THERAPEUTIC TRIAL OF RECONSTITUTED HUMAN HIGH-DENSITY-LIPOPROTEIN IN A CANINE MODEL OF GRAM-NEGATIVE SEPTIC SHOCK

In a controlled, randomized trial, the authors investigated the effect s of reconstituted human high-density lipoprotein (R-HDL) on survival, endotoxemia, cytokine production and pathophysiologic and metabolic e vents in an animal model of gramnegative septic shock. At 0.5, 8 and 1 6 hr after implantation of a clot infected with Escherichia coil, cani nes received intravenous R-HDL (n = 13), control lipid (n = 7) or huma n serum albumin (HSA, n = 7) divided into three doses (0.3, 0.1 and 0. 1 g/kg, respectively) at an hourly rate of 0.1 g/kg. All animals were treated with antibiotics and fluids. Animals treated with R-HDL had lo wer levels of circulating endotoxin and tumor necrosis factor and a sm aller decrease in white blood cell counts than did animals treated wit h lipids and HSA (all P < .05). The survival times of lipid- and HSA-t reated animals were similar (P = .3) and were significantly greater th an those of R-HDL-treated animals (P = .02). During the first 6 hr aft er clot implantation, R-HDL-treated animals had significantly greater abnormalities in liver function test findings compared with lipid- and HSA-treated animals (all P < .05). For the first 24 hr, R-HDL-treated animals had significant increases in HDL levels; however, there were no significant relationships between these levels and the constituents of HDL(apolipoprotein Al and phosphatidylcholine) or liver function a bnormalities and survival times (all r < .2, P > .3). In normal animal s, administration of R-HDL (in similar doses) caused transient elevati on of liver enzymes; in animals given sterile clot i.p., R-HDL caused seizures. Thus, in septic and nonseptic animals, this preparation of R -HDL produced hepatic and neurologic toxicity. However, in septic anim als, R-HDL also improved leukopenia and decreased endotoxemia and circ ulating levels of tumor necrosis factor. If the toxicities associated with R-HDL can be reduced, its antiendotoxin effects should be investi gated for their potential benefits in live bacterial infections.