Importance of the Kidney, Vessels, and Heart with Administration of β₂ Adrenergic Receptor Agonists in Patients Susceptible to Acute Respiratory Distress Syndrome

To the Editor:

We read with great interest the recent article by Perkins and colleagues demonstrating that the administration of a β₂-adrenergic agonist did not improve clinical outcomes but did result in lung fluid clearance in patients undergoing elective esophagectomy (1). This is one of several studies that have demonstrated a decrease in lung water after the administration of a β-agonist in patients with, or susceptible to, acute respiratory distress syndrome (ARDS) while finding no differences in clinical outcomes between drug and placebo (2, 3). Stimulation of the β₂-adrenergic receptors (β₂ARs) has been shown to result in lung fluid clearance, primarily through two distinct pathways: alveolar fluid clearance and relaxation of the pulmonary lymphatics (4). In animals, there is increased lung fluid clearance in response to circulating catecholamines to improve lung diffusion and gas exchange. This lung fluid clearance mechanism initially occurs with birth and carries on through adulthood such that stimulation of the β₂ARs results in activation of epithelial Na⁺ and Cl⁻ channels, which ultimately enhances the removal of fluid. Several important cell and animal studies have confirmed the importance of this β₂AR pathway on lung fluid clearance. Along these lines, as mentioned in the article by Perkins and colleagues, salmeterol has been shown to reduce the incidence of high-altitude pulmonary edema. In addition, β-blockade results in lung fluid accumulation after rapid fluid loading when combined with exercise (5). We have previously demonstrated that rapid fluid loading (30 ml/kg) results in lung fluid accumulation that is dependent on genetic variation of the β₂ARs (6). In addition, we have demonstrated that normobaric hypoxia results in lung fluid clearance (as determined through CT scanning, assessment of pulmonary function, and assessment of lung diffusion for carbon monoxide and nitric oxide) that is dependent on the amount of β₂ARs on lymphocytes (7). Collectively, these data demonstrate the importance of the β₂ARs on lung fluid regulation in humans.

Despite this important effect of β₂AR stimulation on lung fluid clearance, several studies have failed to demonstrate improvements in clinical outcomes (primarily mortality, ventilator-free days, and length of hospital stay) after the infusion or inhalation of short- and long-acting β-agonists (1, 2, 8, 9). Despite this lack of improvement in clinical outcomes, some of these studies have demonstrated a decrease in lung water with the administration of a β-agonist (1–3). We feel that there may be an important effect of these receptors on the kidney leading to this lack of improvement in clinical outcomes, along with alterations in cardiovascular function. In addition to our previous work demonstrating lung fluid accumulation that is dependent on genetic variation of the β₂AR, we have also found that renal sodium (Na⁺) handling after rapid fluid loading was dependent on this same genetic variation. These studies, along with many before them, demonstrate the importance of β₂ARs on renal Na⁺ reabsorption in humans. It is not surprising that the same pathway that results in lung fluid clearance (or Na⁺ absorption from the lung to the blood) is important in renal Na⁺ handling (or Na⁺ absorption from the kidneys to the blood); this conservation of a pathway that does the same thing in two different organs plays an important role in evolution. Toward this end, β₂ARs have been localized to the inner-medullary collecting duct and are thought to play a role in “fine-tuning” of renal Na⁺ handling. In support of this theory and related to the present study, at least one study published cumulative fluid balance data and demonstrated that the administration of albuterol resulted in a greater cumulative fluid balance when compared with placebo (8). Previous research has suggested that negative fluid balance is important in reducing mortality in patients with acute lung injury (10), and it has been established that conservative fluid management strategies are important in patients with ARDS (11). In their study, Perkins and colleagues do, in fact, state that they used a “fluid-conservative hemodynamic approach.” What is missing from our current understanding of β₂AR agonists in ARDS is data on renal Na⁺ handling (urine Na⁺, fractional excretion of Na⁺, etc.), which may allude to possible small differences between drug and placebo that may be important on clinical outcomes. It may seem unlikely that the administration of an inhaled drug can have an effect on the kidneys; however, we have recently observed that the administration of inhaled amiloride (which inhibits epithelial Na⁺) blocks lung fluid clearance and results in an unexpected but dramatic diuresis in healthy subjects exposed to normobaric hypoxia.

We have also demonstrated that the inhaled administration of albuterol (nebulized 2.5 mg in 3 ml normal saline) leads to an increase in cardiac output secondary to smaller increases in heart rate and stroke volume in healthy humans (12). In this same study we also demonstrated a drop in systemic vascular resistance and mean arterial blood pressure with albuterol. We hypothesize that the increase in heart rate in this study was secondary to a drop in blood pressure (that occurs through stimulation of the β₂AR on the vascular walls resulting in vasodilation and a drop in systemic vascular resistance) rather than through direct stimulation of these receptors because the β₁-adrenergic receptors are the primary receptor involved in the chronotropic control of the heart. This may also explain why more subjects on a β₂AR receive vasopressors, when compared with placebo, in previous studies (8). In contrast, 20% of the ventricular wall is comprised of β₂AR, and it is therefore plausible that the administration of these drugs results in increased cardiac output through direct increases in stroke volume. Therefore, there are possible important interactions between cardiovascular alterations and renal Na⁺ handling that should be further studied with this class of drugs.

To summarize, it is clear that the administration of a β-agonist results in lung fluid clearance, but, on average, there has been no positive effect on clinical outcomes in patients susceptible to ARDS. It has been hypothesized that this is due to cardiovascular changes after the administration of a β-agonist. Although this may play a role, it is also possible that the administration of an inhaled β-agonist stimulates renal Na⁺ reabsorption, causing fluid retention, which can be detrimental to patients with ARDS but not in other conditions in which the administration of these drugs has been shown to increase lung fluid clearance and improve clinical outcomes. It is possible, therefore, that a more aggressive diuretic strategy is needed while administering a β-agonist.