OBJECTIVE: The objective of this study was to assess the efficacy of variations in dose and timing of administration of recombinant human IL-10 (rhIL-10) on inflammatory and cardiovascular responses in a human endotoxemia model of sepsis. DESIGN: The authors conducted a randomized, placebo-controlled, double-blind trial. SETTING: The study was conducted in a procedure room of an intensive-care unit. PARTICIPANTS: The study comprised 24 healthy male volunteers. INTERVENTIONS: Interventions consisted of intravenous administration of rhIL-10 at 1, 10, or 25 microg/kg either 2 mins or 2 hrs before Escherichia coli lipopolysaccharide (4 ng/kg) or placebo. MEASUREMENTS AND RESULTS: The placebo group receiving lipopolysaccharide alone demonstrated significant, time-dependent changes in vital signs, white blood cell counts, inflammatory cytokine/cortisol levels, and hemodynamic/cardiovascular (including echocardiographic) parameters over the duration of the study. rhIL-10, administered immediately before (concurrent) lipopolysaccharide resulted in decreased temperature and heart rate responses as well as decreased serum levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-6), IL-1 receptor antagonist, cortisol, and total leukocytes/neutrophils compared with lipopolysaccharide alone. Dose-dependent effects were absent. In contrast, rhIL-10 administration 2 hrs before endotoxin augmented the endotoxin-induced IL-beta and IL-1 receptor antagonist response. rhIL-10 failed to modulate major cardiovascular responses (cardiac output, stroke volume index, ejection fraction, peak systolic pressure/end-systolic volume ratio) to endotoxin in both study groups as assessed by echocardiography. CONCLUSION: Concurrent administration of rhIL-10 suppresses the human inflammatory/stress response but has no effect on the hemodynamic/cardiovascular response to endotoxin. Early administration of rhIL-10 can potentially augment elements of the cytokine inflammatory response to lipopolysaccharide. These findings suggest significant limitations of rhIL-10 as a potential immunomodulatory therapy for sepsis.
RCT Entities:
OBJECTIVE: The objective of this study was to assess the efficacy of variations in dose and timing of administration of recombinant humanIL-10 (rhIL-10) on inflammatory and cardiovascular responses in a humanendotoxemia model of sepsis. DESIGN: The authors conducted a randomized, placebo-controlled, double-blind trial. SETTING: The study was conducted in a procedure room of an intensive-care unit. PARTICIPANTS: The study comprised 24 healthy male volunteers. INTERVENTIONS: Interventions consisted of intravenous administration of rhIL-10 at 1, 10, or 25 microg/kg either 2 mins or 2 hrs before Escherichia colilipopolysaccharide (4 ng/kg) or placebo. MEASUREMENTS AND RESULTS: The placebo group receiving lipopolysaccharide alone demonstrated significant, time-dependent changes in vital signs, white blood cell counts, inflammatory cytokine/cortisol levels, and hemodynamic/cardiovascular (including echocardiographic) parameters over the duration of the study. rhIL-10, administered immediately before (concurrent) lipopolysaccharide resulted in decreased temperature and heart rate responses as well as decreased serum levels of proinflammatory cytokines (tumor necrosis factor-alpha, IL-6), IL-1 receptor antagonist, cortisol, and total leukocytes/neutrophils compared with lipopolysaccharide alone. Dose-dependent effects were absent. In contrast, rhIL-10 administration 2 hrs before endotoxin augmented the endotoxin-induced IL-beta and IL-1 receptor antagonist response. rhIL-10 failed to modulate major cardiovascular responses (cardiac output, stroke volume index, ejection fraction, peak systolic pressure/end-systolic volume ratio) to endotoxin in both study groups as assessed by echocardiography. CONCLUSION: Concurrent administration of rhIL-10 suppresses the human inflammatory/stress response but has no effect on the hemodynamic/cardiovascular response to endotoxin. Early administration of rhIL-10 can potentially augment elements of the cytokine inflammatory response to lipopolysaccharide. These findings suggest significant limitations of rhIL-10 as a potential immunomodulatory therapy for sepsis.
Authors: Matthijs Kox; Lucas T van Eijk; Jelle Zwaag; Joanne van den Wildenberg; Fred C G J Sweep; Johannes G van der Hoeven; Peter Pickkers Journal: Proc Natl Acad Sci U S A Date: 2014-05-05 Impact factor: 11.205
Authors: Dan Ziegler; Alexander Strom; Klaus Strassburger; Bettina Nowotny; Lejla Zahiragic; Peter J Nowotny; Maren Carstensen-Kirberg; Christian Herder; Julia Szendroedi; Michael Roden Journal: PLoS One Date: 2015-04-20 Impact factor: 3.240
Authors: Dorien Kiers; Ben Wielockx; Esther Peters; Lucas T van Eijk; Jelle Gerretsen; Aaron John; Emmy Janssen; Rianne Groeneveld; Mara Peters; Lars Damen; Ana M Meneses; Anja Krüger; Jeroen D Langereis; Aldert L Zomer; Michael R Blackburn; Leo A Joosten; Mihai G Netea; Niels P Riksen; Johannes G van der Hoeven; Gert-Jan Scheffer; Holger K Eltzschig; Peter Pickkers; Matthijs Kox Journal: EBioMedicine Date: 2018-07-04 Impact factor: 8.143
Authors: Robert Grealy; Mary White; Patrick Stordeur; Dermot Kelleher; Derek G Doherty; Ross McManus; Thomas Ryan Journal: Mediators Inflamm Date: 2013-07-02 Impact factor: 4.711