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Clinical Investigations in Critical Care |

Experimental Human Endotoxemia Is Associated With Depression of Load-Independent Contractility Indices*: Prevention by the Lipid A Analogue E5531

Anand Kumar, MD; Eugene Bunnell, MD, FCCP; Melvyn Lynn, PhD; Ramon Anel, MD; Kalim Habet, MD, FCCP; Alex Neumann, MS; Joseph E. Parrillo, MD, FCCP
Author and Funding Information

*From the Division of Cardiovascular Disease and Critical Care Medicine (Drs. Bunnell, Anel, Habet, and Mr. Neumann), Rush-Presbyterian-St. Luke’s Medical Center, Chicago, IL; Division of Cardiovascular Disease and Critical Care Medicine (Dr. Parillo), Cooper Hospital/University Medical Center, Robert Wood Johnson Medical School, Camden, NJ; Section of Critical Care Medicine (Dr. Kumar), University of Manitoba, Winnipeg, MB, Canada; and Eisai Medical Research (Dr. Lynn), Teaneck, NJ.

Correspondence to: Anand Kumar, MD, Section of Critical Care Medicine, Health Sciences Centre, GE706, 820 Sherbrook St, Winnipeg, MB, Canada, R3A 1R9; e-mail: akumar61@yahoo.com



Chest. 2004;126(3):860-867. doi:10.1378/chest.126.3.860
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Objective: To evaluate the efficacy of a novel lipopolysaccharide (LPS) antagonist, E5531, in blocking LPS-induced cardiac responses including myocardial depression (as assessed by relatively load-independent echocardiographic indices of contractility) in a human model of experimental endotoxemia.

Design: Randomized, prospective, placebo-controlled, double-blind trial.

Setting: ICU procedure room.

Participants: Thirty-two healthy, male volunteers.

Interventions: Administration of LPS (4 ng/kg) and either a placebo or one of four sequential doses of E5531 (100 μg, 250 μg, 500 μg, or 1,000 μg) followed by volumetric echocardiography before and during 4-L saline solution infusion (3 L over 3 h, followed by 1 L over 2 h).

Results: In addition to the generation of a hyperdynamic circulation throughout the study period, administration of LPS resulted in a biphasic contractility response. Ejection fraction (EF), rate-corrected mean velocity of circumferential fiber shortening (Vcfc), peak systolic BP (SBP)/end-systolic volume index (ESVI) ratio, and end-systolic pressure (Pes)/ESVI ratio increased at the 3-h post-LPS assessment, compared to a control group of subjects receiving only similar amounts of saline solution (minimum p < 0.001). End-systolic myocardial wall stress (ςes)/ESVI ratio, one of the most load independent of the contractility indices, was unchanged. At 5 h after endotoxin, EF, Vcfc, SBP/ESVI, Pes/ESVI, and ςes/ESVI were all decreased (minimum p < 0.01), indicating myocardial depression. When present, early (3 h after LPS), apparent enhancement of myocardial contractility and later (5 h after LPS) myocardial depression were substantially blunted by administration of E5531 (minimum p < 0.025), typically in a concentration-dependent manner.

Conclusions: Endotoxin generates significant myocardial depression when measured using highly load-independent indices of cardiac contractility. E5531 is a potent inhibitor of the early hyperdynamic cardiovascular and later myocardial depression response seen in experimental human endotoxemia.

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