Effects of Vasopressors on Immune Response

Sponsor

Radboud University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT02675868

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

4.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Endotoxemia	Drug: Norepinephrine Drug: Phenylephrine Drug: Vasopressins Drug: Placebo	Phase 4

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:

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.
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. .
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.
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

Study Design

Study Type:

Interventional

Actual Enrollment :

40 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

The Effects of Different Vasopressors on the Innate Immune Response During Experimental Human Endotoxemia, a Pilot Proof-of-principle Study

Study Start Date :

Jan 1, 2016

Actual Primary Completion Date :

Jul 1, 2016

Actual Study Completion Date :

Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Norepinephrine Noradrenaline is an endogenous catecholamine with sympathomimetic effects. It has mainly α-adrenergic receptor selectivity but also β-effects in higher concentrations. It will be administered at 0.05 μg/kg/min, a clinical relevant dose on the low end of the scale. Other Names: Noradrenaline
Active Comparator: 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.	Drug: Vasopressins Vasopressin is 8-arginine-vasopressin, a synthetic analogue of endogenous nonapeptide hormone. It exerts its action via V1 receptors (ubiquitous vasoconstriction) and V2 receptors (renal water resorption). It will be administered at 0.04 IU/min, a clinically relevant dose. Other Names: Argipressin
Active Comparator: 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.	Drug: Phenylephrine Phenylephrine is a selective α-adrenergic receptor agonist. It will be administered at 0.5 μg/kg/min, based on its relative vasopressor potency in comparison with noradrenaline.
Placebo Comparator: 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.	Drug: Placebo NaCl 0.9% infusion Other Names: NaCl 0,9%

Outcome Measures

Primary Outcome Measures

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

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
-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-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
Breathing frequency (breaths/ min) [1 day]
comparison between pulseoximeter and a health Patch device and VISI mobile device
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
Mean flow velocity of the median cerebral artery [1 day]
As measured via Transcranial Doppler Ultrasound
cerebral microcirculatory flow [1 day]
As measured via Near Infrared Spectroscopy
Tranfer function analysis [1 day]
As derived from transcranial Doppler Ultrasound
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Written informed consent
Age ≥18 and ≤35 yrs
Male
Healthy

Exclusion Criteria:

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