Effects of Vasopressors on Immune Response

NCT02675868 | Completed Phase 4

• 1 other identifier: NL53411.091.015
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Endotoxemia

Keywords

noradrenaline; vasopressin; phenylephrine; endotoxemia; Lipopolysaccharide; vasopressor

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (24)

• concentration plasma IL-6 (pg/ml)

  1 day

• concentration plasma IL-8 (pg/ml)

  1 day

• Leucocyte counts and differentiation

  1 day

• -The phenotype of circulating leukocytes

  1 day

• concentration plasma IL-10 (pg/ml)

  1 day

Study Arms (4)

Norepinephrine

EXPERIMENTAL

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

Vasopressins

ACTIVE COMPARATOR

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

Phenylephrine

ACTIVE COMPARATOR

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

PLACEBO COMPARATOR

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

Norepinephrine DRUG

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

Norepinephrine

Phenylephrine DRUG

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.

Phenylephrine

Vasopressins DRUG

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

Vasopressins

Placebo DRUG

NaCl 0.9% infusion

Also known as: NaCl 0,9%

Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Radboud University Medical Center: lead

Study Sites (1)

Radboudumc

Nijmegen, Gelderland, 6500HB, Netherlands

Location

Related Publications (2)

• 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.

  PMID: 33483132 DERIVED

• 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.

  PMID: 31008870 DERIVED

MeSH Terms

Conditions

Endotoxemia; Diabetes Insipidus

Interventions

Norepinephrine; Phenylephrine; Vasopressins; Arginine Vasopressin

Condition Hierarchy (Ancestors)

Bacteremia; Sepsis; Infections; Toxemia; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pituitary Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Biogenic Monoamines; Biogenic Amines; Catecholamines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Roeland Stolk, MD

  Radboudumc, Intensive Care

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 25, 2016
• First Posted: February 5, 2016
• Study Start: January 1, 2016
• Primary Completion: July 1, 2016
• Study Completion: October 1, 2016
• Last Updated: October 13, 2016

Record last verified: 2016-04

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)