Effects of Vasopressors on Immune Response
- Conditions
- Endotoxemia
- Interventions
- Registration Number
- NCT02675868
- Lead Sponsor
- Radboud University Medical Center
- Brief Summary
Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. Catecholamines exert profound immunomodulatory effects. Noradrenaline in vitro inhibits LPS-induced pro-inflammatory cytokine production, however, the actions on immune function in vivo have not been assessed. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
- Detailed Description
Rationale:
Septic shock is a major medical challenge associated with a high mortality rate and increasing incidence. It has become clear that the majority of septic patients do not succumb to an initial pro-inflammatory "hit", but at a later time-point in a pronounced immunosuppressive state, so called 'immunoparalysis'. Noradrenaline is a catecholamine and the cornerstone treatment for the improvement of hemodynamic parameters in septic shock. However, catecholamines exert profound immunomodulatory effects which have mainly been studied for adrenaline. It profoundly inhibits LPS-induced production of TNF-α, and enhances production of anti-inflammatory IL-10 in vitro, as well as in animal and human models of inflammation. Although in vitro studies have shown that noradrenaline inhibits LPS-induced pro-inflammatory cytokine production as potently as adrenaline, the effects of noradrenaline on the immune system in vivo have not yet been studied. Furthermore, effects on the immune system of viable vasopressor alternatives for the treatment of septic patients, namely phenylephrine and vasopressin, need to be established in humans in vivo.
Objective: To investigate whether noradrenaline exerts immunomodulatory effects in humans in vivo and to compare noradrenaline to other vasopressors (phenylephrine and vasopressin).
Study design: A randomized double-blind placebo-controlled study in healthy human volunteers during experimental endotoxemia.
Study population: 40 healthy male volunteers, aged 18-35 yrs.
Intervention:
1. The noradrenaline group (n= 10): subjects that will receive intravenous infusion of noradrenaline 0.05 μg/kg/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
2. The phenylephrine group (n=10): subjects that will receive intravenous infusion of phenylephrine 0.5 μg/kg/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS. .
3. The vasopressin group (n = 10): subjects that will receive intravenous infusion of vasopressin 0.04 IU/min for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
4. The placebo group (n = 10): subjects that will receive intravenous infusion of NaCl 0.9% for 5 hours, starting 60 minutes before intravenous administration of 2 ng/kg LPS.
Main parameters/endpoints:
The difference of LPS-induced TNF-α plasma concentrations following endotoxemia between the noradrenaline and the placebo groups
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Male
- Target Recruitment
- 40
- Written informed consent
- Age ≥18 and ≤35 yrs
- Male
- Healthy
- Use of any medication
- Smoking
- Previous spontaneous vagal collapse
- History of atrial or ventricular arrhythmia
- (Family) history of myocardial infarction or stroke under the age of 65 years
- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
- Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
- Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
- Renal impairment (defined as plasma creatinin >120 μmol/l)
- Liver enzyme abnormalities
- Medical history of any disease associated with immune deficiency
- CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxin administration
- Participation in a drug trial or donation of blood 3 months prior to the LPS challenge
- Use of recreational drugs within 7 days prior to experiment day
- Recent hospital admission or surgery with general anaesthesia (<3 months)
- Known anaphylaxis or hypersensitivity to the study drugs or their excipients
- Recent anaesthesia with halogenated agents
- Known cardiovascular disease (coronary artery disease)
- Known chronic nephritis
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Vasopressins Vasopressins The vasopressin group: a group of 10 subjects that will receive vasopressin 0.04 IU/min infusion for 5 hours, starting 60 minutes before endotoxin administration. Placebo Placebo The placebo group: a group of 10 subjects that will receive NaCl 0.9% infusion for 5 hours, starting 60 minutes before endotoxin administration. Norepinephrine Norepinephrine The noradrenaline group: a group of 10 subjects that will receive noradrenaline 0.05 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration. Phenylephrine Phenylephrine The phenylephrine group: a group of 10 subjects that will receive phenylephrine 0.5 μg/kg/min infusion for 5 hours, starting 60 minutes before endotoxin administration.
- Primary Outcome Measures
Name Time Method concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups 1 day comparison of subjects treated with noradrenaline compared to subjects treated with placebo
- Secondary Outcome Measures
Name Time Method concentration plasma IL-1beta (pg/ml) 1 day Measured with Luminex assay
symptoms during endotoxin day 1 day 6 point likert scale
blood pressure 1 day mmHg
temperature 1 day tympanic temperature
cytokine production after ex vivo stimulation of leukocytes 1 day phenotype of circulating leucocytes 1 day Heart rate variability 1 day Comparison between Holter and 2 phone applications
Mean flow velocity of the median cerebral artery 1 day As measured via Transcranial Doppler Ultrasound
-The phenotype of circulating leukocytes 1 day Measured with Luminex assay
concentration plasma IL-10 (pg/ml) 1 day Measured with Luminex assay
concentration plasma IL-1RA (pg/ml) 1 day Measured with Luminex assay
concentration plasma IL-6 (pg/ml) 1 day Measured with Luminex assay
concentration plasma IL-8 (pg/ml) 1 day Measured with Luminex assay
Leucocyte counts and differentiation 1 day Measured with Luminex assay
cerebral microcirculatory flow 1 day As measured via Near Infrared Spectroscopy
Breathing frequency (breaths/ min) 1 day comparison between pulseoximeter and a health Patch device and VISI mobile device
Tranfer function analysis 1 day As derived from transcranial Doppler Ultrasound
Stress Levels (in percentage based on heart rate and heart rate variability) 1 day Comparison between health patch device, and 2 phone applications and a subjective stress questionaire
Cerebral vascular resistance 1 day As derived from transcranial Doppler Ultrasound
Cerebral Critical closing pressure 1 day As derived from transcranial Doppler Ultrasound
Microvascular flow (microvascular flow index) 1 day Measured via Sidestream Darkfield Imaging
Pulsatility index of the median cerebral artery 1 day As measured via Transcranial Doppler Ultrasound
Mean flow index via 1 day As measured via Transcranial Doppler Ultrasound
cerebral oxygenation 1 day As measured via Near infrared spectroscopy
Trial Locations
- Locations (1)
Radboudumc
🇳🇱Nijmegen, Gelderland, Netherlands