| Experimental human endotoxemia is associated with depression of load-independent contractility indices: prevention by the lipid a analogue E5531. | |
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MedLine Citation:
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PMID: 15364767 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 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. |
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Authors:
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Anand Kumar; Eugene Bunnell; Melvyn Lynn; Ramon Anel; Kalim Habet; Alex Neumann; Joseph E Parrillo |
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Publication Detail:
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Type: Clinical Trial; Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Chest Volume: 126 ISSN: 0012-3692 ISO Abbreviation: Chest Publication Date: 2004 Sep |
Date Detail:
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Created Date: 2004-09-14 Completed Date: 2004-11-02 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0231335 Medline TA: Chest Country: United States |
Other Details:
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Languages: eng Pagination: 860-7 Citation Subset: AIM; IM |
Affiliation:
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Section of Critical Care Medicine, Health Sciences Centre, GE706, 820 Sherbrook St, Winnipeg, MB, Canada, R3A 1R9. akumar61@yahoo.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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 |
| Chemical | |
Reg. No./Substance:
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0/E 5531; 0/Lipid A; 0/Lipopolysaccharides |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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