A selective V1A receptor agonist, selepressin, is superior to arginine vasopressin and to norepinephrine in ovine septic shock

Septic shock, defined as sepsis with persistent arterial hypotension despite adequate fluid resuscitation, affects about 15% of ICU patients and is an important cause of morbidity and mortality (1). Optimal vasopressor support represents an important aspect in the management of patients with septic shock (2). Arginine vasopressin (AVP) may have a place in the treatment of septic shock when administered in addition to norepinephrine (NE) (2). The addition of AVP may exert beneficial effects directly or by reducing the need for catecholamines, thus limiting their adverse effects, including immune suppression, stimulation of cellular metabolism, and myocardial injury (3). Some recent studies have suggested that AVP administration may also be of benefit in less severe forms of septic shock or as an early intervention to limit edema formation and organ damage, rather than as rescue therapy (4–7), but the effects of this approach on outcomes have not been fully investigated. AVP stimulates several types of receptors (V1A, V1B, V2, oxytocin receptors) and thus has effects other than just V1A receptor-mediated vasopressor actions (8, 9). The agonist potency of AVP at the V1A and V2 receptors is of the same magnitude (i.e., AVP is a mixed V1A/V2 receptor agonist) (8, 10, 11). Because V2 and oxytocin receptor stimulation may aggravate sepsis-induced vasodilation and V2 receptor stimulation may promote fluid accumulation and increase the risk of microvascular thrombosis (12, 13), it is interesting to ask whether a selective V1A receptor agonist would be preferable. In animal models of pneumonia-induced sepsis and septic shock, selective V1A receptor agonists have been reported to reverse hypotension more effectively than other vasopressors (14, 15) and also to reduce vascular/capillary leakage (16), improve heart, lung, and kidney function, and prolong survival (14, 15). We have developed a clinically relevant ovine model of peritonitis-induced septic shock with fever, tachycardia, hyperdynamic state, decreased vascular tone, early capillary leakage, and multiple organ failure, which has been used to test the effects of new therapeutic interventions (17, 18). In the present study, the effects on hemodynamics, oxygen consumption, organ function, and survival time of a selective V1A receptor agonist, selepressin (FE 202158) (10, 11), were compared with those of AVP and NE when administered early and later in the course of sepsis. We hypothesized that selepressin would have more favorable effects on these variables than AVP and NE, especially when administered early. Some of the results of the current study have been previously reported in the form of an abstract (19).