The absorption of excess alveolar fluid is an ATP-dependent process involving vectorial Na⁺ transport out of the alveoli via the apical Na⁺ and Cl⁻ channels and basolateral Na⁺-K⁺ ATPases in the alveolar epithelium [14]. It has been demonstrated, in experimental models, that Na⁺ and Cl⁻ transport is “upregulated” by β₂-agonists via an increase in intracellular cAMP caused by β₂-adrereceptor stimulation leading to an osmotic gradient across the alveolar epithelium and subsequent movement of fluid [14, 15].

In ARDS there is a damage to alveolar barrier with subsequent alveolar flooding leading to refractory hypoxemia. It has been shown that β₂-agonists reduce neutrophil sequestration, activation, and production of inflammatory cytokines. There is some in vivo evidence of reduced permeability of alveolar capillaries and in vitro evidence of enhanced wound repair in epithelial monolayers [15, 16]. These findings suggest that β₂-agonists could potentially maintain alveolar-capillary integrity and therefore decrease alveolar flooding and degree of hypoxemia [15, 16].

At the onset of ARDS, there is an increased neutrophil activation and recruitment suggesting a possible correlation between neutrophil activation and development of the syndrome [15, 16]. The interaction between β₂-agonists and inflammatory response is not fully understood. It has been shown that β-agonists-induced elevation in intracellular cAMP in neutrophils inhibits stimulated neutrophil adhesion to bronchial epithelial cells [17]. Treating ARDS patients with intravenous β₂-agonist, although it increases the number of circulating neutrophils, has no effect on alveolar neutrophil number, neutrophil activation, or alveolar inflammation [18].

Recent evidence suggests that routine use of β₂-agonists in mechanically ventilated ARDS patients is unlikely to be beneficial and in fact could worsen outcomes and leaves us wondering why β₂-agonist therapy has been ineffective in improving or preventing ARDS [8–10].

One potential explanation is that the myocardial stimulation caused by β2-agonists could lead to increased myocardial oxygen demand with adverse effects on cardiac function, especially in ARDS patients with refractory hypoxemia. It is also possible that critically ill patients with underlying coronary artery disease experience adverse cardiac events, including occult ischemia [13]. The cardiovascular effects of β₂-agonists may therefore offset their potential benefit on alveolar edema clearance.

The vasodilatory effect of some β₂-agonists (e.g., albuterol), especially when administered via intravenous route, and the increase in cardiac output cause an increase in ventilation/perfusion mismatch and could potentially have an adverse effect on outcomes [13].

Finally, β₂-agonists may have adverse off-target effects including β₂-adrenergic receptor-mediated increase in cytokines and pro-inflammatory effects [19].

Beta₂-agonists produce smooth muscle relaxation and bronchodilation caused by activation of adenyl cyclase that will produce cAMP. Of note, β₂-adrenoreceptors are also present in submucosal glands, vascular endothelium, mast cells, circulating inflammatory cells such as eosinophils and lymphocytes, type II pneumocytes, and cholinergic ganglia [11]. They are the mainstay of current management of airflow obstruction (chronic obstructive pulmonary disease and asthma) and are divided into three groups: short acting (e.g., albuterol, fenoterol, terbutaline), long acting (e.g., formoterol, salmeterol), and ultra-long acting (e.g., indacaterol, olodaterol, vilanterol, carmoterol) [20]. Short-acting β₂-agonists have a 3–6 h duration of action, whereas that of the long-acting β₂-agonists can exceed 12 h. These agents also differ significantly in their intrinsic efficacy which depends on their affinity and potency [20].

β₂-agonists can be administered via oral, parenteral, or inhalational route. Gut absorption is incomplete and subjected to a significant first-pass effect, while after inhalation or intravenous administration, short-acting β₂-agonists have rapid onset of action (e.g., 1–5 min for albuterol, 30–45 min for salmeterol). The onset of action is related to the lipophilicity of these agents and their ability to activate β₂-adrenergic receptors in their aqueous phase (albuterol and formoterol) [11, 20].

Albuterol, the most frequently prescribed agent in the critical care setting, is 10 % protein bound and has a half-life of 4–6 h. It is metabolized in the liver to the inactive 4-O-sulfate, which is excreted along with albuterol in the urine [11, 20, 21].

Adverse effects associated with β₂-agonists use include: tachyarrhythmias, transient hypoxemia despite bronchodilation (due to ventilation/perfusion mismatch), hyperglycemia, hypokalemia, fine tremor of skeletal muscles, headaches, nausea, and sleep disturbances [20].

The pharmacology and therapeutics of β₂-agonists are summarized in the clinical summary.

Although preliminary data suggested that the use of β₂-agonist in the context of ARDS could potentially accelerate alveolar edema clearance and have beneficial anti-inflammatory and immunomodulatory effects, robust prospective clinical trials demonstrated that the use of β₂-agonists in ARDS patients is unlikely to be beneficial and could worsen outcomes. Routine administration of β₂-agonists in mechanically ventilated critically ill patients with ARDS should therefore be avoided.