Refractory septic shock is defined as persistently low mean arterial blood pressure despite volume resuscitation and titrated vasopressors/inotropes in patients with a proven or suspected infection and concomitant organ dysfunction. Its management typically requires high doses of catecholamines, which can induce significant adverse effects such as ischemia and arrhythmias. Angiotensin II (Ang II), a key product of the renin–angiotensin–aldosterone system, is a vasopressor agent that could be used in conjunction with other vasopressors to stabilize critically ill patients during refractory septic shock, and reduce catecholamine requirements. However, very few clinical data are available to support Ang II administration in this setting. Here, we review the current literature on this topic to better understand the role of Ang II administration during refractory septic shock, differentiating experimental from clinical studies. We also consider the potential role of exogenous Ang II administration in specific organ dysfunction and possible pitfalls with Ang II in sepsis. Various issues remain unresolved and future studies should investigate important topics such as: the optimal dose and timing of Ang II administration, a comparison between Ang II and the other vasopressors (epinephrine; vasopressin), and Ang II effects on microcirculation.

Plasma concentrations of endocan, a proteoglycan preferentially expressed in the pulmonary vasculature, may represent a biomarker of lung (dys)function. We sought to determine whether the measurement of plasma endocan levels early in the course of acute respiratory distress syndrome (ARDS) could help predict risk of death or of prolonged ventilation. All patients present in the department of intensive care during a 150-day period were screened for ARDS (using the Berlin definition). Endocan concentrations were measured at the moment of ARDS diagnosis (T0) and the following morning (T1). We compared data from survivors and non-survivors and data from survivors with less than 10 days of ventilator support (good evolution) and those who died or needed more than 10 days of mechanical ventilation (poor evolution). Results are presented as numbers (percentages), mean ± standard deviation or medians (percentile 25–75). Ninety-six consecutive patients were included [median APACHE II score of 21 (17–27) and SOFA score of 9 (6–12), PaO2/FiO2 ratio 155 (113–206)]; 64 (67%) had sepsis and 51 (53%) were receiving norepinephrine. Non-survivors were older (66 ± 15 vs. 59 ± 18 years, p = 0.045) and had higher APACHE II scores [27 (22–30) vs. 20 (15–24), p < 0.001] and blood lactate concentrations at study inclusion [2.1 (1.3–4.0) vs. 1.5 (0.9–2.6) mmol/L, p = 0.024] than survivors, but PaO2/FiO2 ratios [150 (116–207) vs. 158 (110–206), p = 0.95] were similar in the two groups. Endocan concentrations on the day after ARDS diagnosis were significantly higher in patients with poor evolution than in those with good evolution [12.0 (6.8–18.6) vs. 7.2 (5.4–12.5), p < 0.01]. Blood endocan concentrations early in the evolution of ARDS may be a useful marker of disease severity.

While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss of perfusion to the brain, determining a whole brain ischemic-anoxic injury. Differently from other threatening situations of reduced cerebral perfusion, i.e., caused by increased intracranial pressure or circulatory shock, resuscitated patients after a cardiac arrest experience a sudden restoration of cerebral blood flow and are exposed to a massive reperfusion injury, which could significantly alter cellular metabolism. Current evidence suggests that cell populations in the central nervous system might use alternative metabolic pathways to glucose and that neurons may rely on a lactate-centered metabolism. Indeed, lactate does not require adenosine triphosphate (ATP) to be oxidated and it could therefore serve as an alternative substrate in condition of depleted energy reserves, i.e., reperfusion injury, even in presence of adequate tissue oxygen delivery. Lactate enriched solutions were studied in recent years in healthy subjects, acute heart failure, and severe traumatic brain injured patients, showing possible benefits that extend beyond the role as alternative energetic substrates. In this manuscript, we addressed some key aspects of the cellular metabolic derangements occurring after cerebral ischemia-reperfusion injury and examined the possible rationale for the administration of lactate enriched solutions in resuscitated patients after cardiac arrest.

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 outcomes. Methods: Fifty consecutive critically ill COVID-19 patients were studied with transcranial Doppler (TCD) and 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 the non-invasive ICP curve. A CVH/ICC score was computed using all these variables. The primary composite outcome was unsuccessful in weaning from respiratory support or death on day 7 (defined as UO). Results: At the first assessment (n = 50), only the P2/P1 ratio (median 1.20 [IQRs 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 an 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 a 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: ICC impairment and CVH disturbances are often present in COVID-19 severe illness and could accurately predict an early poor outcome.

The renin-angiotensin system (RAS) plays a pivotal role in a wide series of physiological processes, among which inflammation and blood pressure regulation. 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, and therefore a lot of research has 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 investigations and experimental analyzes quantifying, e.g., the levels and activity of RAS components. We performed a comprehensive meta-analysis of these data in view of disentangling the links between the impaired RAS functioning and the pathophysiological characteristics of COVID-19. We also review the effects of several RAS-targeting drugs and how they could potentially help restore the normal RAS functionality and minimize the COVID-19 severity. Finally, we discuss the conflicting evidence found in the literature and the open questions on RAS dysregulation in SARS-CoV-2 infection whose resolution would improve our understanding of COVID-19.