Evaluation of the anti-endotoxin effects of polymyxin B in a feline model of endotoxemia

Abstract

Directed, effective therapies for feline sepsis are needed to reduce the high morbidity and mortality associated with this disease. We investigated the anti-endotoxin effects of polymyxin B (PMB) in a blinded, placebo controlled fashion, both ex vivo in a feline whole blood culture system and in vivo, using a low-dose endotoxin infusion in cats. Serial measures of systemic inflammation, and hemodynamic stability, were compared between groups. Ex vivo, PMB significantly decreased lipopolysaccharide-induced tumor necrosis factor (TNF) production from whole blood. PMB (1mg/kg over 30min) demonstrated anti-endotoxin effects in vivo, including decreased peak plasma TNF activity (P<0.001) and increased white blood cell count (P=0.019), with no adverse effects. Given the apparent safety and anti-endotoxin effects of PMB in this endotoxemia model, a carefully designed, randomized, blinded, placebo controlled clinical trial evaluating the use of PMB in naturally occurring Gram-negative feline sepsis should be considered.

Fig 1

TNF concentrations in feline whole blood culture after stimulation with control (□) or LPS (▪) and treatment with PMB, in vitro. Data are expressed as mean±SE. *Supernatant TNF activity was significantly less from LPS-stimulated whole blood treated with 1, 5, 10 and 25 μg/ml of PMB compared to blood not treated with PMB (P≤0.004).

Fig 2

Comparison of rectal temperature between cats treated with PMB (□) or placebo (▪). Endotoxin infusion was initiated at time 0. Data are expressed as mean±SE. Temperature in both groups increase significantly over time compared to baseline. There was no significant difference between treatments.

Fig 3

Comparison of systolic arterial BP between cats treated with PMB (□) or placebo (▪). Endotoxin infusion was initiated at time 0. BP decreased significantly in both groups compared to baseline. There was no significant difference between treatments. Data are expressed as mean±SE.

Fig 4

Comparison of WBCC between cats treated with PMB (□) or placebo (▪). Endotoxin infusion was initiated at time 0. Data are expressed as mean±SE. WBCCs in both groups decreased significantly compared to baseline. *The WBCC was significantly higher at 4 and 6 h in the PMB treated cats compared to the placebo group (P=0.019).

Fig 5

Comparison of plasma TNF activity between cats treated with PMB (□) or placebo (▪). Endotoxin infusion was initiated at time 0. Data are expressed as mean±SE. *The TNF activity was significantly lower in the PMB treated cats compared to the placebo group (P<0.001).