In animals and humans, norepinephrine leads to a dysregulation of the immune response and a compromise of the defense function. This is the result of a recent study published in the American Journal of Respiratory and Critical Care Medicine.
Noradrenaline is indispensable in the treatment of critically ill patients. Worldwide, it is used in almost all patients with septic shock and other severe systemic inflammatory events. In vitro data suggest that norepinephrine has predominantly anti-inflammatory properties, but evidence of the suspected immunomodulatory effects in vivo has been sparse in animals and absent in humans.1,2
"...supportive therapies, which are currently applied in an undifferentiated manner, could contribute significantly to the dysregulation of the immune response and may require re-evaluation in the light of the new concept of immune paralysis," warn the authors of a recent study.2
Sepsis-induced immune paralysis is associated with various disorders of the immune system, which result in ineffective elimination of infectious foci and increased susceptibility to secondary infections, often with opportunistic pathogens. This immunosuppression is thus responsible for relevant mortality and morbidity.3
In a study published in the American Journal of Respiratory and Critical Care Medicine in September 2020, Dutch scientists first studied the immunological effects of norepinephrine and vasopressin in human leukocytes in vitro.2 They then conducted experiments on the murine model to evaluate the functional significance of their observations. Finally, they tested the transferability to humans using an in vivo model for systemic inflammation (experimental endotoxemia) and observations in septic patients.
They stimulated leukocytes from human donors in the presence or absence of norepinephrine and vasopressin. In addition, 190 mice received a continuous vasopressin or norepinephrine infusion via a syringe driver and were either given LPS (lipopolysaccharides) or underwent appendectomy and ligation.
Norepinephrine attenuated the production of proinflammatory mediators and reactive oxygen species and increased the production of the anti-inflammatory cytokine IL-10 (obsolete: cytokine synthesis inhibitory factor = CSIF) both in vitro and in the animals exposed to LPS. Intravenous administration of norepinephrine during cecal ligation and puncture resulted in increased bacterial dissemination into the spleen, liver, and blood.
The researchers then randomized 30 healthy volunteers to a five-hour infusion of norepinephrine, vasopressin, or saline and administered LPS intravenously. Norepinephrine increased IL-10 plasma concentrations in these volunteers and decreased the release of the pro-inflammatory cytokine IP-10 (IFN-γ-induced protein 10).
Vasopressin showed no undesirable immunomodulatory effects in any of these trials. They also investigated the association between norepinephrine infusion rates, beta-blocker administration, and plasma cytokines in 195 patients in septic shock. Higher infusion rates correlated with a more anti-inflammatory cytokine balance, while the use of beta-blockers was associated with a more pro-inflammatory cytokine balance.
If these results are confirmed by further trials, the authors think that a re-evaluation of vasopressor therapy for sepsis is advisable.
Septic events can have both hyper-inflammatory and immunosuppressive characteristics. Although hyper-inflammation can also have significant adverse effects (e.g. in patients with macrophage-activation syndrome / MAS), immunosuppressive interventions have not been able to improve outcomes in sepsis.4 Therefore, attention has shifted to the detrimental role of sepsis-induced immunosuppression.3
"With the advent of the era of precision medicine for sepsis, the use of different vasopressors could be tailored to specific subgroups of septic patients in the future based on their (molecular) immunological endotypes," the authors conclude.
References:
1. Bergmann, M. & Sautner, T. Immunomodulatory effects of vasoactive catecholamines. Vienna. Clin. weekly 114, 752-761 (2002).
2. Stolk, R. F. et al Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis. At J Respir Crit Care Med 202, 830-842 (2020).
3. Boomer, J. S. et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306, 2594-2605 (2011).
4. J, L., M, K., Jg, van der H., Mg, N. & P, P. Immunotherapy for the adjunctive treatment of sepsis: from immunosuppression to immunostimulation. Time for a paradigm change? American journal of respiratory and critical care medicine vol. 187 https://pubmed.ncbi.nlm.nih.gov/23590272/ (2013).