Selective V_1a agonism reduces vascular leakage and cardiopulmonary dysfunction in methicillin-resistant Staphylococcus aureus sepsis

Introduction

This randomized, controlled experimental trial was performed to compare the effects of the selective V_1a-receptor agonist (Phe2Orn8) vasotocin (POV) and the mixed V_1a/V₂-receptor agonist (Arg8) vasopressin (AVP) on vascular leakage and cardiopulmonary dysfunction associated with methicillin-resistant Staphylococcus aureus (MRSA) pneumonia-induced septic shock using an established ovine model.

Methods

After instrumentation for chronic hemodynamic monitoring and tracheostomy, sheep were subjected to 48 breaths of cotton smoke (<40°C) and MRSA was placed into both lungs under deep anesthesia. Following a 10 mmHg drop in mean arterial pressure (MAP) from baseline, sheep were randomly assigned to receive intravenous infusions of either POV, AVP or the vehicle (0.9% NaCl; n = 6 each). POV and AVP were titrated to keep MAP above baseline - 10 mmHg. All sheep were awake, mechanically ventilated and fluid resuscitated to maintain hematocrit at baseline ± 3%. Data are expressed as mean ± SEM at 24 hours. Fluids are represented as the average over time to account for individual survival times.

Results

Both treatment strategies significantly reduced fluid input (AVP: 7.7 ± 0.6 ml/kg/hour; POV: 5.8 ± 0.8 ml/kg/hour), positive net fluid balance (AVP: 4.9 ± 0.5 ml/kg/hour; POV: 0.4 ± 0.6 ml/kg/hour), thoracic (AVP: 0.8 ± 0.2 ml/kg/hour; POV: 0.3 ± 0.1 ml/kg/hour) and abdominal fluid (AVP: 0.10 ± 0.04 ml/kg/hour; POV: 0.01 ± 0.01 ml/kg/hour) as well as extravascular lung water (AVP: 22.6 ± 1.4 ml/kg; POV: 15.8 ± 1.9 ml/kg) and increased plasma oncotic pressures (AVP: 12.5 ± 0.9 mmHg; POV: 15.9 ± 1.1 mmHg) vs control animals (9.6 ± 0.4 ml/kg/hour; 7.7 ± 0.4 ml/kg/hour; 2.2 ± 0.4 ml/kg/hour; 0.29 ± 0.13 ml/kg/hour; 22.9 ± 2.8 ml/kg; 8.9 ± 0.1 mmHg, respectively). Notably, POV was superior to AVP in all these variables (P < 0.05 each). Myocardial contractility was higher in the POV group vs AVP and control animals as suggested by higher left ventricular stroke work indexes (66 ± 3 vs 48 ± 7 and 43 ± 3 g/m/m2, respectively; P < 0.05 each) at lower or similar global end-diastolic volumes. Pulmonary dysfunction (decrease in PaO₂/FiO₂ ratio) was attenuated in POV (364 ± 47 mmHg) as compared with AVP (195 ± 66 mmHg; P < 0.05) and control animals (213 ± 76 mmHg; P < 0.05). Whereas one AVP and three control animals had to be sacrificed prematurely, all POV-treated animals survived the 24-hour study period.

Conclusions

In MRSA pneumonia-induced ovine septic shock, the selective V_1a-receptor agonist POV is superior to the mixed V_1a/V₂-receptor agonist AVP in reducing vascular leakage and cardiopulmonary dysfunction when administered as a first-line vasopressor.