After reference 4 10 hours, no statistical analyses were performed, because the small number of animals alive in the placebo and the AVP group did not allow reliable testing anymore. Survival times were calculated using a log-rank test. Group differences were analyzed by pairwise multiple comparison with the Holm-Sidak test. Differences were considered statistically significant for P values of less than 0.05.ResultsBaseline characteristicsThere were no differences among study groups in any of the investigated variables at BL and ST. Mean body weight (37 �� 1 kg) and time to onset of septic shock (7 �� 1 hours) did not differ between groups.Cardiopulmonary hemodynamicsChanges in cardiopulmonary variables are presented in Figures Figures11 and and22 and Table Table1.1.

Septic shock was characterized by decreases in MAP, systemic vascular resistance index, and left ventricular stroke work index (LVSWI) (ST: P < 0.001 versus BL each). All three treatment strategies maintained MAP within the target range of 70 �� 5 mm Hg for the first 4 hours after ST (4 hours: P < 0.01 versus ST each; Table Table1).1). However, after the dose limitation for norepinephrine had been reached, MAP and systemic vascular resistance index fell significantly below ST values in all groups (10 hours: P < 0.05 versus ST each; Table Table1).1). There were no statistically significant differences in cumulative norepinephrine requirements among study groups (Figure (Figure1a1a).Figure 1Cumulative norepinephrine requirements (a) and left ventricular function curves (b). n = 7 each.

AVP, arginine vasopressin; LVSWI, left ventricular stroke work index; NEcum, cumulative norepinephrine dose; PAOP, pulmonary artery occlusion pressure.Figure 2Cardiac filling pressures. Central venous pressure (a) and pulmonary artery occlusion pressure (b). *P < 0.05 versus shock time (ST); ?P < 0.05 versus placebo; ��P < 0.05 versus arginine vasopressin (AVP); n = 7 ...Table 1Cardiopulmonary variables and mesenteric blood flowLVSWI increased significantly in all groups at 2 and 4 hours (P < 0.05 versus ST each). Notably, LVSWI was higher in the V2R-antagonist group than in the AVP group at 8 and 10 hours (Table (Table1).1). Left ventricular contractility, expressed as a Starling-based relationship between LVSWI and preload (pulmonary artery occlusion pressure), was higher in animals treated with the V2R-antagonist than with placebo (Figure (Figure1b).

1b). Cardiac index increased after ST. Heart rate was lower following AVP infusion than in both other groups (8 hours: P = 0.027 versus V2R-antagonist; GSK-3 P = 0.031 versus placebo; Table Table11).Central venous and pulmonary artery occlusion pressures, as surrogate variables of cardiac filling pressures, increased in all groups as compared with ST but were higher in animals treated with the V2R-antagonist as compared with both other groups (Figure 2a,b).