Abstract 317: Development of a Swine Model of Rapidly-Induced Septic Shock Using Single Lipopolysaccharide Infusion and Titratable Inhaled Nitric Oxide to Prevent Severe Pulmonary Vasoconstriction

Abstract

Objective: A serious limitation of LPS-induced swine models of septic shock is severe pulmonary vasoconstriction triggered, in part, by the pulmonary release of thromboxane A2. Efforts to overcome this limitation have included a stepwise increase in LPS dosing, intravenous aspirin derivatives, and inhaled nitric oxide (NO). We studied the effects of titrated inhaled NO given coincident with rapid LPS-infusion aimed at inducing the key features of septic shock over a shorter time period. Methods: We developed a LabVIEW-controlled system for inhaled NO delivery and monitoring. Exploratory studies showed that an NO concentration of up to 300 ppm sufficed to prevent significant pulmonary vasoconstriction despite delivery of a full LPS dose (12.6 μg/kg) in 30 minutes. We used this approach in 6 male domestic pigs (39.2 - 41.1 kg) and assessed hemodynamic and metabolic effects over 6 hours. NO and LPS infusion were started concurrently. Fluid resuscitation and vasopressor therapy were guided by macrohemodynamic measurements using custom-developed LabVIEW-controlled closed-loop algorithms. Results: Shown are medians with IQ25 and IQ75. LPS infusion increased pulmonary vascular resistance from 112 [72, 127] at baseline to 213 [120, 313] dynes-sec/cm 5 after 20 minutes. NO (139 [131, 166] ml/min) rapidly blunted the effect preventing the mean pulmonary artery pressure from exceeding 30 mmHg, avoiding detrimental effects on right ventricular function throughout the experiment. NO was rapidly de-escalated over 30 minutes using a closed-loop algorithm developed to prevent the mean pulmonary artery pressure from exceeding 30 mmHg. Within 60 minutes of LPS infusion start, animals began to develop key features of septic shock including tachycardia, hypotension, and systemic vasodilation triggering fluid resuscitation and norepinephrine administration. Additionally, blood lactate increased from 1.06 [0.90, 1.45] at baseline to 4.14 [2.43, 8.78] mmol/l after 3 hours remaining stable for an additional hour and subsequently decreasing in 3 and increasing in the other 3 animals, with half of the animals surviving the 6-h period. Conclusion: We developed a swine model of rapidly-induced key features of septic shock useful to explore early septic shock management.