Clinical Trial: Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans

Brief Summary:

A number of diseases lead to a so called systemic inflammatory response syndrome (SIRS). This excessive response is self-destructive and leads to major complications of the initial disease: dysfunction of the microcirculation, systemic vasodilation, and increased capillary leakage and oedema. Animal studies have shown that pre-treatment with endotoxin (lipopolysaccharide or LPS) suppress the excessive immune response and when rechallenged, the animal survive a normally lethal dose of endotoxin.

Besides a diminished cytokine response, an increased production of leucocytes in the bone marrow and an increased phagocytosis after pre-treatment with endotoxin is seen. The combination of these factors: diminished systemic inflammatory response and increased cellular immunity makes that endotoxin tolerance is a useful tool for preventing the complications after an excessive inflammatory response.

Further, the presence of cross-tolerance has also been shown: Endotoxin tolerant mice survive more after induction of a normally lethal fungal infection. Endotoxin tolerance is also protective for ischemia/reperfusion injury in kidneys, heart and liver. Little data is known about endotoxin tolerance in human.

The purpose of this study is to induce a state of tolerance through 2 different administration schedules and monitor the effect of tolerance on pro- and anti-inflammatory cytokines, other inflammatory parameters and different proteins involved in the signalling pathway. The effects of tolerance on vascular reactivity will be determined. Finally, the effect of tolerance on ischemia-reperfusion injury will be investigated.


Detailed Summary: See protocol
Sponsor: Radboud University

Current Primary Outcome:

  • inducing endotoxin tolerance [ Time Frame: 5 days ]
  • Hemodynamics [ Time Frame: 5 days ]
  • Markers of Inflammation [ Time Frame: 5 days ]
  • Cytokines [ Time Frame: 5 days ]
  • Mediators of Vascular reactivity [ Time Frame: 5 days ]
  • Sensitivity to norepinephrine [ Time Frame: 5 days ]
  • Endothelial-dependent vasorelaxation [ Time Frame: 5 days ]
  • Cross tolerance [ Time Frame: 6 days ]
  • Ischemia-reperfusion injury [ Time Frame: 6 days ]
  • Effects on tissue saturation (measured by NIRS) [ Time Frame: 24 hrs after LPS administration ]


Original Primary Outcome:

  • inducing endotoxin tolerance
  • Hemodynamics
  • Markers of Inflammation
  • Cytokines
  • Mediators of Vascular reactivity
  • Sensitivity to norepinephrine
  • Endothelial-dependent vasorelaxation
  • Cross tolerance


Current Secondary Outcome:

Original Secondary Outcome:

Information By: Radboud University

Dates:
Date Received: October 28, 2005
Date Started: October 2005
Date Completion:
Last Updated: April 14, 2008
Last Verified: April 2008