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Introduction: The non-selective vasopressin agonist, arginine vasopressin (AVP) is widely used as second line vasopressor in septic shock patients as add-on to norepinephrine (NE). However, animal septic shock studies have shown selective V1a receptor agonists to be superior to AVP in alleviating organ dysfunction. Selepressin (FE 202158) is the first selective V1a agonist to be evaluated in septic shock patients. Hypothesis: Selepressin reduces NE requirements and duration of organ dysfunction in human septic shock. Methods: In a randomized double-blind, placebo controlled trial, septic shock patients in need of vasopressor support (?0.1 µg/kg/min NE for?2h) received selepressin (1.25 ng/kg/min (n=10) or 2.5 ng/kg/min (n=19) or placebo (n=21) until shock resolution or for up to 7 days. If target mean arterial pressure (MAP) of 65 mmHg could not be achieved, open-label NE was added. The co-primary endpoints were ability to maintain target MAP without NE, NE infusion rate and cumulative dose of NE. Secondary endpoints included organ dysfunction and fluid balance. Results: Selepressin dose-dependently reduced the 7-day cumulative dose of open-label NE (placebo: 772 µg/kg, 1.25 ng/kg/min selepressin: 617 µg/kg and 2.5 ng/kg/min selepressin: 249 µg/kg, p=0.007). NE was weaned more rapidly in the selepressin group: 2.5 ng/kg/min selepressin increased the proportion of patients maintaining target MAP without open-label NE compared to placebo (69% vs. 20%, p=0.005) and reduced mean NE infusion rate (0.04 vs. 0.18, p=0.0001) in the first 24h following initiation of study drug. Interestingly, the 2.5 ng/kg/min selepressin group had faster recovery than placebo as shown by a higher proportion of patients out of shock at 48h (57.9 vs. 28.6%, p=0.1) and higher proportion of days alive and free of ventilation within the first 7 days (53.8 vs. 23.1%, p=0.01) in spite of similar baseline NE requirements and SOFA score. Moreover, 7-day cumulative fluid balance was lower in the 2.5 ng/kg/min selepressin group than in placebo (9.0 vs. 6.5 L, p=0.1). Conclusions: Selepressin dose-dependently reduced NE requirements, as well as the need for mechanical ventilation, and appeared to shorten time to shock resolution in septic shock patients.