Primary objective: To determine the effect of hyperbilirubinemia on systemic activation of the innate immune response induced by a lipopolysaccharide (LPS) challenge. Secondary Objective(s): - To determine if hyperbilirubinemia shifts the pro-anti…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
- Decreased and nonspecific blood pressure disorders and shock
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study parameter is the concentration of circulating cytokines at
different time points following LPS administration in the absence or presence
of hyperbilirubinemia.
Secondary outcome
- pro-anti oxidant balance during human endotoxemia in the absence or presence
of hyperbilirubinemia
- endothelial dysfunction during human endotoxemia in the absence or presence
of hyperbilirubinemia as assessed by the measurement of the response to
vasodilators acetylcholine and nitroglycerin. Furthermore, the release of
vascular adhesion molecules indicating activation of the endothelium will be
measured
- subclinical renal damage known to occur during human endotoxemia in the
absence or presence of hyperbilirubinemia
- the interplay between HO-1, NO and bilirubin during human endotoxemia
Background summary
Excessive inflammation, production of free radicals and vascular injury are
considered main contributors to the development of organ dysfunction in
patients with sepsis. Bilirubin is one of the most powerful anti-oxidants of
the human body and the administration of bilirubin in animal models for sepsis
reduces inflammation and mortality. Recent experiments of our research group
have demonstrated beneficial effects of increased concentrations of
endogenously produced bilirubin, induced by atazanavir (CMO numbers 2008/028
and 2009/047). These studies demonstrated an increase in anti-oxidant potential
and, an improved vascular response to acetylcholine in diabetes patients and
healthy volunteers during human endotoxemia. Furthermore, immunomodulatory
effects were observed after infusion with LPS.
However, direct effects of atazanavir (not related to the increase in
bilirubin) could not be excluded. Recently, the departments of clinical
pharmacy and pharmacology-toxicology of the Radboud University Nijmegen Medical
Centre have developed a bilirubin formulation that is suitable for infusion in
humans. Safety and kinetics have been studied recently (CMO 2009/170).
Bilirubin infusion appears to be safe and without side effects.
In the present study, we aim to determine the effects of parenteral treatment
with bilirubin on the innate immune response and end organ damage as assessed
by vascular response and subclinical kidney damage using the human endotoxemia
model. The human endotoxemia model permits the study of key players in the
immune response to a gram negative stimulus in vivo, therefore serving as a
useful tool to investigate potential novel therapeutic strategies for
inflammation/sepsis in a standardized setting in humans in vivo.
Study objective
Primary objective:
To determine the effect of hyperbilirubinemia on systemic activation of the
innate immune response induced by a lipopolysaccharide (LPS) challenge.
Secondary Objective(s):
- To determine if hyperbilirubinemia shifts the pro-anti oxidant balance during
human endotoxemia
- To determine if hyperbilirubinemia attenuates vascular injury as assessed by
the measurement of the response to vasodilators acetylcholine and nitroglycerin
. Furthermore, the release of vascular adhesion molecules indicating activation
of the endothelium will be measured
- To determine if hyperbilirubinemia can attenuate subclinical renal damage
known to occur during human endotoxemia
- To investigate the interplay between HO-1, NO and bilirubin during human
endotoxemia
Study design
Randomized open label placebo controlled parallel intervention study in healthy
human volunteers using human experimental endotoxemia
Intervention
Subjects will be included in one of three different protocols:
1. In this arm, 2 subjects will be infused with 2.9 mg/kg bilirubin (diluted in
albumin 200 mg/ml).
2. Subjects in this group (n=10) will be infused with 387 mg/kg albumin (200
mg/ml) intravenously serving as placebo. This dosage is the exact amount
needed to dilute the bilirubin in arm 1 and 3 normalized for body weight.
Infusion will be performed over 10 minutes. At 15 minutes after the start of
the albumin infusion, a dose of 2 ng/kg LPS derived from E coli O:113 will be
administered.
3. Subjects in this group (n=10) receive 2.9 mg/kg bilirubin (diluted in
albumin 200 mg/ml) intravenously over 10 minutes. At 15 minutes after the
start of the bilirubin infusion, a dose of 2 ng/kg LPS derived from E coli
O:113 will be administered.
Study burden and risks
A medical interview and physical examination are part of this study. Bilirubin
will be administered by continuous infusion and concentrations will be checked
in blood at several time points. In the previously performed safety and
kinetics study no side effects of intravenous bilirubin were observed.
Volunteers will be monitored on the research unit of our intensive care.
Subjects in Arm 1 will receive two intravenous lines (one for blood sampling
and one for bilirubin administration). Blood pressure will be monitored using
non-invasive blood pressure measurements every 30 minutes.
Subjects in arm 2 and 3 will receive an arterial line to facilitate blood
pressure monitoring and blood sampling. The arterial line will be placed under
local anaesthesia using 2% lidocaine. Furthermore a venous cannula will be
placed in these subjects.
The administration of LPS induces flu-like symptoms for approximately 4 hrs.
This model of systemic inflammation has been applied for many years in research
centres all over the world. Endotoxin administration is considered safe and no
long term effects have ever been documented.
At the Radboud University Medical Centre, over 250 volunteers have received
more than 350 injections of lipopolysaccharide. Therefore, there is sufficient
experience with this model at this centre.
In total, a maximum of 400 ml blood will be drawn during the experiment and
urine will be collected.
The subjects will not benefit directly from participation to the study. A
subject fee is provided.
Geert Grooteplein-zuid 10
6525 GA Nijmegen
NL
Geert Grooteplein-zuid 10
6525 GA Nijmegen
NL
Listed location countries
Age
Inclusion criteria
-Age >= 18 and <= 35 years
-Male
-Healthy
Exclusion criteria
-Use of any medication or anti-oxidant vitamin supplements.
-History of allergic reaction to albumin or any other drug used in the study.
-Smoking.
-Previous spontaneous vagal collapse.
-History, signs or symptoms of cardiovascular disease.
-(Family) history of myocardial infarction or stroke under the age of 65 years.
-Cardiac conduction abnormalities on the ECG consisting of a 1st degree (or higher degree) atrioventricular block or a complex bundle branch block.
- Hypertension (defined as a repeated measurement of RR systolic > 160 or RR diastolic > 90 mmHg).
- Hypotension (defined as RR systolic < 100 or RR diastolic < 50 mmHg).
- Renal impairment (defined as plasma creatinin >120 µmol/l).
- Liver enzyme abnormalities or positive hepatitis B serology.
- Subjects with a total bilirubin level above 15 µmol/L and a normal direct bilirubin level suggesting Gilbert Syndrome.
- Positive HIV serology or any other obvious disease associated with immune deficiency.
- Febrile illness in the week before the experiment.
- Participation in a drug trial or donation of blood 3 months prior to the LPS challenge.
- Inability to understand the nature and extent of the trial and the procedures required.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004969-32-NL |
| CCMO | NL38438.091.11 |
| Other | Volgt |