Dose-related effects of norepinephrine on early-stage endotoxemic shock in a swine model

BACKGROUND: The benefits of early use of norepinephrine in endotoxemic shock remain unknown. We aimed to elucidate the effects of different doses of norepinephrine in early-stage endotoxemic shock using a clinically relevant large animal model. METHODS: Vasodilatory shock was induced by endotoxin bolus in 30 Bama suckling pigs. Treatment included fluid resuscitation and administration of different doses of norepinephrine, to induce return to baseline mean arterial pressure (MAP). Fluid management, hemodynamic, microcirculation, inflammation, and organ function variables were monitored. All animals were supported for 6 h after endotoxemic shock. RESULTS: Infused fluid volume decreased with increasing norepinephrine dose. Return to baseline MAP was achieved more frequently with doses of 0.8 µg/kg/min and 1.6 µg/kg/min (P <0.01). At the end of the shock resuscitation period, cardiac index was higher in pigs treated with 0.8 µg/kg/min norepinephrine (P <0.01), while systemic vascular resistance was higher in those receiving 0.4 µg/kg/min (P <0.01). Extravascular lung water level and degree of organ edema were higher in animals administered no or 0.2 µg/kg/min norepinephrine (P <0.01), while the percentage of perfused small vessel density (PSVD) was higher in those receiving 0.8 µg/kg/min (P <0.05) and serum lactate was higher in the groups administered no and 1.6 µg/kg/min norepinephrine (P <0.01). CONCLUSIONS: The impact of norepinephrine on the macro- and micro-circulation in early-stage endotoxemic shock is dose-dependent, with very low and very high doses resulting in detrimental effects. Only an appropriate norepinephrine dose was associated with improved tissue perfusion and organ function.