Effects of Vasopressors on Immune Response

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

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.

Study Overview

• Status: Completed
• Conditions: Endotoxemia
• Intervention / Treatment: Drug: Norepinephrine; Drug: Vasopressins; Drug: Phenylephrine; Drug: Placebo

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

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6500HB
      • Radboudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / 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%

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Roeland Stolk, MD, Radboudumc, Intensive Care

Publications and helpful links

General Publications

• Stolk RF, Naumann 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2016
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: January 25, 2016
• First Submitted That Met QC Criteria: February 2, 2016
• First Posted (Estimate): February 5, 2016

Study Record Updates

• Last Update Posted (Estimate): October 13, 2016
• Last Update Submitted That Met QC Criteria: October 12, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: vasopressin; Lipopolysaccharide; phenylephrine; endotoxemia; vasopressor; noradrenaline
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Bacteremia; Toxemia; Endotoxemia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Natriuretic Agents; Cardiotonic Agents; Respiratory System Agents; Hemostatics; Coagulants; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Nasal Decongestants; Antidiuretic Agents; Adrenergic alpha-1 Receptor Agonists; Norepinephrine; Vasopressins; Arginine Vasopressin; Phenylephrine; Oxymetazoline
• Other Study ID Numbers: NL53411.091.015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO