Response

To the Editor:

We thank Drs Orso and Copetti for their comments on our recent review in CHEST, summarizing the current understanding of molecular mechanisms and clinical implications of septic cardiomyopathy.¹ We agree with the authors that, among many factors/mechanisms causing sepsis-induced cardiac dysfunction, adrenergic overstimulation, due to endogenous elevated catecholamine levels and exogenous catecholamine administration, is thought to play a debatable role in the pathophysiology of septic cardiomyopathy. Indeed, blockade of β₁-adrenergic receptor signaling and/or enhancement of cardiac β₂-adrenergic receptor signaling could be potential therapeutic strategies to inhibit inflammation in the septic heart.² Of note, despite the beneficial effects shown by experimental and a few (small) clinical trials, β-adrenergic blockade therapy in septic shock is not yet established, as results are conflicting³: In particular, landiolol, a selective β₁-blocker with a 4-min half-life, showed detrimental effects on cerebral oxygenation when therapy is aimed at attaining a certain heart rate.⁴ Moreover, another study revealed that enteral metoprolol (a selective β₁-blocker) therapy in patients with septic myocardial depression leads to a significant increase in the required doses of catecholamines.⁵ In our opinion, further experimental and clinical research is required to elucidate a valid strategy to target the hyperactivation of the sympathetic nervous system during septic shock. This clearly includes not only β-adrenergic receptors but also α-adrenergic receptors (eg, the α₂-adrenergic receptor), as there are increasing experimental data showing that α₂-adrenergic blockade attenuates septic cardiomyopathy by increasing cardiac norepinephrine concentration and inhibiting cardiac endothelial activation.⁶ We were encouraged to perform a concise review including treatment advances based on randomized controlled clinical trials, and thus our review focused on treatment strategies with existing robust clinical evidence. As mentioned in our article, we agree with Drs Orso and Copetti that adequately powered and well-performed randomized controlled trials are necessary to clarify the debatable role of β-blockers in septic cardiomyopathy therapy.