Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome

Abstract

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

Keywords: ARDS; COVID-19; clearance; endothelin-1; prognosis.

Figure 1

ICU admission ET-1 levels in the three critically ill groups. Systemic arterial (A) and central venous (B) ET-1 was measured in the COVID-19 ARDS (N = 18), non-COVID-19 ARDS (N = 14), and non-COVID-19 non-ARDS (N = 20) patients by enzyme-linked immunosorbent assay (ELISA). The systemic arterial:central venous (A:V) ET-1 ratio was calculated thereafter (C). The horizontal line represents an A:V ET-1 ratio of 1. Data are presented as box plots. Line in the middle of the box, median value; box edges, 25th to 75th centiles; whiskers, range of values; bullets, outliers. One-way ANOVA followed by Kruskal–Wallis was performed to test for differences between the groups. * p < 0.05, *** p < 0.01, **** p < 0.0001.

Figure 2

Systemic arterial:central venous (A:V) ET-1 ratio in the three critically ill groups at two time-points in the ICU. The A:V ET-1 ratio is shown upon ICU admission (time-point 1) in the COVID-19 ARDS (N = 18), non-COVID-19 ARDS (N = 14), and non-COVID-19 non-ARDS (N = 20) groups and on Day 3 after admission (time-point 2) in the COVID-19 ARDS patients (N = 10), the non-COVID-19 ARDS patients (N = 13), and the non-COVID-19 critically ill patients (N = 17). The vertical line represents an A:V ET-1 ratio of 1.

Figure 3

ICU admission ET-1 levels and ratio and 28-day ICU mortality. Systemic arterial, central venous, and A:V ET-1 ratio in the 28-day ICU survivors and non-survivors of COVID-19 ARDS. Systemic arterial and central venous ET-1 was measured in the COVID-19 ARDS survivors (N = 12) and non-survivors (N = 5) by enzyme-linked immunosorbent assay (ELISA). The systemic arterial:central venous (A:V) ET-1 ratio was calculated thereafter. The horizontal line represents an A:V ET-1 ratio of 1. Data are presented as box plots. Line in the middle of the box, median value; box edges, 25th to 75th centiles; whiskers, range of values; bullets, outliers. Grey box plots represent the survivors, and the black box plots the non-survivors. * p < 0.05 by Mann–Whitney.

Figure 4

Distribution of the ICU admission A:V ET-1 ratio in COVID-19 ARDS survivors and non-survivors. Distribution of the A:V ET-1 ratio in COVID-19 ARDS survivors (A) and non-survivors (B). COVID-19 ARDS patients were assigned into two groups, low (green color) and high (red color), based on the cut-off value generated by the ROC curve (0.701). Distribution is shown as a 3D pie chart. p = 0.009 by the chi-square test.

Figure 5

Summary of the research workflow and main findings. A simultaneous blood draw was performed in each COVID-19-induced ARDS patient from a central venous line (jugular or subclavicular vein) and from a peripheral arterial line catheter (radial artery). Endothelin-1 (ET-1) levels were measured in plasma blood samples by enzyme-linked immunosorbent assay (ELISA). Patients were divided based on 28-day ICU mortality. Although systemic arterial (A) and central venous (V) ET-1 levels did not differ in survivors and non-survivors, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors compared to survivors, indicating net pulmonary ET-1 release. The abnormal clearance of ET-1 may lead to pulmonary vasoconstriction, microvascular dysfunction, and enhanced vascular permeability, which are considered the pathogenetic mechanisms of pulmonary hypertension and several related vascular complications. This figure has been designed using assets from “https://www.freepik.com/ (accessed on 12 September 2024)”.