Vasoactive drugs and the distribution of crystalloid fluid during acute sepsis

Introduction: Crystalloid fluid is combined with vasoactive drugs when treating acute sepsis. We used kinetic analysis to compare the effects of vasoactive drugs on the hemodynamics and the volume kinetics of crystalloid fluid in non-septic and septic sheep. Specific attention was given to the effects of drugs and sepsis on fluid distribution to the “third fluid space.” Methods: Forty-nine sheep were studied, of which 25 were made septic by cecal puncture and administration of lipopolysaccharide. A bolus infusion of 20–25 mL/kg of crystalloid fluid was given 1 h later, together with therapeutic doses of phenylephrine, norepinephrine, isoprenaline, dopamine, or esmolol. Central hemodynamics were monitored, and blood samples for the calculation of volume kinetics were taken. The distribution and elimination of the infused volume were calculated using mixed-model kinetics with extensive covariate analyses based on 1134 measurements of the hemoglobin-derived plasma dilution (23 per experiment) and 193 measurements of urine output collected over 180 min. Results: Sepsis induced a hyperkinetic, hypotensive, and vasodilatory state. Cardiac output averaged 12.1 L/min in septic sheep vs. 7.6 L/min in non-septic sheep, and mean arterial pressure was 72 vs. 109 mmHg, respectively. Differences in hemodynamic variables between the non-septic and septic sheep were all statistically significant (P <0.001), however, the modifying influences of vasopressors on hemodynamics and fluid distribution were weakened in the septic state. The rate constant for urine output (k₁₀) was strongly decreased by sepsis, modestly reduced by β₁-adrenergic stimulation, and increased by α₁-adrenergic stimulation. Fluid was able to access the remote slow-exchange interstitial fluid space (“third fluid space”) only during sepsis. In theory, fluid accumulation in this space would decrease by α₁-adrenergic stimulation and increase by β₁-adrenergic stimulation, but differences were small due to the overall weak effects of adrenergic drugs in the septic sheep. We hypothesize that the changeover from brisk urine flow in the non-septic sheep to marked accumulation of fluid in the “third fluid space” was due to inflammatory-induced alterations in the interstitial matrix. Conclusion: Vasoactive drugs were less effective in septic compared to non-septic sheep. Most importantly, acute sepsis was characterized by a marked accumulation of fluid in an interstitial fluid space with slow turnover.