ILOPROST in Septic Shock With Persistent Microperfusion Defects (I-MICRO)

Septic shock remains a major cause of death in critically ill patients. Alterations in microcirculation have long been proposed as a key pathophysiological factor of organ dysfunction and death in septic shock patients. Persistence of mottling, prolonged skin recoloration time and cyanosis of the extremities are the easily and frequently observed manifestations of these microcirculatory disorders. Ilomedin is a prostaglandin analog with a potent vasodilatory effect together with anti-thrombotic properties (inhibition of platelet aggregation) preferentially at the microcirculatory level. An increase in cardiac output with increased arterial oxygen delivery has been observed in clinical and preclinical studies with no episodes of hypotension. Improvement in mesenteric perfusion has moreover been observed in experimental sepsis using Ilomedin. Our group has furthermore reported that administration of Ilomedin in patients with refractory septic shock (peripheral hypoperfusion) resulted in a rapid and sustained improvement in peripheral perfusion. Altogether, Ilomedin may prevent or improve recovery of organ dysfunction in septic shock patients through recruitment of the microcirculation and, thereby, ultimately improve outcome.

In the 32 participating centers: patients with septic shock and persistent peripheral hypoperfusion despite hemodynamic optimization (skin mottling and/or finger skin recoloration time \> 3sec, and/or knee skin recoloration time \> 4sec), after 6 to 24 hours of norepinephrine onset will be eligible for randomization.

Patients fulfilling the eligibility criteria will be included and randomized by the intensivist in two groups:

\*Experimental group: The patient will receive treatment with intravenous Iloprost (blinded) therapy at a dose of 0.5 ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes up to a maximum posology of 1.5ng/kg/min for 48h.

Placebo group: The patient will receive treatment with intravenous NaCl 0.9% (placebo-double blinded) therapy at a dose of 0.5ng/kg/min with increments of 0.5 ng/kg/min every 30 minutes according to body weight with a maximum posology of 1,5 ng/kg/min for 48h.

Primary outcome will be Delta Sequential Organ Failure Assessment (SOFA) score between infusion onset and day 7.

\*within the 12 first hours after randomization : blood samples : 15 ml of blood will be collected at the same time as the sample routinely collected, within the 12 first hours after randomization in ICU, when the patients are perfused.

The blood will be drawn and worked as follows:

* 2 x EDTA tubes of 5 ml : After centrifugation each tube will be directly divided into 4 aliquots of 500 µL (8 aliquots per patient)
* 1 x aprotinine tube of 5 ml : After centrifugation, it will be directly divided into 4 aliquots of 500 µL

The aliquots previously will be stored locally, and will be transported to the "Centre de Ressources Biologiques" (CRB) of the Lariboisière Hospital.

Eligibility Criteria:
Inclusion Criteria:

* Patients over 18 years of age
* Signed informed consent or inclusion under the emergency provisions of the law (Article L1122 -1-3 of the PHC / modified by Order n°2016-800 of June 16 2016 - art. 2).
* Patients with septic shock defined by the third international definition:

  * suspected or proven infection,
  * and organ dysfunction defined by an acute change in total SOFA score \>or=2
  * and persistent hypotension requiring vasopressor treatment to maintain mean arterial pressure \> 65 mmHg despite standard of care hemodynamic optimization
  * and serum lactate level \> 2 mmol/L despite standard of care hemodynamic optimization
  * and persistence of peripheral hypoperfusion (skin mottling and/or finger skin recoloration time \> 3sec, and/or knee skin recoloration time \> 4sec) despite standard of care hemodynamic optimization
  * Within 6 to 24 hours after norepinephrine onset

Exclusion Criteria:

* Refusal to participate in the study
* Pregnancy, breastfeeding
* Hypersensitivity to Ilomedin or to any of the excipients.
* Conditions where the hemorrhagic risk may be increased due to the effects of Ilomedin on platelets (i.e., evolving hemorrhage, trauma, intracranial hemorrhage, active gastric ulcer).
* Platelet count \< 10000 /mm3
* unstable angina.
* severe cardiac rhythm disorders since Norepinephrine onset
* severe hypoxemia (PaO2/FiO2 \<100)
* myocardial infarction in the last 6 months
* lack of Social Insurance
* persons deprived of liberty
* persons of a protective measure