key: cord-1014863-vbsxtpqo authors: Clemente-Moragón, Agustín; Martínez-Milla, Juan; Oliver, Eduardo; Santos, Arnoldo; Flandes, Javier; Fernández, Iker; Rodríguez-González, Lorena; Serrano del Castillo, Cristina; Ioan, Ana-María; López-Álvarez, María; Gómez-Talavera, Sandra; Galán-Arriola, Carlos; Fuster, Valentín; Pérez-Calvo, César; Ibáñez, Borja title: Metoprolol in Critically Ill Patients With COVID-19 date: 2021-09-07 journal: J Am Coll Cardiol DOI: 10.1016/j.jacc.2021.07.003 sha: 68c8bee9c6b123d3883d965a9aa7bcbef4fd009b doc_id: 1014863 cord_uid: vbsxtpqo BACKGROUND: Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting. OBJECTIVES: The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19–associated ARDS. METHODS: A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography. RESULTS: Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO(2):FiO(2)) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17). CONCLUSIONS: In this pilot trial, intravenous metoprolol administration to patients with COVID-19–associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19–associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic. C oronavirus disease-2019 (COVID- 19) , caused by severe acute respiratory syndrome-coronavirus-2 (SARS- infection, is an ongoing pandemic affecting more than 145 million people worldwide and responsible for more than 3 million deaths to date. An estimated 6%-18% of COVID-19 cases progress to an acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) (1) . There is currently a lack of specific therapies for COVID-19-associated ARDS. In the early stages of SARS-CoV-2 infection, the host immune system is activated to block disease progression. However, in some cases rapid replication of SARS-CoV-2 in the respiratory tract triggers an exacerbated inflammatory response and a cytokine storm (2) . This situation leads to progression to ARDS together with other clinical complications, such as septic shock, microthrombi, coagulopathy, and multiple organ dysfunction (3) . CoV-2 infection (5, 6) , is highly dependent on the action of neutrophils. Activated neutrophils contribute to alveolar injury by releasing prestored inflammatory mediators (reactive oxygen species and myeloperoxidase [MPO] ) and by interacting with other cells, such as platelets, to induce microthrombi. In addition, the formation of neutrophil extracellular traps (NETs) and highly injurious histones activates the inflammasome and triggers the release of proinflammatory cytokines (7) . NETs released from alveolar-infiltrated activated neutrophils increase pulmonary inflammation and serum levels of proinflammatory cytokines, leading to extensive lung damage and microthrombotic events in COVID-19 patients (2, 3, 8, 9) . Despite the massive worldwide impact of COVID-19, there is a shortage of effective therapies to prevent transition from moderate to severe disease and to improve prognosis. Given the intense pressure COVID-19 is placing on ICUs worldwide, there is an urgent need to identify therapies to reduce the number of days in the ICU. The most sought-after interventions are those able to mitigate COVID-19-associated immune dysregulation (10). An attractive candidate approach is to use host-directed therapies, which have emerged in recent years as an adjuvant strategy to limit damage during infectious or sterile exacerbated inflammation. Beta-adrenergic receptor antagonists (b-blockers) have been used for many decades to treat cardiovascular conditions such as hypertension, arrhythmias, and myocardial infarction (11). Observational retrospective studies have established a link between b-blocker therapy and increased survival in critically ill patients caused by different conditions, such as sepsis (12) (13) (14) , acute respiratory failure (15) , severe traumatic brain injury (16, 17) , and others (18, 19) . Recent findings show that the b1-selective blocker metoprolol has a direct effect on neutrophils, dampening their deleterious effects during exacerbated inflammation (20) . In the context of ischemia/ reperfusion (acute myocardial infarction), metoprolol targeting of neutrophils has been shown to have a strong cardioprotective effect, both in animal models and in patients (20) (21) (22) (23) Clemente-Moragón et al. Given the cardiovascular effects of metoprolol, patients were monitored invasively and by echocardiography before and on every day after metoprolol injection/control. As expected, metoprolol significantly reduced heart rate (P < 0.01) and invasively measured systolic blood pressure (P < 0.05), although both remained within the physiological range (Supplemental Table 2 ). Echocardiography showed no deterioration of cardiac function parameters after metoprolol treatment (Supplemental Table 3 ). Overall, metoprolol intravenous administration was shown to be safe and without side effects in severe COVID-19 patients with ARDS on IMV. Figure 2C ). All patients were discharged from the ICU, and 1 patient in each group died before hospital discharge. The COVID-19 pandemic and associated ARDS is placing an immense burden on health care systems. 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