Aldosterone levels do not predict 28-day mortality in patients treated for COVID-19 in the intensive care unit

In this study, we attempted to find an association between serum aldosterone levels measured on days 1, 3, 5, and 7 and overall survival in the intensive care unit (ICU) for a period of 28 days. Even though mean plasma aldosterone levels were higher in patients who did not survive 28 days, the results were not statistically significant, indicating that aldosterone is not associated with ICU mortality. A previous study by Willard et al.14 Worse prognosis was reported in patients with higher aldosterone levels at admission; Specifically, those with higher plasma aldosterone levels were more likely to be admitted to the ICU. This may indicate that plasma aldosterone levels may be associated with the rate of ICU admission but not the total days survived in the ICU. Studies suggest that SARS-CoV-2, by competing with angiotensin II for the ACE2 receptor, indirectly increases Ang-II levels, which should lead to increased aldosterone biosynthesis. It is possible that aldosterone production in COVID-19 patients increases with disease severity and reaches a peak when the patient's condition demands ICU admission. More research is needed to reach any definite conclusions.

Systemic inflammation generated by SARS-CoV-2 is the hallmark of COVID-19, and one of the most widely used biomarkers for inflammation is an acute phase protein CRP, which is secreted by the liver in response to elevated interleukin-6 levels. Is biosynthesized in.14,15, Interestingly, our results showed a statistically significantly lower level of serum CRP in patients who died during the 28-day stay in the ICU, yet this was not associated with higher mortality. This result contradicts previous findings indicating an association between CRP serum concentration and disease severity.16,17,18,19,20, This discrepancy may be a result of the small size of the group that survived more than 28 days.

High serum creatinine levels have been shown to be another strong predictor of ICU admission and mortality.21, Our study provides additional evidence that high serum creatinine concentration is a predictor of COVID-related ICU mortality; Higher creatinine levels at days 1, 3, and 5 were observed in patients who died within 28 days compared to the group of survivors. Several large studies, including meta-analyses, have confirmed the association of high creatinine levels with increased mortality in critically ill patients.21,22,23,

In our study, univariate analysis showed increased mortality in the group of patients with higher APACHE II, SAPS II, and SOFA scores. Multivariate analysis showed that age (HR = 1.03, P= 0.033) was a strong predictor of mortality in the entire study population, which was similar to the finding of the meta-analysis by Kaussar et al.24, COVID-19 is a disease that is difficult to predict. In intensive care units, several scales are routinely used to assess the risk of death and to estimate the severity of condition and organ function on admission. Our study selected the most commonly used and valued ICU scales. In a study by Monk et al, no benefit was demonstrated of any mortality scoring system applied to COVID-19. The study showed that SOFA, SAPS II, APACHE II and ISARIC 4-C scores accurately predicted mortality in critically ill patients with COVID-19. SOFA scores performed best. Studies conducted by our team have shown a correlation of the values ​​obtained in the SOFA, APACHE II and SAPS II scales with mortality.12,

Comorbidities associated with higher mortality following SARS-CoV-2 infection are hypertension and diabetes. There is a strong association between hospital mortality due to COVID-19 and hypertension, coronary heart disease and diabetes.25, although our study did not show a statistically significant effect of these factors on mortality. Researchers have postulated that the use of RAS blockers, such as ACE inhibitors or angiotensin receptor blockers (ARBs), which are often administered in these conditions, may contribute to the upregulation of ACE2, which could potentially lead to SARS-CoV-2 infection in cells. Can promote entry. Giving worse results. The Brace Corona clinical trial later proved that neither continuing nor discontinuing these drugs had a significant impact on mortality or progression of COVID-19.26, Mineralocorticoid antagonists also failed to show any effect on mortality in a recent meta-analysis27, Activation of the RAAS by SARS-CoV-2 may lead to a direct increase in aldosterone production; One of the sites of production may be endothelial cells of pulmonary vessels.29, High levels of aldosterone may induce severe forms of COVID-19 by promoting inflammatory response and inducing electrolyte disorders such as hypokalemia, especially in older patients.

In case of high aldosterone concentrations correlating with mortality, one of the treatment options for COVID-19 could be the use of mineralocorticoid receptor antagonists (MRAs). Reports on impact of MRA on COVID-19 are unclear22,28,29, MRAs, ACE inhibitors (ACE-I), and angiotensin receptor blockers (ARBs) were analyzed for their effects on COVID-19. Many patients discontinued RAASi treatment during the first phase of the COVID-19 pandemic due to the ability of these drugs to increase ACE 2 expression and levels. Multiple studies have shown that RAASi use is not associated with risk of COVID-1928,29,30, Compared with ACE-I and ARBs, using MRAs in COVID-19 may offer some advantages. Additionally, MRAs increase the proliferation of ACE 2 by stimulating the ADAM metalloproteinase domain 17 protein, which can bind SARS-CoV-2 as a competitive interceptor.29, MRA can suppress the expression of the type II transmembrane serine protease TMPRSS2, which inhibits the viral absorption of SARS-CoV-2 into target cells by promoting membrane fusion of the spike glycoprotein through proteolytic cleavage between the S1 and S2 subunits and cleaving ACE. Increases. 2, which, in turn, activates the cathepsin L-dependent pathway31,

Inhibiting these pathways induced by MRA can suppress or reduce viral entry into human cells. This may be beneficial in COVID-19 infection and acute respiratory distress syndrome32,33, The reason for measuring aldosterone levels in our ward was to investigate the correlation of its levels with mortality, potentially resulting from appropriate treatment. The results of our study do not justify the use of MRA in the treatment of COVID-19 patients.

There are some limitations to this study that need to be considered when interpreting the findings. First, this is a single-center study with small simple size. Second, this is a retrospective, cross-selection study; Thus, further prospective studies should confirm the findings. Furthermore, the chemiluminescent immunoassay method cannot reveal aldosterone serum levels. Wiegand et al.34 demonstrated that “aldosterone in serum of patients with SARS-CoV-2 infection cannot be accurately estimated using direct competitive immunoassay. When measured using the gold-standard LCMSMS, serum aldosterone is found to be remarkably low in most patients with COVID-19. However, the chemiluminescent immunoassay method used for aldosterone determination in our study is a well-validated measurement method that is routinely used for aldosterone level determination in laboratory practice. The method used in the study was compared with a manual radioimmunoassay (RIA), according to CLSI EP9 (Clinical and Laboratory Standards Institute-Measurement Procedure Comparison and Bias Estimation) guidelines. The correlation coefficients were 0.98 (for serum) and 0.90 (for urine). In addition, this parameter is subject to monthly international control (RIQAS external quality control system operated by Randox).

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