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In a small study, intravenous administration of the beta-blocker metoprolol to critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS) safely blunted lung inflammation associated with the disease.
Metoprolol administration also resulted in better oxygenation and fewer days on intensive mechanical ventilation (IMV) and in the intensive care unit (ICU), compared with no treatment.
These data suggest that metoprolol repurposing for the treatment of ARDS in COVID-19 patients is a safe and inexpensive strategy with the potential to improve outcomes, the researchers say.
"Metoprolol repurposing for the treatment of ARDS associated with COVID-19 is a safe and cheap intervention that can help to alleviate the massive personal and healthcare burden associated with the pandemic," they conclude.
The results, from the MADRID-COVID pilot trial from Agustin Clemente-Moragon, BSc, Centro National de Investigaciones Cardiovasculares, Madrid, Spain, and colleagues, were published online August 30 in the Journal of the American College of Cardiology.
In previous work, the researchers showed that metoprolol, but not other clinically available intravenous beta-blockers, abrogates neutrophil-driven exacerbated inflammation, neutrophil-platelet interaction, and formation of neutrophil extracellular traps (NETs) in a mouse model of acute lung injury.
These results prompted the current pilot trial in 20 patients, ages 18 to 80 years, with COVID-19-associated ARDS.
Randomization was stratified by age (59 and younger vs 60 and older), history of hypertension (yes or no), and circulating neutrophil counts (<6000 vs ≥6000). Bronchoalveolar lavage (BAL) fluid and blood samples were obtained from patients at randomization and 24 hours after the third metoprolol dose in the treatment group, and on day 4 in controls.
Because of the cardiovascular effects of metoprolol, patients were monitored invasively and by echocardiography, the authors note.
As expected, metoprolol significantly reduced heart rate (P < .01) and systolic blood pressure (P < .05), although both remained within the physiological range.
Echocardiography showed no deterioration of cardiac function after metoprolol treatment.
To assess the ability of metoprolol to address neutrophil-mediated exacerbated lung inflammation, the researchers analyzed leukocyte populations in BAL samples by flow cytometry at baseline and on day 4.
At baseline, the metoprolol and control groups showed no differences in BAL neutrophil content. But on day 4, after 3 days of treatment with metoprolol, neutrophil content was significantly lower in the metoprolol group (median: 14.3 neutrophils/µl) than in the control group (median: 397 neutrophils/µl).
Metoprolol-treated patients also had lower total inflammatory-cell content and lower monocyte/macrophage content. Lymphocytes did not differ between the groups.
The investigators also explored the impact of metoprolol on the chemokine, monocyte chemoattractant protein-1 (MCP-1), as it has been shown to promote pulmonary fibrosis in late-stage ARDS.
They found that MCP-1 was significantly attenuated after 3 days of metoprolol treatment. At baseline, the median MCP-1 level was 298 pg/mL; on day 4 after metoprolol, it was 203 pg/mL (P = .009).
MCP-1 levels remained unchanged in control patients.
An Elegant Study
In an accompanying editorial, Mourad H. Senussi, MD, assistant professor at Baylor College of Medicine, Houston, Texas, writes: "Although the study has a small sample size, we commend the authors, who attempt to shed light on the important pathophysiologic underpinnings that help establish biological plausibility for this inexpensive, safe, and widely available medication."
In an interview with Medscape Medical News, Senussi added that metropolol is not itself something primarily used to treat COVID-19 per se. "Rather, the drug blunts the sympathetic–host response. There is a fine balance between that sympathetic surge that is helpful to the body, and then a sympathetic surge that if left unchecked, can lead to significant damage. And so, I think this study really shows that medications like metoprolol can help blunt that initial sympathetic effect."
A larger study is "absolutely" warranted, he added, "This is a drug that is readily available, safe, and inexpensive. The study design here was simple and most importantly, showed biological plausibility."
Senussi also noted that, although the benefit was noted in COVID-19 patients, the study sets the groundwork for further research in the use of beta-blockade in the critically ill.
"Further studies are needed to elucidate and identify where along the inflammatory spectrum these critically ill patients lie, which patients would benefit from beta-blockers, and at what timepoint during their hospital stay."
The MADRID-COVID authors and Senussi have disclosed no relevant financial relationships.