Septic shock is associated with a high mortality risk. Fluid overload occurs when fluids are administered to fluid unresponsive patients, but also when inappropriate resuscitation goals are pursued. Alongside, evidence confirms that abnormal peripheral perfusion after resuscitation is associated with increased morbidity and mortality. Targeted resuscitation associates with lower mortality, less organ dysfunction, and less intensity of treatment. Over-resuscitation may contribute to a worse outcome.

Many patients remain hypovolemic after initial resuscitation. Others present very low diastolic arterial pressures (DAP) reflecting profound vasoplegia and may benefit from early norepinephrine (NE) instead of fluids. Administering fluids in this setting could increase the risk of fluid overload. In addition, relevant myocardial dysfunction is present in a significant number of patients. Pulse pressure (PP) and DAP evaluation may help clinicians to individualize initial management sparing unnecessary fluid loading.

Objective: To test if a CRT-targeted resuscitation based on clinical hemodynamic phenotyping can improve a hierarchical clinical outcome - mortality, time to cessation of vital support, and length of hospital stay, all within 28 days - in septic shock patients as compared to usual care.

A2 is a multicenter randomized controlled trial (RCT) comparing a CRT-targeted, hemodynamics-based resuscitation strategy with usual care in patients with early septic shock during a 6 h intervention period. A sample size of 1500 patients was calculated to detect a 6% absolute reduction in mortality in the CRT group, and the win-ratio method will be used to test the superiority in the hierarchical outcomes mentioned above.

The combination of a CRT-targeted strategy with a clinical hemodynamic phenotyping may aid to personalize initial resuscitation with potential additional fluid-sparing effects. To categorize patients at baseline according to PP may conduct patients with low PP (<40mmHg) to fluid responsiveness (FR) assessment and eventually fluid boluses, while patients with normal PP will be treated according to DAP, adjusting NE when to avoid further fluids loading in patients who normalize CRT.

Fluid resuscitation will be focused on FR+ hypoperfused patients to prevent harmful fluid administration in FR- patients.

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.

III. Rationale for ANDROMEDA-SHOCK-2 intervention strategy. There are four relevant actions that may increase the efficacy of A2 intervention strategy to decrease mortality and organ dysfunction due to potential fluid-sparing effects or at least by promoting a more rational septic shock resuscitation.

1. Use of CRT as a target A key aspect of ANDROMEDA-SHOCK was a more rational approach to fluid resuscitation based on selecting a more appropriate target such as CRT. In fact, almost a 25% of patients assigned to the CRT arm had a normal CRT at baseline, and thus received no further fluid resuscitation. This fact is per se fluid sparing. In addition, a significant number of patients corrected CRT at 2h with initial fluid boluses. This rapid response of CRT to flow-increasing maneuvers makes CRT particularly suitable as a target. In addition, a recent clinical-physiological study suggested that normalization of CRT was associated to resolution of profound tissue hypoperfusion as assessed by hypoxia surrogates, and regional/sublingual microcirculatory variables. For these reasons and other considerations described elsewhere, a CRT-targeted resuscitation will be applied as the intervention arm of A2.

2. Clinical hemodynamic phenotyping Hypotension assessed by mean arterial pressure (MAP) is the hallmark of sepsis-related acute circulatory dysfunction, and since duration of hypotension is related to morbidity and mortality, current guidelines recommend fluids and vasopressors administered in a stepwise fashion to increase MAP levels to >65 mmHg to ensure minimal organ perfusion pressure. This "MAP-driven strategy" has probably led to an unwanted side-effect, a reductionist approach to clinical hemodynamic monitoring where among numerous variables provided by the blood pressure signal, only MAP is considered for decision-making at the bedside. Moreover, this standardized resuscitation strategy is debatable since septic shock patients are highly heterogeneous. For example, a recent report showed that 30% of septic shock patients admitted to ICU were already fluid unresponsive, and others have suggested that early start of NE instead of fluids could be associated with better outcomes in predominantly vasoplegic patients.

   Pulse pressure (PP) as a surrogate of stroke volume. In normal conditions, DAP is mainly determined by vascular tone and it remains nearly constant from the ascending aorta to the peripheral vessels. Thus, detection of low DAP at peripheral vessels should reflect systemic vasodilation as long as the aortic valve is competent. However, DAP is not considered for septic shock definition, and with few exceptions, its relationship with clinical outcomes has not been widely described. Nevertheless, evaluation of the loss of vascular tone through the severity of diastolic hypotension could have profound implications on therapeutic decisions since there are not robust clues to rapidly predict when hypotension will be sustainably corrected with fluid loading. Thus, rapid assessment of severity of vasodilation could influence therapeutic decisions such as the early introduction of NE, which theoretically may avoid unnecessary fluid administration while promptly restoring tissue perfusion. A low DAP (<50 mmHg) may impair myocardial perfusion of the left ventricle (LV), especially in the case of tachycardia where diastolic time is limited.

3. Systematic and repeated assessment of fluid responsiveness.

   Fluid administration is the first line therapy to reverse sepsis-induced tissue hypoperfusion. For this purpose, fluids are administered either as fluid loading at the emergency department, or later as fluid challenges during advanced ICU-based resuscitation. However, as any other drug, fluids have a narrow therapeutic index. Insufficient fluid resuscitation may lead to progressive tissue hypoperfusion and organ dysfunction, while excess fluids could induce detrimental fluid overload.

   Fluid responsiveness (FR) is a physiological cardiovascular condition where an increase in preload induced by a fluid bolus leads to an increase in cardiac output (CO) by more than 10-15%. In non-fluid responsive (FR-) patients, fluid administration does not significantly increase CO and may contribute to congestion and fluid overload. The rationale to assess FR is then to try to optimize fluid resuscitation in critically ill patients by focusing fluid boluses in FR+ hypoperfused patients and by preventing harmful fluid administration in FR- patients.

   Multiple tests have been described to assess FR at the bedside. They allow to determine the position of the patient's heart on its systolic function curve and are based upon changes in cardiac output or stroke volume resulting from various changes in preload conditions, induced by heart-lung interactions, postural maneuvers or by the infusion of small amounts of fluids. By applying the appropriate tests, FR can be assessed in a wide variety of clinical settings. However, despite their relative simplicity, lack of cost, and side effects, the use of FR tests has not completely permeated into routine clinical practice. One of the contributing factors is that even under the optimal conditions of their use, their sensitivity and specificity is not perfect, and all have significant limitations. This may be linked to the unreliability of the test, but also to the lack of precision of the measurement method used to estimate its effects.

   In A2, FR assessment will be performed systematically in every patient with abnormal CRT randomized to the intervention arm and presenting a low PP. FR assessment will be repeated after every fluid bolus (500 ml of crystalloids in 30 minutes) to decide on further fluid administration if CRT target was not achieved. A FR- status or a safety issue may command to move to other steps of the intervention algorithm.

4. Selective Critical Care Echocardiography

IV. Usual Care group Recruited centers for A2 should exhibit a historical mortality for septic shock of <40%. Patients allocated to the control (usual care) group will be managed by the clinical staff according to usual practice at their sites including decisions about hemodynamic and perfusion monitoring, and all treatments, but should follow general recommendations of the Surviving Sepsis Campaign to avoid extremes of clinical practice.

All data regarding insertion of invasive monitoring devices, intravenous-fluid resuscitation, vasoactive support, mechanical ventilation, and other supportive therapies will be collected by the study coordinator or monitors. Lead investigators at a site will not serve as the bedside treating physician for patients in the usual-care group.fluid administration in FR- patients.

V. Physiological substudies Several substudies will be performed in all or part of the participating centers including venous congestion substudy (VExUS), sublingual microcirculation substudy, and renal doppler resistive index substudies. These substudies are highly relevant since they will compare the impact of A2 intervention strategy on effective organ perfusion microcirculatory flow, and venous congestion, thus determining if this resuscitative strategy is associated with a more harmonic resuscitation as expressed by a "perfusion without congestion" result.

Inclusion Criteria:

• Consecutive adult patients (≥ 18 years) with septic shock according to Sepsis-3 consensus conference (septic shock defined as suspected or confirmed infection, plus hyperlactatemia and NE requirements due to persistent hypotension, after a fluid load of at least 1000 mL in one hour)

Exclusion Criteria:

• More than 4 hours since septic shock diagnosis,
• Anticipated surgery or acute hemodialysis procedure to start during the 6h intervention period
• Active bleeding,
• Do not resuscitate status,
• Child B-C Cirrhosis
• Underlying disease process with a life expectancy < 90 days and/or the attending clinician deems aggressive resuscitation unsuitable
• Refractory shock (high risk of death within 24h)
• Pregnancy
• Concomitant severe acute respiratory distress syndrome.
• Patients in whom CRT cannot be accurately assessed.