Clinical trial NCT02675868: Effects of Vasopressors on Immune Response
Official title: The Effects of Different Vasopressors on the Innate Immune Response During Experimental Human Endotoxemia, a Pilot Proof-of-principle Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Endotoxemia
Keywords: noradrenaline
vasopressin
phenylephrine
endotoxemia
Lipopolysaccharide
vasopressor
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2016-02-05
Enrollment: 40
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: 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

Primary outcomes:
measure: concentration plasma TNFalpha (pg/ml) following endotoxemia between the noradrenaline and the placebo groups
timeFrame: 1 day
Secondary outcomes:
measure: concentration plasma IL-6 (pg/ml)
timeFrame: 1 day
measure: concentration plasma IL-8 (pg/ml)
timeFrame: 1 day
measure: Leucocyte counts and differentiation
timeFrame: 1 day
measure: -The phenotype of circulating leukocytes
timeFrame: 1 day
measure: concentration plasma IL-10 (pg/ml)
timeFrame: 1 day
measure: concentration plasma IL-1RA (pg/ml)
timeFrame: 1 day
measure: concentration plasma IL-1beta (pg/ml)
timeFrame: 1 day
measure: symptoms during endotoxin day
timeFrame: 1 day
measure: blood pressure
timeFrame: 1 day
measure: temperature
timeFrame: 1 day
measure: cytokine production after ex vivo stimulation of leukocytes
timeFrame: 1 day
measure: phenotype of circulating leucocytes
timeFrame: 1 day
measure: Heart rate variability
timeFrame: 1 day
measure: Breathing frequency (breaths/ min)
timeFrame: 1 day
measure: Stress Levels (in percentage based on heart rate and heart rate variability)
timeFrame: 1 day
measure: Mean flow velocity of the median cerebral artery
timeFrame: 1 day
measure: cerebral microcirculatory flow
timeFrame: 1 day
measure: Tranfer function analysis
timeFrame: 1 day
measure: Cerebral vascular resistance
timeFrame: 1 day
measure: Cerebral Critical closing pressure
timeFrame: 1 day
measure: Microvascular flow (microvascular flow index)
timeFrame: 1 day
measure: Pulsatility index of the median cerebral artery
timeFrame: 1 day
measure: Mean flow index
timeFrame: via 1 day
measure: cerebral oxygenation
timeFrame: 1 day
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc
state: Gelderland
Study officials:
affiliation: Radboudumc, Intensive Care
name: Roeland Stolk, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.