Beta 2 antagonism in acute respiratory failure

Post hoc analyses from the B-type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL)-II-ICU study suggest an association between beta-blocker usage at admission and improved mortality in patients treated in the intensive care unit for acute respiratory failure. Although this evidence is encouraging, there is a need for a phase 2 proof-of-concept randomized controlled trial of beta-blocker therapy in patients admitted with acute respiratory failure.

In this issue of Critical Care, Noveanu and colleagues [1] present intriguing observational data from the B-type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL)-II-ICU study evalu ating the association between beta-blocker therapy and mortality in 314 patients. Current dogma suggests a role for beta 2 agonism in the management of respiratory disease, most notably in asthma and chronic obstructive pulmonary disease (COPD). Beta 2 agonism was also recently investigated in the intensive care unit (ICU) for acute respiratory distress syndrome (ARDS) [2]. In addition to broncho dilatation and improvements in ventilatory mechanics, purported benefi cial eff ects include improved endothelial function, cytoprotection, an anti-infl am matory eff ect, increased surfactant production, and increased alveolar fl uid clearance [3]. However, despite these potential benefi cial eff ects, a large randomized controlled trial (RCT) of nebulized salbutamol in ARDS, which has been published only in abstract form, was stopped early for futility. In addition, there is ongoing controversy over the safety of long-acting beta 2 agonists in the management of asthma, and data suggest that beta 2 agonism may increase cardiovascular morbidity in those with risk factors for cardiovascular disease [4].
Th e BASEL-II-ICU study was a prospective randomized trial evaluating the eff ect of BNP-guided therapy versus standard care in ICU patients with acute respiratory failure [1]. Beta-blocker therapy instituted before or after ICU care was associated with improved mortality both in-hospital and at 1 year in multivariable analyses. Th is association was demonstrated in stratifi ed analyses for both cardiac and non-cardiac causes of acute respiratory failure. Among the factors limiting the generalizability of the data were the strict exclusion criteria, and many conditions commonly seen in the ICU, including sepsis, shock, renal failure, trauma, and prior cardiopulmo nary resuscitation, were excluded. Furthermore, only 13% of the cohort with acute respiratory failure received invasive mechanical ventilation, although 50% did receive non-invasive mechanical ventilation. It would also be useful to know what causes of death were modifi ed by beta 2 antagonism in acute respiratory failure. Another limitation of this observational data is that the models are at substantial risk of over-fi tting given that the authors evaluated 40 variables despite having only 51 in-hospital deaths [5].
Why might beta 2 agonism be ineff ective and antagonism be benefi cial in acute respiratory failure? First, many patients admitted with acute respiratory failure will suff er cardiac ischemia, a condition that potentially can be prevented with a beta-blocker [6]. Beta-receptors form an integral component of the sympathetic nervous system. Th e three beta-receptor subtypes help coordinate neural, circulatory, gastro intes tinal, digestive, urinary, hematological, metabolic, and immune function during the 'fi ght-or-fl ight response' induced by periods of stress. Initially, beta agonism diverts energy to vital organs and upregulates homeo static mechanisms such as platelet activation and coagu lation; however, prolonged beta adrenergic activa tion may prove detrimental. Data from RCTs have shown a benefi cial eff ect of beta-blocker therapy in the treatment of chronic heart failure [7]. Obser vational data suggest a possible benefi cial role for beta antagonism in trauma [8], including traumatic brain injury [9], and sepsis [10]. Two other studies have highlighted the benefi ts and risks of beta-blockers. Th e Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), an RCT of 45,852 acute myocardial

Abstract
Post hoc analyses from the B-type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL)-II-ICU study suggest an association between beta-blocker usage at admission and improved mortality in patients treated in the intensive care unit for acute respiratory failure. Although this evidence is encouraging, there is a need for a phase 2 proof-of-concept randomized controlled trial of beta-blocker therapy in patients admitted with acute respiratory failure.
infarction patients randomly assigned to a beta-blocker or placebo, surprised many clinicians when it demonstrated no impact on 30-day mortality [11]. Th is trial demonstrated less re-infarction and ventricular fi brillation with beta-blocker therapy, but these benefi cial eff ects were counterbalanced by an excess of death due to shock with beta-blocker therapy. Similarly, the Perioperative Ischemic Evaluation Study (POISE-1), an RCT of 8,351 non-cardiac surgery patients randomly assigned to a beta-blocker or placebo, demon strated that a peri operative beta-blocker prevented perioperative myo cardial infarction but increased the risk of death or stroke [12]. In POISE-1, the negative consequences of beta-blockade appeared to have occurred through an excess of clinically important hypotension. Th is excess is similar to the excess of cardiogenic shock witnessed with beta-blockade in COMMIT. Th ese data highlight the potential benefi ts of a beta-blocker but also the need to exclude patients in shock or at high risk of shock and to intensely monitor and manage hemo dynamic instability. Reassuringly, current data suggest that cardio-selective beta-blockers do not induce respira tory physiological impairment. In particular, beta-blockers are associated with improved outcomes in patients with COPD [13], a group theoreti cally at high risk from bronchospasm with beta antago nism.
Th e data emerging from beta adrenergic modulation in respiratory failure mirror those of statins. Statins were initially designed as cholesterol-lowering agents to reduce cardiovascular risk, and their pleiotropic eff ects were soon realized and matched by observational data showing associations between statin use and improved outcomes in cohorts with pneumonia and lung injury. Because a small prospective phase 2 RCT suggested potential benefi t [14], statins are being investigated as a therapy for ARDS in at least two large RCTs in Europe and the US. Now, an appropriate phase 2 proof-ofconcept RCT investigating beta 2 antagonism in acute respiratory failure with strict eligibility criteria would be an appropriate approach to defi ne the role of betablockers in acute respiratory failure.
Abbreviations ARDS, acute respiratory distress syndrome; BASEL, B-type natriuretic peptide for Acute Shortness of Breath Evaluation; BNP, B-type natriuretic peptide; COMMIT, Clopidogrel and Metoprolol in Myocardial Infarction Trial; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; POISE-1, Perioperative Ischemic Evaluation Study; RCT, randomized controlled trial.

Competing interests
AstraZeneca (London, UK) funded the drugs for the POISE-1 trial, for which PJD was the principal investigator. AstraZeneca manufactures metoprolol CR and beta-blockers. RMS and DFM declare that they have no competing interests.
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