Selective V_1aagonism attenuates vascular dysfunction and fluid accumulation in ovine severe sepsis

Abstract

Vasopressin analogs are used as a supplement to norepinephrine in septic shock. The isolated effects of vasopressin agonists on sepsis-induced vascular dysfunction, however, remain controversial. Because V(2)-receptor stimulation induces vasodilation and procoagulant effects, a higher V(1a)- versus V(2)-receptor selectivity might be advantageous. We therefore hypothesized that a sole, titrated infusion of the selective V(1a)-agonist Phe(2)-Orn(8)-Vasotocin (POV) is more effective than the mixed V(1a)-/V(2)-agonist AVP for the treatment of vascular and cardiopulmonary dysfunction in methicillin resistant staphylococcus aureus pneumonia-induced, ovine sepsis. After the onset of hemodynamic instability, awake, chronically instrumented, mechanically ventilated, and fluid resuscitated sheep were randomly assigned to receive continuous infusions of either POV, AVP, or saline solution (control; each n = 6). AVP and POV were titrated to maintain mean arterial pressure above baseline - 10 mmHg. When compared with that of control animals, AVP and POV reduced neutrophil migration (myeloperoxidase activity, alveolar neutrophils) and plasma levels of nitric oxide, resulting in higher mean arterial pressures and a reduced vascular leakage (net fluid balance, chest and abdominal fluid, pulmonary bloodless wet-to-dry-weight ratio, alveolar and septal edema). Notably, POV stabilized hemodynamics at lower doses than AVP. In addition, POV, but not AVP, reduced myocardial and pulmonary tissue concentrations of 3-nitrotyrosine, VEGF, and angiopoietin-2, thereby leading to an abolishment of cumulative fluid accumulation (POV, 9 ± 15 ml/kg vs. AVP, 110 ± 13 ml/kg vs. control, 213 ± 16 ml/kg; P < 0.001 each) and an attenuated cardiopulmonary dysfunction (left ventricular stroke work index, PaO(2)-to-FiO(2) ratio) versus control animals. Highly selective V(1a)-agonism appears to be superior to unselective vasopressin analogs for the treatment of sepsis-induced vascular dysfunction.

Selepressin in Septic Shock

“…Similar findings for the role of selective Via receptor agonism to those reported in the study by Maybauer et al (1) were noted in ovine models of fecal peritonitis and methicillinresistant Staphylococcus aureus pneumonia causing severe sep sis (11)(12)(13). In those studies, selective V ia agonism reduced fluid accumulation and norepinephrine requirements while increasing MAP, pulmonary gas exchange, and global oxygen transport (11).…”

The Selective Vasopressin Type 1a Receptor Agonist Selepressin (FE 202158) Blocks Vascular Leak in Ovine Severe Sepsis*

“…More recently, we have studied the effects of POV versus AVP in our conscious ovine model of methicillin-resistant Staphylococcus aureus (MRSA) pneumonia-induced severe sepsis using the same fluid resuscitation and vasopressor titration protocol as in the present study (45). This model is characterized by a more severe vascular leak syndrome than the P. aeruginosa pneumonia-induced severe sepsis model studied here (46).…”

Early Management of Severe Sepsis

“…41 , 42 A similar fi nding has been noted in an experimental sepsis model. 43 Hence, although the cardiac output increases, vasodilatation occurs and the BP may remain unchanged. 41 Increased shear stress increases the expression of nitric oxide synthetase with increased release of nitric oxide.…”

“…Myocardial edema due to excess fl uid administration compounds the myocardial dysfunction. 43 Evidence of the harmful effects of aggressive fl uid resuscitation on the outcome of sepsis is supported by experimental studies as well as by data accumulated from clinical trials. 43 , 56 Multiple clinical studies have demonstrated an independent association between an increasingly positive fl uid balance and increased mortality in patient with sepsis.…”