Metoprolol in Critically Ill Patients With COVID-19

Association Between Metoprolol and  168pg.net Prognosis of COVID-19 Patients
Journal of the American College of Cardiology, Volume seventy nine, Issue 1, 4–11 January 2022, Pages e7
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Cheng-Yi Wang, Ching-Yi Chen, Chih-Cheng Lai
More Analysis Needed to Minimize Confounding
Journal of the American College of Cardiology, Volume 79, Issue 1, 4–11 January 2022, Pages e9
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Charles de Roquetaillade, Jérémie Guillemin, Victor Beaucoté, Romain Barthelemy, Benjamin Glenn Chousterman
Beta-Blockers in COVID-ARDS
Journal of the American College of Cardiology, Volume 79, Issue 1, four–eleven January 2022, Pages e11
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Mourad H. Senussi
Beta-Blockers in the Critically Ill
Journal of the American College of Cardiology, Volume seventy eight, Issue 10, 7 September 2021, Pages 1012-1014
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Abstract
Background
Severe coronavirus ailment-2019 (COVID-19) can progress to an acute respiration misery syndrome (ARDS), which includes alveolar infiltration by way of activated neutrophils. The beta-blocker metoprolol has been proven to ameliorate exacerbated inflammation inside the myocardial infarction putting.

Objectives
The reason of this look at turned into to assess the effects of metoprolol on alveolar infection and on respiration feature in sufferers with COVID-19–related ARDS.

Methods
A general of 20 COVID-19 patients with ARDS on invasive mechanical air flow were randomized to metoprolol (15 mg each day for three days) or manipulate (no remedy). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/manage. The protection of metoprolol administration changed into evaluated by means of invasive hemodynamic and electrocardiogram tracking and echocardiography.

Results
Metoprolol administration became with out aspect consequences. At baseline, neutrophil content material in BAL did now not differ among agencies. Conversely, sufferers randomized to metoprolol had considerably fewer neutrophils in BAL on day four (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] inside the metoprolol and control agencies, respectively; P = 0.016). Metoprolol additionally reduced neutrophil extracellular traps content and different markers of lung inflammation. Oxygenation (PaO2:FiO2) drastically progressed after three days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = zero.003), whereas it remained unchanged in control topics. Metoprolol-handled sufferers spent fewer days on invasive mechanical air flow than those in the manipulate institution (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17).

Conclusions
In this pilot trial, intravenous metoprolol administration to sufferers with COVID-19–related ARDS was secure, reduced exacerbated lung infection, and advanced oxygenation. Repurposing metoprolol for COVID-19–associated ARDS seems to be a safe and cheaper strategy that can alleviate the load of the COVID-19 pandemic.

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Key Words
acute careARDSCOVIDmetoprolol
Abbreviations and Acronyms
ARDSacute respiratory misery syndromeBALbronchoalveolar lavageCOVID-19coronavirus sickness-2019ICUintensive care unitIMVinvasive mechanical ventilationNETneutrophil extracellular trap
Coronavirus ailment-2019 (COVID-19), due to extreme acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contamination, is an ongoing pandemic affecting greater than 145 million people worldwide and responsible for extra than three million deaths up to now. An anticipated 6%-18% of COVID-19 instances development to an acute breathing distress syndrome (ARDS) requiring in depth care unit (ICU) admission and invasive mechanical air flow (IMV) (1). There is currently a lack of precise healing procedures for COVID-19–related ARDS.

In the early stages of SARS-CoV-2 contamination, the host immune system is activated to dam sickness progression. However, in some instances speedy replication of SARS-CoV-2 inside the respiration tract triggers an exacerbated inflammatory response and a cytokine hurricane (2). This situation leads to development to ARDS collectively with other scientific headaches, such as septic surprise, microthrombi, coagulopathy, and a couple of organ dysfunction (3).

ARDS of different etiologies (four), such as SARS-CoV-2 infection (5,6), is fantastically dependent on the motion of neutrophils. Activated neutrophils make a contribution to alveolar injury by liberating prestored inflammatory mediators (reactive oxygen species and myeloperoxidase [MPO]) and by interacting with different cells, together with platelets, to set off microthrombi. In addition, the formation of neutrophil extracellular traps (NETs) and enormously injurious histones activates the inflammasome and triggers the release of seasoned-inflammatory cytokines (7). NETs released from alveolar-infiltrated activated neutrophils increase pulmonary inflammation and serum ranges of proinflammatory cytokines, main to significant lung damage and microthrombotic events in COVID-19 sufferers (2,three,8,9).

Despite the large international effect of COVID-19, there is a scarcity of effective remedies to prevent transition from moderate to excessive disease and to enhance prognosis. Given the extreme stress COVID-19 is putting on ICUs worldwide, there may be an pressing want to discover treatment plans to reduce the quantity of days in the ICU. The maximum sought-after interventions are the ones capable of mitigate COVID-19–associated immune dysregulation (10). An attractive candidate technique is to use host-directed treatment options, which have emerged in latest years as an adjuvant method to restrict harm in the course of infectious or sterile exacerbated inflammation.

Beta-adrenergic receptor antagonists (β-blockers) had been used for plenty a long time to deal with cardiovascular situations including high blood pressure, arrhythmias, and myocardial infarction (11). Observational retrospective studies have installed a hyperlink among β-blocker therapy and elevated survival in significantly ill patients because of specific situations, together with sepsis (12, thirteen, 14), acute breathing failure (15), severe disturbing mind harm (sixteen,17), and others (18,19). Recent findings show that the β1-selective blocker metoprolol has a direct impact on neutrophils, dampening their deleterious consequences throughout exacerbated irritation (20). In the context of ischemia/reperfusion (acute myocardial infarction), metoprolol focused on of neutrophils has been shown to have a robust cardioprotective effect, both in animal fashions and in patients (20, 21, 22, 23). More lately, our group verified that metoprolol (however no longer other clinically to be had intravenous β-blockers) abrogates neutrophil-pushed exacerbated infection, neutrophil-platelet interaction, and NETs formation in a mouse version of LPS-caused acute lung harm (24). These experimental statistics precipitated us to analyze whether remedy with intravenous (IV) metoprolol should ameliorate lung irritation—and ultimately enhance prognosis—in patients with COVID-19–associated ARDS.

Methods
Study design and populace
The MADRID-COVID (Intravenous Metoprolol in Respiratory Distress Due to COVID-19) pilot trial became authorised via the Fundación Jiménez Díaz University Hospital ethics committee (Eudract registry number 2020-002310-41). All sufferers, or a close relative, gave written consent to participate. Inclusion criteria have been age 18-80 years, rt-PCR–confirmed SARS-CoV-2 infection (in both nasal swab or bronchoalveolar lavage), invasive mechanical air flow ≤seventy two hours, coronary heart charge ≥60 beats/min, and invasive systolic blood stress ≥a hundred and twenty mm Hg. Exclusion criteria blanketed prolonged health center admission (>five days) earlier than enrollment, concomitant acute heart failure, left ventricular ejection fraction <50%, right ventricular systolic dysfunction, concomitant pulmonary embolism, moderate-severe peripheral artery disease, moderate-severe valvular heart disease, moderate-severe COPD, or active treatment with β-blockers before enrollment. A total of 20 patients with ARDS secondary to SARS-CoV-2 infection under IMV were enrolled and randomized to IV metoprolol tartrate (Recordati) (3 × 5 mg boluses, 2 minutes apart, daily for 3 days; n = 12) or control (no treatment; n = 8). Two minutes after each bolus, blood pressure and heart rate were measured, and if they were above the limits set, the next bolus was injected.

Randomization was stratified by age (≤59 years vs >fifty nine years), records of hypertension (yes/no), and circulating neutrophil counts (<6,000 vs ≥6,000). Bronchoalveolar lavage (BAL) fluid and blood samples were received from sufferers at randomization (baseline) and 24 hours after the third metoprolol dose/manage (day four). The essential take a look at goal turned into to assess the effect of metoprolol on inflammatory markers (specifically neutrophil infiltration and NETs). The most important secondary desires were to assess the effect of metoprolol on days on invasive mechanical air flow and days inside the ICU after randomization, in addition to pulmonary feature. The main protection outcome measure became hemodynamic complications (cardiogenic surprise, severe hypotension, or extreme bradycardia/atrioventricular block).

Because this turned into a pilot trial, pattern size changed into calculated based totally at the capacity of figuring out changes in lung infection (neutrophil infiltration). Based on previous experimental research, we speculated that 20 patients would be enough to hit upon a huge organic effect of metoprolol on this context.

Flow cytometry of BAL samples
For waft cytometry (FCM) studies, BAL samples (eight mL) were previously inactivated with 2 mL of a cell antigen stabilization reagent containing formaldehyde (TransFix, Cytomark Ltd). Samples had been then centrifuged (5 mins at 540g), the supernatant discarded, and the cell pellet resuspended in 200 μL phosphate-buffered saline. Afterwards, one hundred μL of cellular suspension was stained for 15 mins at room temperature with the subsequent color combination: antihuman CD15-fluorescein isothiocyanate, CD33-phycoerythrin, and CD3-V-450 and CD45-V-500 (Becton Dickinson Biosciences). After staining, 2 mL of FACS lysing solution (Becton/Dickinson Biosciences) become introduced, and after 5 minutes incubation, the sample turned into centrifuged and resuspended in 100 μL phosphate-buffered saline. Before acquisition, the fluorescent dye DRAQ5 (Biostatus Limited) (25,26) and Perfect-COUNT microspheres (Cytognos SL) (27) were brought for the choice of DNA-superb cells and cellular count, respectively. Samples had been run on a FACSCanto II waft cytometer (Becton Dickinson Biosciences) geared up with FACSDiva software (Becton Dickinson Biosciences), and information was received approximately all occasions corresponding to nucleated cells present within the stained sample aliquot.

Data have been analyzed with INFINICYT software (Cytognos SL). FCM analysis protected a first-step identification of nucleated cells by using DRAQ5 staining. Leukocyte populations had been recognized with a gating method based totally on ahead scatter, facet scatter, and CD45 expression. Neutrophils and macrophages had been diagnosed from their surprisingly higher mild-scattering residences, their unique sample o

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