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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 322-323, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200704-643ED

Editorials

Are beta2-Agonists Safe in Patients with Acute Exacerbations of COPD?

Guy F. Joos, M.D., Ph.D.

Ghent University Hospital, Ghent, Belgium

Exacerbations, particularly those that result in hospitalization, are significant events in the natural history of chronic obstructive pulmonary disease (COPD) and are associated with increased morbidity and mortality (1, 2). According to the ATS/ERS guidelines, bronchodilators, corticosteroids, and antibiotics form the cornerstone of the treatment of acute COPD exacerbations (3). There is substantial evidence showing that both inhaled beta-adrenergic agonists and anticholinergic agents can improve airflow during acute exacerbations. Indeed, an increase in the FEV1 and the forced vital capacity by 15 to 29 percent over a period of 60 to 120 minutes after administration of such therapy has been observed in several studies (4). Available data do not support the use of methylxanthines as first line bronchodilators in view of an unfavorable benefit/risk ratio. In severe exacerbations, however, methylxanthines might be added as second-line agents after inhaled bronchodilators (5).

Our knowledge of the pathophysiologic basis of COPD exacerbations continues to grow, with increased understanding of the derangements in ventilatory mechanics, muscle function, and gas exchange with ensuing respiratory failure (6). During acute exacerbations of COPD, the worsening of gas exchange is primarily produced by an increased ventilation/perfusion inequality, an effect that is amplified by a decrease in mixed venous oxygen tension resulting from greater oxygen consumption (7, 8). The administration of beta-adrenergic agents to stable patients with airways obstruction often results in a transient decrease in PaO2, despite concomitant bronchodilation. This has been attributed to the pulmonary vasodilator action of these agents, increasing blood flow to poorly ventilated lung regions resulting in greater ventilation–perfusion (V/Q) inequalities, and to a shunt-like effect (9, 10). Little is known, however, on the effects of inhaled bronchodilator agents on pulmonary gas exchange in acute exacerbations of COPD; in particular, data for the commonly used beta2-agonists, salbutamol (albuterol) and terbutaline, are lacking.

In this issue of the Journal (pp. 350–355), Polverino and colleagues report the effects of the nebulized beta2-agonist salbutamol on gas exchange in patients hospitalized with an exacerbation of COPD (11). They measured spirometry, arterial blood gases, systemic hemodynamics, and V/Q relationships, both at the time of exacerbation and at convalescence. Outcomes were assessed 30 and 90 minutes after nebulization of 5.0 mg salbutamol. The results presented by Polverino and coworkers nicely show that, contrary to expectations, the administration of salbutamol at the time of exacerbation does not aggravate the already compromised pulmonary gas exchange. This is a reassuring finding.

After hospitalization, patients with COPD frequently receive further treatment with inhaled bronchodilators, and recovery from their exacerbation may take up to 3 months (12). The potential side effects of beta2-agonists, including tremors, headache, nausea, and palpitations, are also a concern when patients with COPD are treated in their stable phase. Moreover, adverse cardiovascular effects, such as changes in heart rate, blood pressure, and electrocardiographic tracings, are possible, but rare (10). A meta-analysis of randomized placebo-controlled trials of beta2-agonists in patients with asthma or COPD found that administration of a single dose of a beta2-agonist increased heart rate by 9.12 beats per minute and reduced serum potassium concentration by 0.36 mmol/L, compared with placebo. For trials lasting from 3 d to 1 yr, beta2-agonist treatment increased the risk for cardiovascular events, mainly sinus tachycardia (relative risk 3.06) (13). In a large cohort study of patients with COPD over the age of 55, no increase in the risk of fatal or nonfatal acute myocardial infarction was found (14). It is already known that beta2-agonists can have an effect on pulmonary gas exchange in stable COPD. For instance, in a group of patients with arterial hypoxemia at rest, Khoukaz and Gross reported small but statistically significant declines in PaO2 after the administration of both salmeterol (–2.74 mm Hg) and salbutamol (–3.45 mm Hg). There was no subject in whom PaO2 declined to levels below 59 mm Hg. It was concluded that the declines observed were small, transient, and of doubtful clinical significance (9). Polverino and colleagues demonstrated similar findings when they studied their patients at the time of convalescence. At this time point, and in contrast to the time of excacerbation, nebulized salbutamol resulted in a further V/Q imbalance and in mild-to-moderate decreases in arterial hypoxemia. The decrease in PaO2 was rather small (–6.7 mm Hg) and was not of major concern, since PaO2 levels were still above the cutoff level of 55 mm Hg, where supplemental oxygen should be considered (11).

Both short-acting beta-adrenergic agonists and anticholinergic agents induce similar bronchodilation in acute exacerbations of COPD (15). The choice of agent for a given patient may be influenced by factors such as the time to peak effect (which is slightly more rapid with beta-adrenergic agonists) and the frequency of adverse effects (generally fewer and milder with an anticholinergic agent). Moreover, both agents can be given together, especially if there is little response to a single drug. The current status on the use of bronchodilators in acute exacerbations of COPD is well reflected in the GOLD guidelines, stating that short-acting inhaled beta2-agonists are usually the preferred bronchodilators and that, if a prompt response to these drugs does not occur, the addition of an anticholinergic is recommended (16). The data reported by Polverino and colleagues add further evidence supporting the safety aspects of this statement (11).

FOOTNOTES

Conflict of Interest Statement: G.F.J. has received funding ($270,000 from GlaxoSmithKline [GSK] over 2004–2006, $250,000 from AstraZeneca [AZ] over 2004–2006, $50,000 from Boehringer Ingelheim over 2004–2006, $30,000 from Novartis over 2004–2006), lecture fees ($3,200 from GSK per annum 2004–2006, $2,000 from AZ per annum 2004–2006, $2,000 from Boehringer Ingelheim per annum 2004–2006) and has served on Scientific Boards ($2,000 from GSK per annum 2004–2006, $2,000 from AZ per annum 2004–2006, $600 from Boehringer Ingelheim per annum 2004–2006, $1500 from Altana per annum 2004–2006); all these entities have an interest in therapies for COPD.

REFERENCES

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  16. Global Initiative for Chronic Obstructive Pulmonary Disease. Global Strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. 2006. [Accessed 2007 Apr 26]. Available from: www.goldcopd.com

Related articles in AJRCCM:

Gas Exchange Response to Short-Acting beta2-Agonists in Chronic Obstructive Pulmonary Disease Severe Exacerbations
Eva Polverino, Federico P. Gómez, Hernán Manrique, Néstor Soler, Josep Roca, Joan Albert Barberà, and Roberto Rodríguez-Roisin
AJRCCM 2007 176: 350-355. [Abstract] [Full Text]  




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