Selective V1a receptor agonists in experimental septic shock
- Daniel Traber1
© BioMed Central Ltd 2007
Published: 26 September 2007
Septic shock is caused by hypotension secondary to vasodilation. This hypotension is resistant to fluid resuscitation and requires the use of vasopressor agents. Recently, it was shown that it may be due to a deficiency in the vasopressor hormone arginine–vasopressin (AVP), a mixed V1a/V2 receptor agonist, leading to the clinical use of AVP in septic shock. We tested the hypothesis that the selective V1a receptor agonist FE 202158 is at least as effective as AVP in a sheep model of pneumonia-induced septic shock.
Materials and methods
Sheep were surgically instrumented ahead of the study. After obtaining baseline data, they were anesthetized and insufflated with 48 breaths of cotton smoke and 1,011 colony forming units of Pseudomonas aeruginosa instilled into their airways via a tracheostomy. The sheep were then placed on a ventilator and awakened for the study. They were resuscitated with Ringer's solution to maintain left atrial and central venous pressures and hematocrit at baseline levels. If, despite fluid management, the mean arterial pressure (MAP) fell by 10 mmHg from baseline, a continuous intravenous infusion of AVP or FE 202158 was initiated and titrated to keep MAP within this limit, except in a septic control group and in a nonseptic sham group.
In the septic control group, MAP fell by ~30 mmHg and the systemic vascular resistance index (SVRI) by ~50% over the 24-hour study. In the AVP group, although the MAP and SVRI were maintained above septic control group levels, they could not be brought back to sham group levels. In contrast, in the FE 202158 group, the MAP and SVRI were maintained at sham group levels. The septic control group accumulated ~7 l fluid over the 24-hour study (~20% body weight), while this was reduced by ~50% in the AVP group, and was totally prevented in the FE 202158 group. The fluid accumulation was associated with a constant hematocrit, suggesting that it was extravascular. It was also correlated with a fall in plasma total protein and oncotic pressure, suggesting protein leakage from the vasculature and probably reflecting sepsis-induced vascular leak syndrome. The full prevention of this fluid and protein leakage with FE 202158 was reversed to AVP group levels by infusing the selective V2 receptor agonist desmopressin together with FE 202158.
FE 202158 was not only fully effective at preventing a sepsis-induced decrease in MAP and SVRI, but was superior to AVP at reducing vascular leak syndrome because of its V1a receptor selectivity.