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Is Norepinephrine Hurting Immune Response to Sepsis?

July 20, 2020

Written by Meghan Breed

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Norepinephrine (NE) appears to cause a dose-dependent dysregulation of the host immune response.  This leads to attenuation of pro-inflammatory mediators and reactive oxygen species and augmentation of anti-inflammatory mediators which may inhibit the host’s ability to fight off infection.

Why does this matter?
Sepsis is the leading cause of death worldwide (20% global mortality).  For most of us, our go-to vasopressor in septic shock has been norepinephrine. However, this may be causing immunoparalysis which could lead to ineffective clearance of infection and increased susceptibility to secondary infections.

Norepi takes us back to the basics (basic science)…

In vitro, murine (mice) and human studies revealed the following:  

  • Norepinephrine exerts anti-inflammatory effects in human leukocytes.

    • Using whole blood (in vitro), the immune system was stimulated in the presence of NE; results showed a decrease in pro-inflammatory mediators such as TNF-alpha and an increase in anti-inflammatory cytokines such as IL-10.  Interestingly, vasopressin did not alter cytokine levels.

  • Anti-inflammatory effects of NE involve beta-2 adrenergic stimulation and protein kinase A.

    • NE has affinity for both alpha and beta adrenergic receptors; however, it appears that the beta-2 adrenergic receptors play the most important role in immune system modulation. Beta-2 adrenergic receptor antagonists reversed the effects of NE on TNF-alpha

  • Norepinephrine suppresses immunometabolism.

    • NE affects energy metabolism, particularly oxidative phosphorylation capacity; pre-treatment with a beta-2 adrenergic receptor antagonist mitigated these findings.

  • Norepinephrine infusion exerts anti-inflammatory effects in mice.

    • NE dose-dependently attenuated pro-inflammatory mediators and enhanced anti-inflammatory cytokine levels in mice on NE infusions.  Again, vasopressin exerted no immunomodulatory effect.

  • Norepinephrine infusion increased bacterial dissemination in experimental sepsis.

    • Mice underwent cecal ligation and puncture while on NE infusion to induce sepsis.  Mice on NE had a trend towards higher bacterial concentration.

  • Norepinephrine exerts anti-inflammatory effects in lipopolysaccharide (LPS)-challenged healthy volunteers and in patients with septic shock.

    • Healthy subjects were placed on NE, vasopressin, or placebo; circulating plasma concentrations were measured. NE resulted in enhanced IL-10 response (anti-inflammatory).

    • 195 ICU patients underwent analysis of TNF-alpha and IL-10 levels within 24 hours of beginning NE infusion.  TNF-alpha/IL-10 ratios were lower in patients on NE.  Interestingly, several patients included had taken their home beta blocker within 24 hours of enrollment and had high TNF-alpha/IL-10 ratios, reflecting a better pro/anti-inflammatory balance.

Given the vast majority of the data presented was from in vitro and murine studies, this is unlikely to change practice patterns; however, it might make me consider adding vasopressin earlier to mitigate some of the dose-dependent immunoparalysis of NE.  The study also brings to light the hot topic of beta-blocker use in sepsis which appears to potentially play a role in immune modulation.

Norepinephrine Dysregulates the Immune Response and Compromises Host Defense During Sepsis. Am J Respir Crit Care Med. 2020 Jun 10. doi: 10.1164/rccm.202002-0339OC. [Epub ahead of print]

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What are your thoughts?