 1981;7(1):55-65.
 
Tantucci C, Bruni B, Dottorini ML, et al. Comparative evaluation of cardioselectivity of metoprolol OROS and atenolol: a double-blind, placebo-controlled crossover study. Am Heart J. 1990;120(2):467-472. [CrossRef]
 
Thiringer G, Svedmyr N. Interaction of orally administered metoprolol, practolol and propranolol with isoprenaline in asthmatics. Eur J Clin Pharmacol. 1976;10(3-4):163-170. [CrossRef]
 
Lawrence D.S, Sahay JN, Chatterjee SS, Cruickshank JM. β-Blockers in asthma. Drugs. 1983;25(suppl 2):232-236. [CrossRef]
 
Matthys H, Doshan HD, Rühle KH, Applin WJ, Braig H, Pohl M. Bronchosparing properties of celiprolol, a new beta 1, alpha 2-blocker, in propranolol-sensitive asthmatic patients. J Cardiovasc Pharmacol. 1986;8(suppl 4):S40-S42. [CrossRef]
 
Sue DY, Hansen JE, Wasserman K. Beta-adrenergic blockade with pindolol (LB-46) in mild to moderate asthma. Chest. 1981;80(5):537-542. [CrossRef]
 
Short PM, Williamson PA, Lipworth BJ. Effects of hydrocortisone on acute β-adrenoceptor blocker and histamine induced bronchoconstriction. Br J Clin Pharmacol. 2012;73(5):717-726. [CrossRef]
 
Hanania NA, Mannava B, Franklin AE, et al. Response to salbutamol in patients with mild asthma treated with nadolol. Eur Respir J. 2010;36(4):963-965. [CrossRef]
 
Short PM, Williamson PA, Anderson WJ, Lipworth BJ. Randomized placebo-controlled trial to evaluate chronic dosing effects of propranolol in asthma. Am J Respir Crit Care Med. 2013;187(12):1308-1314. [CrossRef]
 
Basu K, Palmer CN, Tavendale R, Lipworth BJ, Mukhopadhyay S. Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. J Allergy Clin Immunol. 2009;124(6):1188-1194. [CrossRef]
 
Friren B, Michaud JE. Safety comparison of topical brinzolamide 1% and timolol 0.5% in patients with asthma or chronic obstructive pulmonary disease. Today’s Therapeutic Trends. 2004;22(1):69-80.
 
Schoene RB, Abuan T, Ward RL, Beasley CH. Effects of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol. 1984;97(1):86-92.
 
Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002;240(6):430-435. [CrossRef]
 
Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol. 2005;144(3):317-322. [CrossRef]
 
Badgett RG, Lawrence VA, Cohn SL. Variations in pharmacology of beta-blockers may contribute to heterogeneous results in trials of perioperative beta-blockade. Anesthesiology. 2010;113(3):585-592.
 
Wheeldon NM, McDevitt DG, Lipworth BJ. Selectivity of antagonist and partial agonist activity of celiprolol in normal subjects. Br J Clin Pharmacol. 1992;34(4):337-343. [CrossRef]
 
Baudouin SV, Aitman TJ, Johnson AJ. Prazosin in the treatment of chronic asthma. Thorax. 1988;43(5):385-387. [CrossRef]
 
Patel KR, Kerr JW. The airways response to phenylephrine after blockade of alpha and beta receptors in extrinsic bronchial asthma. Clin Allergy. 1973;3(4):439-448. [CrossRef]
 
Dorow P. The role of alpha-receptors in bronchoconstriction induced by beta-blockade. Respiration. 1982;43(5):359-362. [CrossRef]
 
Short PM, Williamson PA, Lipworth BJ. Sensitivity of impulse oscillometry and spirometry in beta-blocker induced bronchoconstriction and beta-agonist bronchodilatation in asthma. Ann Allergy Asthma Immunol. 2012;109(6):412-415. [CrossRef]
 

Figures

Figure Jump LinkFigure 1. PRISMA (Preferred Reporting Items for Systematic Reviews) flow diagram for study selection.Grahic Jump Location
Figure Jump LinkFigure 2. Mean change in FEV1 following acute selective β-blocker exposure. df = degrees of freedom.Grahic Jump Location
Figure Jump LinkFigure 3. Fall in FEV1 of ≥ 20% following acute selective β-blocker exposure. M-H = Mantel-Haenszel. See Figure 2 legend for expansion of other abbreviation.Grahic Jump Location
Figure Jump LinkFigure 4. Mean change in FEV1 following acute nonselective β-blocker exposure. See Figure 2 legend for expansion of abbreviation.Grahic Jump Location
Figure Jump LinkFigure 5. Symptoms following acute nonselective β-blocker exposure. See Figure 2 and 3 legends for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6. Mean change in FEV1 and response to β2-agonist by class of β-blocker. Mean FEV1 response to β2-agonists was +22.7% for placebo, +16.0% for selective β-blockade, and −0.7% for nonselective β-blockade. Following meta-analysis, absolute mean difference in FEV1 between placebo was −10.2% and −20.0% for selective and nonselective β-blockers, respectively, suggesting the placebo β2-agonist response is partially blunted by selective and completely blunted by nonselective β-blockade. Baseline represented by the dotted horizontal line. Unweighted 95% CIs calculated from pooling mean percentage change in FEV1 from all studies.Grahic Jump Location
Figure Jump LinkFigure 7. Mean change in FEV1 for individual selective β-blockers. Baseline represented by dotted horizontal line. dose = mean dose; n = number of patients.Grahic Jump Location
Figure Jump LinkFigure 8. Mean change in FEV1 for individual nonselective β-blockers. Baseline represented by dotted horizontal line. See Figure 7 legend for expansion of abbreviations.Grahic Jump Location

Tables

References

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Jackson SH, Beevers DG. Comparison of the effects of single doses of atenolol and labetalol on airways obstruction in patients with hypertension and asthma. Br J Clin Pharmacol. 1983;15(5):553-556. [CrossRef]
 
Lammers JW, Folgering HT, van Herwaarden CL. Ventilatory effects of atenolol and bevantolol in asthma. Clin Pharmacol Ther. 1985;38(4):428-433. [CrossRef]
 
Larsson K. Influence of labetalol, propranolol and practolol in patients with asthma. Eur J Respir Dis. 1982;63(3):221-230.
 
Lawrence DS, Sahay JN, Chatterjee SS, Cruickshank JM. Asthma and beta-blockers. Eur J Clin Pharmacol. 1982;22(6):501-509. [CrossRef]
 
Löfdahl CG, Svedmyr N. Cardioselectivity of atenolol and metoprolol. A study in asthmatic patients. Eur J Respir Dis. 1981;62(6):396-404.
 
Löfdahl CG, Dahlöf C, Westergren G, Olofsson B, Svedmyr N. Controlled-release metoprolol compared with atenolol in asthmatic patients: interaction with terbutaline. Eur J Clin Pharmacol. 1988;33(suppl):S25-S32. [CrossRef]
 
Matthys H, Doshan HD, Rühle KH, et al. The bronchosparing effect of celiprolol, a new beta 1- alpha 2-receptor antagonist on pulmonary function of propranolol-sensitive asthmatics. J Clin Pharmacol. 1985;25(5):354-359. [CrossRef]
 
Mue S, Sasaki T, Ohmi T, et al. Influence of Acebutolol on the haemodynamic and respiratory function of asthmatic patients. J Pharmacother. 1979;2(2):67-71.
 
Nair S, Maguire WC, Laddu AR. The effect of acebutolol, a beta adrenergic blocking agent, and placebo on pulmonary functions in asthmatics. Int J Clin Pharmacol Ther Toxicol. 1981;19(12):519-526.
 
Nicolaescu V, Manicatide M, Stroescu V. -Adrenergic blockade with practolol in acetylcholine-sensitive asthma patients. Respiration. 1972;29(2):139-154. [CrossRef]
 
Nicolaescu V, Racoveanu C, Manicatide M. Effects of exercise on practolol-treated asthmatic patients. Eur J Clin Pharmacol. 1973;6(1):3-8. [CrossRef]
 
Repsher LH, Vincent ME, Medakovic M. The effect of single doses of labetalol, metoprolol and placebo on ventilatory function in patients with bronchial asthma. J Hypertens. 1986;4(suppl 5):S510-S512.
 
Skinner C, Gaddie J, Palmer KN. Comparison of intravenous AH 5158 (ibidomide) and propranolol in asthma. BMJ. 1975;2(5962):59-61. [CrossRef]
 
Sue DY, Hansen JE, Wasserman K. The value of exercise in testing beta blockade and airway reactivity in asthmatic patients. Am Heart J. 1982;104(2 pt 2):442-445. [CrossRef]
 
Suzuki S, Mue S, Ohmi T. Effect of atenolol on pulmonary function in asthma. Acta Ther. 1981;7(1):55-65.
 
Tantucci C, Bruni B, Dottorini ML, et al. Comparative evaluation of cardioselectivity of metoprolol OROS and atenolol: a double-blind, placebo-controlled crossover study. Am Heart J. 1990;120(2):467-472. [CrossRef]
 
Thiringer G, Svedmyr N. Interaction of orally administered metoprolol, practolol and propranolol with isoprenaline in asthmatics. Eur J Clin Pharmacol. 1976;10(3-4):163-170. [CrossRef]
 
Lawrence D.S, Sahay JN, Chatterjee SS, Cruickshank JM. β-Blockers in asthma. Drugs. 1983;25(suppl 2):232-236. [CrossRef]
 
Matthys H, Doshan HD, Rühle KH, Applin WJ, Braig H, Pohl M. Bronchosparing properties of celiprolol, a new beta 1, alpha 2-blocker, in propranolol-sensitive asthmatic patients. J Cardiovasc Pharmacol. 1986;8(suppl 4):S40-S42. [CrossRef]
 
Sue DY, Hansen JE, Wasserman K. Beta-adrenergic blockade with pindolol (LB-46) in mild to moderate asthma. Chest. 1981;80(5):537-542. [CrossRef]
 
Short PM, Williamson PA, Lipworth BJ. Effects of hydrocortisone on acute β-adrenoceptor blocker and histamine induced bronchoconstriction. Br J Clin Pharmacol. 2012;73(5):717-726. [CrossRef]
 
Hanania NA, Mannava B, Franklin AE, et al. Response to salbutamol in patients with mild asthma treated with nadolol. Eur Respir J. 2010;36(4):963-965. [CrossRef]
 
Short PM, Williamson PA, Anderson WJ, Lipworth BJ. Randomized placebo-controlled trial to evaluate chronic dosing effects of propranolol in asthma. Am J Respir Crit Care Med. 2013;187(12):1308-1314. [CrossRef]
 
Basu K, Palmer CN, Tavendale R, Lipworth BJ, Mukhopadhyay S. Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. J Allergy Clin Immunol. 2009;124(6):1188-1194. [CrossRef]
 
Friren B, Michaud JE. Safety comparison of topical brinzolamide 1% and timolol 0.5% in patients with asthma or chronic obstructive pulmonary disease. Today’s Therapeutic Trends. 2004;22(1):69-80.
 
Schoene RB, Abuan T, Ward RL, Beasley CH. Effects of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol. 1984;97(1):86-92.
 
Korte JM, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002;240(6):430-435. [CrossRef]
 
Baker JG. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol. 2005;144(3):317-322. [CrossRef]
 
Badgett RG, Lawrence VA, Cohn SL. Variations in pharmacology of beta-blockers may contribute to heterogeneous results in trials of perioperative beta-blockade. Anesthesiology. 2010;113(3):585-592.
 
Wheeldon NM, McDevitt DG, Lipworth BJ. Selectivity of antagonist and partial agonist activity of celiprolol in normal subjects. Br J Clin Pharmacol. 1992;34(4):337-343. [CrossRef]
 
Baudouin SV, Aitman TJ, Johnson AJ. Prazosin in the treatment of chronic asthma. Thorax. 1988;43(5):385-387. [CrossRef]
 
Patel KR, Kerr JW. The airways response to phenylephrine after blockade of alpha and beta receptors in extrinsic bronchial asthma. Clin Allergy. 1973;3(4):439-448. [CrossRef]
 
Dorow P. The role of alpha-receptors in bronchoconstriction induced by beta-blockade. Respiration. 1982;43(5):359-362. [CrossRef]
 
Short PM, Williamson PA, Lipworth BJ. Sensitivity of impulse oscillometry and spirometry in beta-blocker induced bronchoconstriction and beta-agonist bronchodilatation in asthma. Ann Allergy Asthma Immunol. 2012;109(6):412-415. [CrossRef]
 
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