Vasoactive drugs and the distribution of crystalloid fluid during acute sepsis in sheep

Intravenous administration of electrolyte-based crystalloid fluid, such as Ringer’s solution and isotonic saline, is a cornerstone in the treatment of intensive care patients. Fluid is evenly distributed across the extracellular space in healthy humans, but maldistribution might occur in severe diseases such as sepsis.

The present study compared the distribution of crystalloid fluid in 24 healthy and 25 septic sheep and examined whether any maldistribution could be corrected using vasoactive drugs. Subgroups of five animals were given 3 µg/kg/min of phenylephrine and 50 µg/kg/min of dopamine. One group in the non-septic sheep study was given isoprenaline (0.1 µg/kg/min), and in the septic sheep, noradrenaline (1 µg/kg/min) or esmolol (β1-receptor blocker; 50 µg/kg/min). An intravenous infusion of 20–24 mL/kg of crystalloid fluid was administered over 20–30 minutes, and the fluid distribution was calculated using population volume kinetics. Covariate analysis was applied to test the influence of adrenergic receptors (α1-, β1-, or dopamine) on fluid distribution.

The research article in published in the Journal of Intensive Medicine on October 17, 2025, by Dr. Robert G. Hahn, Dr. Yuhong Li, and Dr. Randal O. Dull, reports that acute sepsis had a marked effect on the central hemodynamics by inducing a hyperkinetic, hypotensive, and vasodilatory state. Cardiac output was higher in the septic sheep (mean 12.1 vs. 7.6 L/min), while mean arterial pressure was lower (72 vs. 109 mmHg) than in the non-septic sheep. Sepsis markedly reduced the ratio between urine output and the infused fluid volume (9% vs. 122%, respectively; all differences P < 0.001). Vasoactive drugs strongly changed vascular resistance in the healthy sheep, while changes were small in the septic animals.

A three-volume kinetic model was fitted to all data on plasma dilution and urine output. “The most important kinetic finding was that the brisk urine flow in the non-septic sheep was replaced by accumulation of fluid in a slow-exchange ‘third fluid space’ in the septic sheep,” states Prof. Hahn. This accumulation was likely caused by inflammatory mediators such as cytokines, nitric oxide, and proteases, which alter the fibroblast-matrix interactions that normally keep the interstitial space compressed. Other kinetic differences between the groups were attributable to adrenergic receptor stimulation: urine output was strongly reduced by sepsis, modestly reduced by β1-adrenergic stimulation, and increased by α1-adrenergic stimulation. Further modifications were minor, but β1-adrenergic stimulation accelerated distribution of fluid from plasma and decreased return flow, both contributing to peripheral edema.

“The effects of adrenergic stimulation on hemodynamics and fluid distribution were noticeably weaker in septic sheep than in non-septic ones,” says Prof. Hahn. “It therefore appears unlikely that adrenergic drugs can normalize fluid distribution during sepsis.”

There was a 50-minute delay between the induction of sepsis and fluid infusion. During that period, hemoconcentration averaged 10%, indicating a slow hypovolemic process likely due to increased capillary albumin leakage and/or inhibited lymphatic flow. This albumin leakage seemed to prevent lymphatic flow from being completely arrested, as competition exists between lymphatic flow and translocation of fluid to the “third fluid space.” Inhibition of lymphatic flow likely underlies the characteristic hypovolemia, peripheral edema, and hypoalbuminemia seen in systemic inflammatory disorders.

In conclusion, vasoactive drugs strongly affected hemodynamics and urine output in healthy sheep, while their influence on the distribution of infused crystalloid fluid between compartments was modest. The magnitude of all adrenergic influences on fluid distribution was less pronounced in sheep with acute sepsis. The kinetic parameters in the septic sheep are consistent with inflammation-induced disruption of the interstitial matrix and increasingly negative interstitial pressure—creating a suction effect—and inhibition of lymphatic pumping that together leads to filling of the “third space.”

Reference

DOI: https://doi.org/10.1016/j.jointm.2025.08.008

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About Professor Robert G. Hahn

Professor Robert G. Hahn worked as a full-time clinical anesthetist from 1979 to 1993 before transitioning to academia, where he has held multiple professorial positions. His research focuses on the physiology and monitoring of fluid overload in transurethral surgery and kinetic modelling of infusion fluids. With a strong methodological interest, his current work explores clinically applicable approaches for monitoring fluid therapy and detecting preoperative dehydration. Professor Hahn has supervised 20 PhD students and authored over 400 scientific papers and several books, including Hemodynamic Monitoring and Fluid Therapy during Surgery (Cambridge University Press).