Effects of Vasopressors on Immune Response

Endotoxemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02675868
• Other study ID #: NL53411.091.015
• Status: Completed
• Phase: Phase 4
• First received: January 25, 2016
• Last updated: October 12, 2016
• Start date: January 2016
• Est. completion date: October 2016

Study information

• Verified date: April 2016
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: October 2016
• Est. primary completion date: July 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Endotoxemia

Intervention

Drug:
• Norepinephrine
Noradrenaline is an endogenous catecholamine with sympathomimetic effects. It has mainly a-adrenergic receptor selectivity but also ß-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.
• Phenylephrine
Phenylephrine is a selective a-adrenergic receptor agonist. It will be administered at 0.5 µg/kg/min, based on its relative vasopressor potency in comparison with noradrenaline.
• 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.
• Placebo
NaCl 0.9% infusion

Locations

Country	Name	City	State
Netherlands	Radboudumc	Nijmegen	Gelderland

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	1 day	No
Secondary	concentration plasma IL-6 (pg/ml)	Measured with Luminex assay	1 day	No
Secondary	concentration plasma IL-8 (pg/ml)	Measured with Luminex assay	1 day	No
Secondary	Leucocyte counts and differentiation	Measured with Luminex assay	1 day	No
Secondary	-The phenotype of circulating leukocytes	Measured with Luminex assay	1 day	No
Secondary	concentration plasma IL-10 (pg/ml)	Measured with Luminex assay	1 day	No
Secondary	concentration plasma IL-1RA (pg/ml)	Measured with Luminex assay	1 day	No
Secondary	concentration plasma IL-1beta (pg/ml)	Measured with Luminex assay	1 day	No
Secondary	symptoms during endotoxin day	6 point likert scale	1 day	No
Secondary	blood pressure	mmHg	1 day	No
Secondary	temperature	tympanic temperature	1 day	No
Secondary	cytokine production after ex vivo stimulation of leukocytes		1 day	No
Secondary	phenotype of circulating leucocytes		1 day	No
Secondary	Heart rate variability	Comparison between Holter and 2 phone applications	1 day	No
Secondary	Breathing frequency (breaths/ min)	comparison between pulseoximeter and a health Patch device and VISI mobile device	1 day	No
Secondary	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	1 day	No
Secondary	Mean flow velocity of the median cerebral artery	As measured via Transcranial Doppler Ultrasound	1 day	No
Secondary	cerebral microcirculatory flow	As measured via Near Infrared Spectroscopy	1 day	No
Secondary	Tranfer function analysis	As derived from transcranial Doppler Ultrasound	1 day	No
Secondary	Cerebral vascular resistance	As derived from transcranial Doppler Ultrasound	1 day	No
Secondary	Cerebral Critical closing pressure	As derived from transcranial Doppler Ultrasound	1 day	No
Secondary	Microvascular flow (microvascular flow index)	Measured via Sidestream Darkfield Imaging	1 day	No
Secondary	Pulsatility index of the median cerebral artery	As measured via Transcranial Doppler Ultrasound	1 day	No
Secondary	Mean flow index	As measured via Transcranial Doppler Ultrasound	via 1 day	No
Secondary	cerebral oxygenation	As measured via Near infrared spectroscopy	1 day	No