Experimental human endotoxemia is associated with depression of load-independent contractility indices: prevention by the lipid a analogue E5531.

Abstract

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 microg, 250 microg, 500 microg, or 1,000 microg) 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 (sigmaes)/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 sigmaes/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.

• Authors: Anand Kumar, Eugene Bunnell, Melvyn Lynn, Ramon Anel, Kalim Habet, Alex Neumann, Joseph E Parrillo
• Journal: Chest (Chest) Vol. 126 Issue 3 Pg. 860-7 (Sep 2004) ISSN: 0012-3692 [Print] United States
• PMID: 15364767 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Lipid A
• Lipopolysaccharides
• E 5531

Topics

• Adolescent
• Adult
• Cardiac Output, Low (drug therapy, physiopathology)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Endotoxemia (drug therapy)
• Escherichia coli
• Hemodynamics (drug effects, physiology)
• Humans
• Intensive Care Units
• Lipid A (analogs & derivatives, therapeutic use)
• Lipopolysaccharides (toxicity)
• Male
• Myocardial Contraction (drug effects, physiology)