CompletedNCT02675868Updated Oct 13, 2016

Effects of Vasopressors on Immune Response

A Phase 4 interventional study of Norepinephrine and Phenylephrine in Endotoxemia, sponsored by Radboud University Medical Center. Completed at 1 site in Netherlands. Open to male participants aged 18 Years to 35 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2016-10-13.

Sponsored by Radboud University Medical Center · Phase 4, Interventional, and Basic science

Phase: Phase 4
Study type: Interventional
Enrollment: 40
Allocation: Randomized
Ages: 18 Years to 35 Years
Sex: Male

Study 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.

Read the 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

Conditions studied

Endotoxemia

Browse trials for

Endotoxemia 84

Keywords

noradrenaline
vasopressin
phenylephrine
endotoxemia
Lipopolysaccharide
vasopressor

Who can participate

Ages eligible: 18 Years to 35 Years
Sexes eligible: Male
Accepts healthy volunteers: Yes

Inclusion criteria

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

Exclusion criteria

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

Study design

Phase: Phase 4
Primary purpose: Basic science
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Triple (Participant, Investigator, Outcomes assessor)
Enrollment: 40 participants (actual)

Study arms

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
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
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
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

Interventions

DrugNorepinephrine
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.
Also known as: Noradrenaline
DrugPhenylephrine
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.
DrugVasopressins
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.
Also known as: Argipressin
DrugPlacebo
NaCl 0.9% infusion
Also known as: NaCl 0,9%

What researchers measure

Primary outcomes

concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups
comparison of subjects treated with noradrenaline compared to subjects treated with placebo
Time frame: 1 day

Secondary outcomes

concentration plasma IL-6 (pg/ml)
Measured with Luminex assay
Time frame: 1 day
concentration plasma IL-8 (pg/ml)
Measured with Luminex assay
Time frame: 1 day
Leucocyte counts and differentiation
Measured with Luminex assay
Time frame: 1 day
-The phenotype of circulating leukocytes
Measured with Luminex assay
Time frame: 1 day
concentration plasma IL-10 (pg/ml)
Measured with Luminex assay
Time frame: 1 day
concentration plasma IL-1RA (pg/ml)
Measured with Luminex assay
Time frame: 1 day
concentration plasma IL-1beta (pg/ml)
Measured with Luminex assay
Time frame: 1 day
symptoms during endotoxin day
6 point likert scale
Time frame: 1 day
blood pressure
mmHg
Time frame: 1 day
temperature
tympanic temperature
Time frame: 1 day
cytokine production after ex vivo stimulation of leukocytes
Time frame: 1 day
phenotype of circulating leucocytes
Time frame: 1 day
Heart rate variability
Comparison between Holter and 2 phone applications
Time frame: 1 day
Breathing frequency (breaths/ min)
comparison between pulseoximeter and a health Patch device and VISI mobile device
Time frame: 1 day
Stress Levels (in percentage based on heart rate and heart rate variability)
Comparison between health patch device, and 2 phone applications and a subjective stress questionaire
Time frame: 1 day
Mean flow velocity of the median cerebral artery
As measured via Transcranial Doppler Ultrasound
Time frame: 1 day
cerebral microcirculatory flow
As measured via Near Infrared Spectroscopy
Time frame: 1 day
Tranfer function analysis
As derived from transcranial Doppler Ultrasound
Time frame: 1 day
Cerebral vascular resistance
As derived from transcranial Doppler Ultrasound
Time frame: 1 day
Cerebral Critical closing pressure
As derived from transcranial Doppler Ultrasound
Time frame: 1 day
Microvascular flow (microvascular flow index)
Measured via Sidestream Darkfield Imaging
Time frame: 1 day
Pulsatility index of the median cerebral artery
As measured via Transcranial Doppler Ultrasound
Time frame: 1 day
Mean flow index
As measured via Transcranial Doppler Ultrasound
Time frame: via 1 day
cerebral oxygenation
As measured via Near infrared spectroscopy
Time frame: 1 day

Study locations

1 site

Radboudumc
Nijmegen, Gelderland 6500HB, Netherlands

References and documents

Publications

Stolk RF, Reinema F, van der Pasch E, Schouwstra J, Bressers S, van Herwaarden AE, Gerretsen J, Schambergen R, Ruth M, van der Hoeven HG, van Leeuwen HJ, Pickkers P, Kox M. Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study. Br J Anaesth. 2021 Mar;126(3):652-664. doi: 10.1016/j.bja.2020.11.040. Epub 2021 Jan 20. PubMed 33483132 ↗
van Loon LM, Stolk RF, van der Hoeven JG, Veltink PH, Pickkers P, Lemson J, Kox M. Effect of Vasopressors on the Macro- and Microcirculation During Systemic Inflammation in Humans In Vivo. Shock. 2020 Feb;53(2):171-174. doi: 10.1097/SHK.0000000000001357. PubMed 31008870 ↗

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT02675868
Lead sponsor: Radboud University Medical Center
Responsible party: Sponsor
First posted: Feb 5, 2016
Start date: Jan 2016
Primary completion: Jul 2016
Completion: Oct 2016
Last update: Oct 13, 2016

Study contacts

Roeland Stolk, MD

principal investigator · Radboudumc, Intensive Care

Oversight

Data monitoring committee: No

View the source record on ClinicalTrials.gov ↗

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