Effects of vasoactive drugs on crystalloid fluid kinetics in septic sheep

PURPOSE: Crystalloid fluid and vasoactive drugs are used in the early treatment of sepsis. The purpose of the present study was to examine how these drugs alter plasma volume expansion, peripheral edema, and urinary excretion. METHODS: Twenty-five anesthetized sheep were made septic by cecal puncture and a short infusion of lipopolysaccharide. After 50 min, a slow infusion of isotonic saline was initiated: the saline either contained no drug, norepinephrine (1 μg/kg/min), phenylephrine (3 μg/kg/min), dopamine (50 μg/kg/min), or esmolol (50 μg/kg/min). Ten min later, 20 mL/kg Ringer´s lactate solution was given over 30 min. Central hemodynamics, acid-base balance, and the urinary excretion were monitored. Frequent measurements of the blood hemoglobin concentration were used as input in a kinetic analysis, using a mixed effects modeling software. RESULTS: The fluid kinetic analysis showed slow distribution and elimination of Ringer´s lactate, although phenylephrine and dopamine accelerated the distribution. Once distributed, the fluid remained in the peripheral tissues and did not equilibrate adequately with the plasma. Overall, stimulation of adrenergic alpha(1)-receptors accelerated, while beta(1)-receptors retarded, the distribution and elimination of fluid. A pharmacodynamic E(max) model showed that Ringer´s lactate increased stroke volume by 13 ml/beat. Alpha(1)-receptors, but not beta(1)-receptors, further increased stroke volume, while both raised the mean arterial pressure. Modulation of the beta(1)-receptors limited the acidosis. CONCLUSIONS: Stimulation of adrenergic alpha(1)-receptors with vasoactive drugs accelerated, while beta(1)-receptors retarded, the distribution and elimination of fluid. The tendency for peripheral accumulation of fluid was pronounced, in particular when phenylephrine was given.