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


METHODS
Randomized, prospective, placebo-controlled, double-blind trial.


METHODS
ICU procedure room.


METHODS
Thirty-two healthy, male volunteers.


METHODS
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.
Kumar
Anand
A
Section of Critical Care Medicine, Health Sciences Centre, GE706, 820 Sherbrook St, Winnipeg, MB, Canada, R3A 1R9. akumar61@yahoo.com
Bunnell
Eugene
E
Lynn
Melvyn
M
Anel
Ramon
R
Habet
Kalim
K
Neumann
Alex
A
Parrillo
Joseph E
JE
D000293:Adolescent; D000328:Adult; D002303:Cardiac Output, Low / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D019446:Endotoxemia / Q000188:drug therapy*; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007362:Intensive Care Units; D008050:Lipid A / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology
D008050:Lipid A; D008070:Lipopolysaccharides; C092845:E 5531