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

Septic shock is associated with a high mortality risk related to progressive
tissue hypoperfusion. 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. A robust body of evidence
confirms that abnormal peripheral perfusion after initial or advanced
resuscitation is associated with increased morbidity and mortality. In the
ANDROMEDA-SHOCK study capillary refill time (CRT)-targeted resuscitation was
safe and associated with lower mortality (34.9% vs. 43.4%), beneficial effects
on organ dysfunction, and less intensity of treatment. From a clinical point of
view, many patients despite been fluid loaded in pre- ICU settings, are still
fluid responsive and may benefit from further administration of fluid boluses.
Patients that present with very low diastolic arterial pressures (DAP)
reflecting profound vasodilatation are unlikely to benefit from fluid
administration as first line treatment. Recent data suggest that these patients
may benefit from early norepinephrine (NE). Continued fluid administration is
unlikely to correct vascular tone and increases the risk of fluid overload. In
addition, a recent echocardiography-based study confirms 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. Eventually, to assess basic universally available
clinical hemodynamic signals such as pulse pressure (PP) and DAP may allow
clinicians to individualize initial management avoiding the classic approach to
continue to administer fluids to all septic shock patients.

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

Multicenter, open-label, randomized controlled trial conducted under
supervision of an independent Data Safety Monitoring Board (DSMB). Recruited
patients will be randomized to intervention arm (CRT-P) or usual care (UC).

Recruited patients will be randomized to intervention arm (CRT-P) or usual care
(UC).

Usual Care (UC) group:
Patients allocated to the UC group will be managed by the clinical staff
according to usual practice at their sites including following general
recommendations of the Surviving Sepsis Campaign to avoid extremes of clinical
practice.

Intervention arm group (CRT-P):
Intervention in this group will follow the therapeutic algorithm as described
in Figure 1 in the protocol.
In short, interventions included in the algorithm are:
• Fluid Responsiveness (FR) assessment using standard procedures
• Fluid boluses (500 ml of crystalloids or 5% albumin) administered in 30 min
intervals, and repeated as needed if capillary refill time (CRT) is still
abnormal
• Transthoracic Echocardiography to rule out significant cardiac dysfunction
• Titration of dose of noradrenaline to achieve a MAP >65 mmHg and a diastolic
arterial pressure >= 50 mmHg.

The suspected benefit is that survival rate in the treatment group can be
improved with fluids resuscitation guided by changes in capillary refill time
(CRT). There is no additional risk for patients concerning the measurements of
peripheral perfusion, pulse pressure and transthoracic echocardiography as all
these techniques are noninvasive and harmless.
A refractory shock may occur in the event a patient does not respond to initial
therapy and patient may fail to correct CRT after the whole algorithm
procedures. On this circumstances, rescue therapies will be considered by the
attending physician, but these will not be standardized since the protocol is
interrupted at that point, although monitoring and registration during the 6h
intervention period and thereafter continue until the end of the study.