Hemodynamic Phenotype-Based, Capillary Refill Time-Targeted Resuscitation In Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial (A2)

I. Introduction Septic shock is associated with a high mortality risk related to progressive tissue hypoperfusion. However, despite extensive research on the best monitoring and resuscitation strategies, many uncertainties remain. Over-resuscitation, particularly when inducing fluid overload, might contribute to a worse outcome. Fluid overload more likely occurs when fluids are administered to fluid unresponsive patients, but also when inappropriate resuscitation goals are pursued, or a "one-size-fits-all" strategy is followed.

From a hemodynamic point of view, several pathogenic mechanisms determine a progressive circulatory dysfunction. While loss of vascular tone and relative hypovolemia predominate in early phases, more complex mechanisms such as endothelial and microcirculatory dysfunction, progressive vasoplegia, and myocardial dysfunction may be involved later. In effect, from a clinical point of view, many patients despite been fluid loaded in pre-intensive care unit (ICU) settings, are still evidently hypovolemic and benefit from further administration of fluid boluses. Others, however, present very low diastolic arterial pressures (DAP) reflecting profound vasoplegia, and recent data suggest that these patients may benefit from early norepinephrine (NE) instead of fluids on the contrary, administering fluids may fail to correct vascular tone and increase the risk of fluid overload. In addition, a recent echocardiography-based study confirmed that a relevant myocardial dysfunction is present in a significant number of patients and that several cardiovascular phenotypes with a potentially different therapeutic approach may be recognized. Despite research efforts, no universally applicable clinical phenotyping method for septic shock patients has been translated to usual practice. This is particularly problematic since echocardiography is not immediately available in the majority of centers worldwide, and therefore initial decisions on fluid resuscitation are usually based on clinical grounds and tend to follow the "one-size-fits-all" principle, leading to the risk of fluid overload.

II. ANDROMEDA-SHOCK Study The excellent prognosis associated with CRT recovery, its rapid-response time to fluid loading, its relative simplicity, its availability in resource-limited settings, and its capacity to change in parallel with perfusion of physiologically relevant territories such as the hepatosplanchnic region, constitute strong reasons to consider CRT as the target for fluid resuscitation in septic shock patients.

ANDROMEDA-SHOCK was a multicenter, randomized controlled trial comparing CRT- versus lactate-targeted resuscitation in patients with early septic shock. The main outcome was 28-day mortality, and secondary outcomes included organ dysfunction and treatment intensity. The hypothesis was that targeting CRT would lead to decreased mortality and organ dysfunction due to less fluid administration and treatment intensity.

CRT-targeted resuscitation was associated with lower mortality (34.9% vs. 43.4%), beneficial effects on organ dysfunction, and less intensity of treatment. The superiority of this strategy was also supported by a subsequent Bayesian analysis. The key novelty of A2 is to combine a CRT-targeted strategy with a clinical hemodynamic phenotyping that may aid to personalize initial resuscitation with potential additional fluid-sparing effects.