ARDS involves injury to the lung tissue due to inflammation and the accumulation of fluid in the alveoli, the air sacs in the lungs where the exchange of gases occurs with blood vessels.
The accumulation of fluids in the alveoli due to leaking blood vessels limits the lungs’ ability to supply oxygen to the rest of the body. ARDS thus requires admission to the intensive care unit (ICU) and invasive mechanical ventilation to compensate for limited lung function.
A recent study, which appears in the Journal of the American College of Cardiology, reports that metoprolol can reduce lung inflammation and improve respiratory function in people with COVID-19-induced ARDS. Metoprolol is a common beta-blocker designed to treat high blood pressure, and it may provide an inexpensive treatment for severe COVID-19.
Excessive immune response
The infection by SARS-CoV-2 activates an immune response that aims to block the progression of the disease.
However, in some cases of severe COVID-19, uncontrolled and excessive activation of the immune system can occur in response to the rapidly replicating virus, causing ARDS and other complications, such as organ failure.
The initial damage to the tissues due to a SARS-CoV-2 infection results in the production of signaling molecules called cytokines. The cytokines and other molecules released from the damaged tissues recruit immune cells, such as neutrophils and macrophages, to the lungs and result in the activation of these cells.
The excessive production of cytokines, which scientists term a cytokine storm, and the overactivation of neutrophils and macrophages are hallmarks of ARDS associated with severe COVID-19.
After recruitment to the lungs, the activated neutrophils and macrophages themselves produce cytokines and contribute to the cytokine storm.
Besides cytokines, activated neutrophils release granules and produce neutrophil extracellular traps (NETs) that help kill viruses and bacteria. NETs are web-like structures that consist of DNA and proteins that immobilize bacteria and viruses.
While activated neutrophils play a critical role in defending the body from the virus, hyperactivation of neutrophils can cause damage to the lung tissue and blood vessels, as observed in ARDS. Consistent with this, the number of neutrophils in the lungs correlates with the severity of COVID-19 and can predict the risk of complications, such as ARDS.
These data suggest that neutrophils could be a promising target for reducing lung inflammation in people with severe COVID-19.
Beta-blockers for curbing immune response
Beta-blockers are a class of drugs that block the effects of the two hormones that mediate the fight-or-flight response: epinephrine and norepinephrine. Doctors commonly use beta-blockers to treat cardiovascular conditions.
Dr. Sverre Kjeldsen, professor at the University of Oslo in Norway, who was not involved in the study, told Medical News Today:
“Very sick COVID-19 patients are under enormous stress — they have the strongest activation of the sympathetic nervous system that you can imagine. Release of huge amounts of noradrenaline (norepinephrine) and adrenaline (epinephrine) do damage to almost every organ, including the lungs, and treatment with metoprolol, a beta-1 selective adrenoreceptor blocker, at least partially inhibits the damaging effects of these plasma catecholamines.”
In an editorial published last year, Dr. Kjeldsen also notes that beta-blockers could be candidates for the treatment of patients with severe COVID-19 due to the drugs’ ability to reduce inflammation and combat fluid accumulation in the lungs.
The team led by researchers at the Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) has now shown that the beta-blocker metoprolol can reduce lung inflammation and improve blood oxygen levels. The results come from a small pilot study involving COVID-19 patients with ARDS.
Specifically, the team found that metoprolol reduced neutrophil count in the lungs and resulted in lower levels of neutrophil activation.
The study’s first author, Agustín Clemente-Moragón, a Ph.D. fellow at CNIC, told MNT:
“In the last years, our research group (the Translational Laboratory for Cardiovascular Therapy and Imaging) at the Spanish National Centre for Cardiovascular Research (CNIC) has generated a vast knowledge about the disruptive and unique role of the beta-blocker metoprolol against neutrophil-driven inflammatory responses.”
“These experimental data prompted us to investigate in the MADRID-COVID pilot trial whether 3-day intravenous metoprolol administration (15 milligrams each day) could result in promising outcomes in patients with COVID-19-associated ARDS.”
Study co-author Dr. Valentin Fuster, CNIC general director and director of Mount Sinai Heart, told MNT: “We have very little therapy that has been shown to be of significance at this late stage of the disease. […] [T]he significance of this study is that, if this is correct, now have a new approach with a very cheap drug, that is very affordable.”
The study involved 20 COVID-19 patients with ARDS who had been on mechanical ventilation for fewer than 3 days. The patients were randomized to receive either intravenous (IV) metoprolol, that is, administered directly into a vein, or standard care in the control group.
The experimental group consisted of 12 patients who received IV metoprolol daily for 3 days, whereas the remaining 8 patients, in the control group, received standard care.
The researchers collected blood samples and fluid from the lungs of the patient before the onset of treatment and on the fourth day, 24 hours after the last dose of metoprolol.
They found that metoprolol administration, compared with standard care, resulted in a reduction in the number of specific immune cells in the fluid samples collected from the lungs of the COVID-19 patients.
Specifically, there was a decrease in the number of neutrophils in the fluid samples collected from the lungs of the patients who received metoprolol.
Moreover, metoprolol treatment reduced the level of pro-inflammatory cytokines, such as MCP-1 in the lungs and IL-8 in the blood.
The researchers also observed a drop in markers associated with the production of NETs by neutrophils after metoprolol treatment, which indicates a reduction in neutrophil activation.
These results suggest that metoprolol can reduce lung inflammation and limit the recruitment and activation of neutrophils in COVID-19 patients with ARDS.
Investigating the impact of metoprolol on clinical outcomes, the researchers found that metoprolol administration improved blood oxygen levels.
Although there was a link between metoprolol treatment and fewer days on mechanical ventilation and earlier discharge from intensive care, these results did not reach statistical significance.
Notably, there were no side effects associated with metoprolol treatment.
The authors conclude that the “[IV] administration of the clinically approved beta-blocker metoprolol to critically ill patients with ARDS caused by COVID-19 is safe and disrupts the exacerbated lung inflammation associated with the disease.”
Describing the strengths of the study, Clemente-Moragón said, “Metoprolol is a clinically available and cheap drug (daily treatment costs less than $3), which could potentially reduce the extreme pressure COVID-19 is placing on ICUs worldwide, even in countries where vaccines are not rolled out to a large extent yet.”
“In addition, this treatment could be beneficial for all patients with COVID-19 without contraindications for metoprolol (with only a few patients not being good candidates to receive it), and this benefit could possibly be greater if started before intubation,” he added.
In an editorial accompanying the article, Dr. Mourad Senussi commends the authors for the study and writes, “Although a small-sized, single-center study amid a multitude of others exploring potential treatment modalities for COVID-19, this study uses a readily available, safe, and inexpensive medication; has a simple study design; and, most importantly, shows biological plausibility.”
Dr. Senussi is the medical director of the cardiac care unit at Baylor St. Luke’s Medical Center in Houston, TX, and was not involved in the research.
Limitations and caveats
The researchers acknowledge that the study had a few limitations. Firstly, they note that the study had a small sample size and took place at a single location. Furthermore, there was potential for bias, because the doctors were aware of which patients belonged to the treatment and control groups.
To address these concerns, Dr. Fuster said that they were in the process of preparing for a larger randomized controlled trial to further test the ability of metoprolol to reduce lung inflammation in patients with COVID-19-associated ARDS.
“Although all these data need to be corroborated in a larger trial, our recent study could be enough to consider its use in some patients, such as young patients admitted to ICU with severe COVID-19,” said Clemente-Moragón.
The authors also note, “we cannot rule out a selection bias resulting in patients with very poor condition according to physicians not considered for inclusion.”
Furthermore, Dr. Senussi noted that caution must be exercised while interpreting the study results. Speaking to MNT, he said:
“This is not a treatment per se of COVID-19 but rather a means to attenuate the intense inflammatory response that has beneficial downstream effects. This medication was given early during the course of the illness to critically ill patients on ventilators. Patients who were very sick and unstable could not receive this medication,” Dr. Senussi continued.