More Analysis Needed to Minimize Confounding.

We read with great interest the pilot study by Clemente-Moragón et al (1) investigating the effect of the β-blocker metoprolol on the clinical outcomes of critically ill patients with COVID-19. Although Clemente-Moragón et al (1) demonstrated that intravenous metoprolol provides additional benefits in reducing lung inflammation, improving oxygenation, and shortening invasive mechanical ventilation time for these patients with COVID-19–associated acute respiratory distress syndrome (ARDS), we have several serious concerns about some residual confounding factors.

First, although the study and control group had similar baseline characteristics (age, sex, body mass index, comorbidities, previous treatment with a renin-angiotensin system inhibitor, anticoagulant, corticosteroid, melatonin, and acetylcysteine), the use of other anti-inflammatory agents was unclear, such as anti–interleukin (IL)-6 or the Janus kinase inhibitor. These agents could significantly influence both the outcome and the lung inflammation of patients with COVID-19 (2,3). In addition, the effect of statin on lung inflammation has been demonstrated in the animal sepsis model (4). Therefore, the use of these medications, including anti–IL-6, Janus kinase inhibitor, and statin, should be clarified in this study.

Second, significant associations between the release of neutrophil extracellular traps and bacterial and viral infections have been observed. For patients who are critically ill with COVID-19, coinfection is not uncommon (5). Therefore, the confounding effect of coinfection among COVID-19 patients with ARDS cannot be neglected in this study.

Finally, the no–double-blind study design may be associated with the bias in the care of the study participants, such as intensive care unit stay or extubation.

In conclusion, before these issues are clarified, this study’s findings should be interpreted cautiously.