Effects of Vasopressors on Immune Response
Condition: Endotoxemia
MeSH terms: Endotoxemia
Study type: Interventional
Phase: Phase 4

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
    

Intervention name(s): Norepinephrine; Phenylephrine; Vasopressins; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 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.; 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.; 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.; NaCl 0.9% infusion
Other intervention name(s): Noradrenaline; Argipressin; NaCl 0,9%
Intervention MeSH terms: Phenylephrine; Vasopressins; Arginine Vasopressin; Oxymetazoline; Norepinephrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: noradrenaline; vasopressin; phenylephrine; endotoxemia; Lipopolysaccharide; vasopressor