title: Potentially Inadvertent Immunomodulation: Norepinephrine Use in Sepsis.
abstract: Septic shock is a major cause of death worldwide and a considerable healthcare burden in the twenty-first century. Attention has shifted from damaging effects of the proinflammatory response to the detrimental role of antiinflammation, a phenomenon known as sepsis-induced immunoparalysis. Sepsis-induced immunoparalysis may render patients vulnerable to secondary infections and is associated with impaired outcome. The immunoparalysis hypothesis compels us to reevaluate the current management of septic shock and to assess whether we are inadvertently compromising or altering the host immune response. In this perspective, we discuss the potential detrimental role of norepinephrine, the cornerstone treatment for septic shock, in sepsis-induced immunoparalysis. We provide a short overview of the current understanding of the immunologic pathophysiology of sepsis, followed by a detailed description of the immunomodulatory effects of norepinephrine and alternative vasopressors. We conclude that although the development of novel therapies aimed at reversing immunoparalysis is underway, the use of norepinephrine may aggravate the development, extent, and duration of sepsis-induced immunoparalysis. Current in vitro and animal data indicate that norepinephrine treatment exerts immunosuppressive and bacterial growth-promoting effects and may increase susceptibility toward infections. However, evidence in humans is circumstantial, as immunologic effects of norepinephrine have not been investigated properly in experimental or clinical studies. Alternatives such as vasopressin/selepressin, angiotensin II, and phenylephrine could have a fundamental advantage over norepinephrine with respect to their immunologic properties. However, also for these agents, in vivo immunologic data in humans are largely lacking. As such, human studies on the immunomodulatory properties of norepinephrine and viable alternatives are highly warranted.
authors.affiliation: 1 Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|2 Radboud Centre for Infectious Diseases, Nijmegen, the Netherlands.
authors.forename: Roeland F
authors.initials: RF
authors.lastname: Stolk
authors.affiliation: 3 Center of Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; and.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: 4 Department of Critical Care Medicine, University of Pittsburgh and University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
authors.affiliation: 1 Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|2 Radboud Centre for Infectious Diseases, Nijmegen, the Netherlands.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.affiliation: 1 Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|2 Radboud Centre for Infectious Diseases, Nijmegen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: 1 Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|2 Radboud Centre for Infectious Diseases, Nijmegen, the Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
mesh_terms: D000276:Adjuvants, Immunologic / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007154:Immune System Diseases / Q000209:etiology*; D016867:Immunocompromised Host / Q000187:drug effects* / Q000276:immunology; D056747:Immunomodulation / Q000187:drug effects* / Q000276:immunology; D009638:Norepinephrine / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D012772:Shock, Septic / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D014662:Vasoconstrictor Agents / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D014667:Vasopressins / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D000276:Adjuvants, Immunologic; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D009638:Norepinephrine
keywords: catecholamines; cytokines; immunoparalysis; norepinephrine; septic shock