Clinical trial NCT00246714: Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans
Official title: Pathophysiology and Clinical Relevance of Endotoxin Tolerance in Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Endotoxemia
Keywords: endotoxin tolerance
humans
cross-tolerance
pro and anti-inflammatory cytokines
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2005-10-30
Enrollment: 16
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

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 description: See protocol

Eligibility criteria: Inclusion Criteria:

* Healthy male volunteers

Exclusion Criteria:

* drug-, nicotine-, alcohol abuses
* tendency towards fainting
* BMI \< 18 kg/m2

Primary outcomes:
measure: inducing endotoxin tolerance
timeFrame: 5 days
measure: Hemodynamics
timeFrame: 5 days
measure: Markers of Inflammation
timeFrame: 5 days
measure: Cytokines
timeFrame: 5 days
measure: Mediators of Vascular reactivity
timeFrame: 5 days
measure: Sensitivity to norepinephrine
timeFrame: 5 days
measure: Endothelial-dependent vasorelaxation
timeFrame: 5 days
measure: Cross tolerance
timeFrame: 6 days
measure: Ischemia-reperfusion injury
timeFrame: 6 days
measure: Effects on tissue saturation (measured by NIRS)
timeFrame: 24 hrs after LPS administration
Secondary outcomes:
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Center
state: Gelderland
Study officials:
affiliation: Radboud University Nijmegen Medical Center
name: Peter Pickkers, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: