ABSTRACT
Background: The coronavirus-related disease (COVID-19) is mainly characterized by a respiratory involvement, with few available therapeutics for critically cases. The renin-angiotensin system (RAS) has a relevant role in the pathogenesis of COVID-19, as the virus enter host's cells via the angiotensin-converting enzyme 2 (ACE2) and RAS disequilibrium promote inflammation and fibrosis. Exogenous angiotensin-(1-7) might modulate RAS in COVID-19 patients; however, no data on its safety are available in this setting. Methods: This investigator-initiated, open label, phase I clinical trial was conducted to test the safety of intravenous administration of Angiotensin-(1-7) in severe COVID-19 patients admitted in two intensive care units (ICU) in Belo Horizonte, Brazil. In addition to standard of care, intravenous administration of Angiotensin-(1-7) was started at 5 mcg/Kg*day and increased to 10 mcg/Kg*day after 24 hours and continued for a maximum of 7 days or until ICU discharge. The rate of serious adverse events (SAEs) served as the primary outcome of the study. Results: Between August and December 2020, 28 patients were included (mean age of 55.8 + or -12.0 years). All but one patient underwent dose escalation after 24 hours and 8 (28.5%) received the treatment until day 7. No significant differences in mean blood pressure and heart rate were observed before and after the initiation of the drug. During the period of intervention, 5/28 (17.8%) patients required vasopressors, 4 at low dose norepinephrine (i.e. <0.05 mcg/kg*min), while one patient required higher doses because of septic shock. One patient presented with sinus bradycardia, which was considered possibly related to the study drug and resolved after discontinuation. Six patients (21.4%) died before ICU discharge. Conclusions: Intravenous infusion of Angiotensin-(1-7) up to 10 mcg/Kg*day was safe in severe COVID-19 patients and could represent a potential therapeutic strategy in this setting.
Subject(s)
Fibrosis , Shock, Septic , Inflammation , Drug-Related Side Effects and Adverse Reactions , COVID-19 , BradycardiaABSTRACT
The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes. One of its key components, the angiotensin-converting enzyme 2, has been identified as the entry point of the SARS-CoV-2 virus into the host cells, so many studies have been devoted to study RAS dysregulation in COVID-19. Here we discuss the alterations of the regulatory RAS axes due to SARS-CoV-2 infection on the basis of a series of recent clinical and experimental analyzes, which, for example, quantify the levels and activity of RAS components, in order to disentangle the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. Finally, we discussed the effects of some RAS-targeting drugs, and how they could potentially contribute to restore the normal RAS functionality and minimize COVID-19 severity.
Subject(s)
COVID-19ABSTRACT
The mono-carboxypeptidase Angiotensin-Converting Enzyme 2 (ACE2) is an important player of the renin-angiotensin system (RAS). ACE2 is also the receptor for SARS-CoV-2, the new coronavirus that causes COVID-19. It has been hypothesized that following SARS-CoV-2/ACE2 internalization Ang II level would increase in parallel to a decrease of Ang-(1-7) in COVID-19 patients. In this preliminary report, we analyzed the plasma levels of angiotensin peptides in 19 severe COVID-19 patients and 19 non-COVID-19 volunteers. Unexpectedly, a significant increase in circulating Ang-(1-7) and lower Ang II plasma level were found in critically ill COVID-19 patients. Accordingly, an increased Ang-(1-7)/ Ang II ratio was observed in COVID-19 suggesting a RAS dysregulation toward an increased formation of Ang-(1-7) in these patients.
Subject(s)
COVID-19 , Chronobiology DisordersABSTRACT
Introduction: One of the possible mechanisms by which the new coronavirus (SARS-Cov2) could induce brain damage is the impairment of cerebrovascular hemodynamics (CVH) and intracranial compliance (ICC) due to the elevation of intracranial pressure (ICP). The main objective of this study was to assess the presence of CVH and ICC alterations in patients with COVID-19 and evaluate their association with short-term clinical outcome.Methods: 50 consecutive critically ill COVID-19 patients were studied with transcranial Doppler (TCD) and a non-invasive monitoring of ICC. Subjects were included upon ICU admission; CVH was evaluated using mean flow velocities in the middle cerebral arteries (mCBFV), pulsatility index (PI) and estimated cerebral perfusion pressure (eCPP) while ICC was assessed by using the P2/P1 ratio of estimated ICP curve (B4C device). The primary composite outcome was unsuccessful weaning from respiratory support or death on day 7.Results: At the first assessment (n= 50) only P2/P1 (1.20 [1.00-1.28] vs. 1.00 [0.88-1.16]; p=0.03) and eICP (14 [11-25] vs. 11 [7-15] mmHg; p=0.01) were significantly higher among patients with unfavorable outcome (UO) than others. Patients with UO had a significantly higher CVH/ICC score (9 [8-12] vs. 6 [5-7]; p<0.001) than those with favorable outcome; the area under the receiver operating curve (AUROC) for CVH/ICC score to predict UO was 0.86 (95% CIs 0.75-0.97); a score > 8.5 had 63 (46-77)% sensitivity and 87 (62-97)% specificity to predict UO. For those patients undergoing a second assessment (n=29) after a median of 11 (5-31) days, all measured variables were similar between the two time-points. No differences in the measured variables between ICU non-survivors (n=30) and survivors were observed.Conclusions: ICCI and CVH disturbances are often present in COVID-19 severe illness and could accurately predict early poor outcome.
Subject(s)
COVID-19 , Cerebrovascular DisordersABSTRACT
Introduction: One of the possible mechanisms by which the new coronavirus (SARS-Cov2) could induce brain damage is the impairment of cerebrovascular hemodynamics (CVH) and intracranial compliance (ICC), due to the elevation of intracranial pressure (ICP). The main objective of this study was to assess the presence of CVH and ICC alterations in patients with COVID-19 and evaluate their association with short-term clinical outcome. Methods: 50 consecutive critically ill COVID-19 patients were studied with transcranial Doppler (TCD) and a non-invasive monitoring of ICC. Subjects were included on ICU admission; CVH was evaluated using mean flow velocities in the middle cerebral arteries (mCBFV), pulsatility index (PI) and estimated cerebral perfusion pressure (eCPP), while ICC using the P2/P1 ratio of estimated ICP curve (B4C device). The primary composite outcome was unsuccessful weaning from respiratory support or death at day 7.Results: On the first assessment (n= 50), only P2/P1 (1.20 [1.00-1.28] vs. 1.00 [0.88-1.16]; p=0.03) and eICP (14 [11-25] vs. 11 [7-15] mmHg; p=0.01) were significantly higher among patients with UO than others. Patients with UO had a significantly higher CVH/ICC score (9 [8-12] vs. 6 [5-7]; p<0.001) than those with favorable outcome; the area under the receiver operating curve (AUROC) for CVH/ICC score to predict UO was 0.86 (95% CIs 0.75-0.97); a score > 8.5 had 63 (46-77)% sensitivity and 87 (62-97)% specificity to predict UO. For those patients undergoing a second assessment (n=29) after a median of 11 (5-31) days, all measured variables were similar between the two time-points. No differences in the measured variables between ICU non-survivors (n=30) and survivors were observed.Conclusions: ICCI and CVH disturbances are often present in COVID-19 severe illness and could accurately predict early poor outcome.