ADRESS : Efficacy of the Alpha 2 agonist dexmedetomidine for sympathetic Deactivation in REfractory Septic Shock: a randomized, controlled trial

INTERVENTION: Product Name: , Product Code:SCP101878468, Pharmaceutical Form: , Other descriptive name: , Strength: , Product Name: , Product Code:SCP112629113, Pharmaceutical Form: , Other descriptive name: , Strength: , Product Name: , Product Code:SCP124183469, Pharmaceutical Form: , Other descriptive name: , Strength: , Product Name: , Product Code:SCP12667971, Pharmaceutical Form: , Other descriptive name: , Strength: , Product Name: DEXMÉDÉTOMIDINE VIATRIS 100 microgrammes/mL, solution à diluer pour perfusion, Product Code:PRD9896862, Pharmaceutical Form: SOLUTION FOR INFUSION, Other descriptive name: , Strength: CONDITION: Septic shock ; MedDRA version: 20.0Level: PTClassification code: 10040047Term: Sepsis Class: 100000004862 Therapeutic area: Not possible to specify INCLUSION CRITERIA: Age = 18 years., Septic shock, defined according to the ‘Sepsis‐3’ criteria: Proven or suspected infection, with a SOFA score increase of =2 points ; Persistent hypotension requiring vasopressors to maintain a MAP >65 mmHg ; And a serum lactate level >2 mmol/L despite adequate fluid resuscitation., Catecholamine resistance, defined as: The need for an equivalent dose of norepinephrine tartrate =0.5 µg/kg/min (according to the NEE vasopressor score, accounting for any concomitant administration of vasopressin, for example) for more than 2 consecutive hours AND Persistent circulatory failure with at least one of the following criteria present within the 2 hours preceding randomization: Hyperlactatemia >2 mmol/L And/or mottling (score =1) And/or oliguria (urine output <0.5 ml/kg/h over the last 2 hours)., Adequate fluid resuscitation: =30 ml/kg OR absence of preload dependence criteria (e.g., passive leg raise, pulse pressure variation)., Patient under invasive mechani PRIMARY OUTCOME: Main Objective: Evaluate the impact of dexmedetomidine (DEX) as an adjunctive treatment for refractory septic shock on 30‐day mortality in mechanically ventilated patients compared to standard care. Primary end point(s): Vital status at 30 days after randomization (Day 30). Secondary Objective: Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on 72‐hour mortality., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on vasopressor doses during the first hours (6h, 12h, 24h) following randomization., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the rate of use of rescue therapies., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on blood pressure changes during the first 24 hours following randomization., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the duration of vasopressor dependence during the first 30 days following randomization., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the duration of mechanical ventilation during the first 30 days following randomization., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on lactate clearance during the first hours (6h, 12h, 24h)., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the evolution of the SOFA score (Sepsis‐related Organ Failure Assessment) 3 days after randomization., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the evolution of daily fluid balance and the volume of resuscitation fluids during the first 5 days (Day 0 to Day 4) following randomization., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on the occurrence of new‐onset or persistent atrial fibrillation within 14 days following randomization., Evaluate the effect of dexmedetomidine (DEX) as an adjunctive treatment in addition to standard care in patients with septic shock resistant to vasopressors, compared to standard care, on ICU mortality and 90‐day mortality., Assess the tolerability of dexmedetomidine in this population based on the occurrence of bradycardia during the treatment period (including in case of treatment resumption)., Assess the tolerability of dexmedetomidine in this population regarding delayed awakening., Assess the tolerability of dexmedetomidine in this population regarding the incidence of ICU delirium., Ancillary study: Determine the impact of dexmedetomidine on sympathetic activity and the renin‐angiotensin‐aldosterone axis. SECONDARY OUTCOME: Secondary end point(s):Ancillary Study Criteria: Serum electrolyte panel (Na?, K?, Cl?) at H0 (randomization), H+12, H+24, H+48, and Day 5; plasma measurements of endogenous catecholamines and plasma assays of the renin–angiotensin system (angiotensin I and II, aldosterone) at H0 (randomization), H+12, H+48, and Day 5. Urinary electrolyte panel (Na?, K?, Cl?) and urinary measurements of endogenous catecholamines and the renin–angiotensin system (angiotensin I and II, aldosterone) at H+24. Secondary end point(s):Efficacy criteria: Cumulative dose and peak of vasopressors in norepinephrine equivalent (NEE score, Kotani et al. 2023) at 6h, 12h, and 24h after randomization. Secondary end point(s):Efficacy Criteria: Difference between total fluid intake (including IV infusions, enteral nutrition, blood products, flushes, and diluents) and total fluid losses (including urine output, drain outputs, and gastric tube losses) over 6 days (from Day 0 to Day 5). Secondary end point(s):Efficacy criteria: Evolution of mean arterial pressure (MAP) and MAP/Neq ratio (Neq = norepinephrine equivalent) within the first 24 hours after randomization (H0, H+6, H+12, H+24). Secondary end point(s):Efficacy Criteria: Lactate level at randomization, then at H+6, H+12, and H+24. Secondary end point(s):Efficacy criteria: Number of mechanical ventilation–free days during the 30 days following randomization (Day 0 ? Day 30). Secondary end point(s):Efficacy criteria: Number of vasopressor‐free days during the 30 days following randomization (Day 0 ? Day 30). Secondary end point(s):Efficacy Criteria: Occurrence of new‐onset or persistent atrial fibrillation within 14 days following randomization. Secondary end point(s):Efficacy criteria: Rate of use of vasopressin (VP) or other rescue therapies during the 30 days following randomization (Day 0 ? Day 30). Secondary end point(s):Efficacy Criteria: SOFA score at Day 0 and Day 3 after randomization. Secondary end point(s):Efficacy criteria: Vital status at 72 hours after randomization. Secondary end point(s):Efficacy Criteria: Vital status at ICU discharge and at 90 days after randomization. Secondary end point(s):Tolerance Criteria: Number of coma‐free days at Day 30 (or at ICU discharge if discharged before Day 30), defined as the number of days with a RASS score = ‐3. Secondary end point(s):Tolerance Criteria: Occurrence of bradycardia during the treatment period: heart rate (HR) < 50 bpm requiring therapeutic intervention (discontinuation of dexmedetomidine due to bradycardia, administration of atropine, adrenaline, isoprenaline, or external electrical pacing). Secondary end point(s):Tolerance Criteria: Occurrence of ICU delirium during the stay, screened daily using the CAM‐ICU score (Appendi X2) until Day 30 (or ICU discharge if discharged before Day 30) in patients with a RASS score (Appendi X2) = ‐3.