Infusion of increasing doses of endotoxin induces progressive acute lung injury but prevents early pulmonary hypertension in pigs

Administration of a single bolus of endotoxin is a model of sepsis response in experimental animal studies. Large animal species, such as pigs and sheep, are more sensitive to endotoxin administration due to an initial excessive pulmonary hypertensive response frequently resulting in acute right heart dysfunction. We investigated whether infusion of high-dose endotoxin in pigs but administered in an increasing dose results in inflammatory response without excessive pulmonary hypertension and right heart dysfunction. Piglets of both sexes weighing 25 to 30 kg were anesthetized and mechanically ventilated. After instrumentation and baseline measurements, animals received an infusion of total 500 mu g kg(-1) i.v. endotoxin (Escherichia coli LPS) over 2 h in an increasing dose of 0.5 to 12 mu g kg(-1) min(-1). Hemodynamic, respiratory, and oxygenation parameters were measured every hour. At 1 and 5 h following endotoxin, plasma levels of inflammatory and organ damage parameters were measured. Endotoxin infusion induced progressive arterial hypoxemia, an increase in peak inspiratory pressure, sustained pulmonary hypertension, and systemic hypotension that persisted throughout the experiment. Endotoxin plasma levels peaked at 1 h following infusion and declined toward baseline values at 5 h thereafter. In contrast, plasma levels of nitrite/nitrate, IL-1ra (as marker of cytokine response), remained markedly increased at 5 h after endotoxin infusion as compared with baseline values. Plasma markers of organ damage were significantly increased. Our data show that the dosing of endotoxin in an increasing manner in pigs produces a reliable model of an experimental sepsis response and organ dysfunction without immediate overwhelming pulmonary hypertension resulting in cardiovascular failure.