Noradrenaline drives immunosuppression in sepsis: clinical consequences

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Effect of Vasopressors on the Macro- and Microcirculation During Systemic Inflammation in Humans In Vivo

Item does not contain fulltextAIM: Comparing the effects of different vasopressors in septic shock patients is hampered by high heterogeneity and the fact that current guidelines dictate the use of norepinephrine. Herein, we studied the effects of three vasopressor agents, norepinephrine, phenylephrine, and vasopressin, on the macro- and microcirculation during experimental human endotoxemia, a standardized, controlled model of systemic inflammation in humans in vivo. METHODS: We performed a randomized controlled study in which 40 healthy male volunteers were assigned to a 5-h infusion of either 0.05 mug/kg/min norepinephrine (n = 10), 0.5 mug/kg/min phenylephrine (n = 10), 0.04 IU/min vasopressin (n = 10), or saline (n = 10), starting 1 h before intravenous administration of 2 ng/kg lipopolysaccharide (LPS). The macrocirculation was monitored using arterial catheter-derived parameters with additional blood pressure waveform contour analysis (PCA) until 4.5 h following LPS administration. Sublingual microcirculatory density and flow were assessed using a handheld video microscope until 6 h post-LPS. RESULTS: LPS administration affected all macrocirculatory and microcirculatory parameters. The LPS-induced decrease in blood pressure and systemic vascular resistance (SVR) was refractory to low-dose norepinephrine and phenylephrine, and to a lesser extent, to vasopressin. Only vasopressin exerted effects on PCA parameters compared with placebo, by mitigating the LPS-induced decrease in diastolic blood pressure by stabilizing SVR and cardiac output. The endotoxemia-induced decreased indices of microvascular flow and density were not influenced by vasopressor therapy. CONCLUSIONS: In a highly controlled model of systemic inflammation in humans in vivo, a 5-h infusion of various vasopressors revealed distinctive effects on macrohemodynamic variables without affecting the sublingual microcirculation

Vasopressors Do Not Influence Cerebral Critical Closing Pressure During Systemic Inflammation Evoked by Experimental Endotoxemia and Sepsis in Humans

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The impact of ADRB2 polymorphisms on immune responses and norepinephrine-induced immunosuppression

Rationale: To evaluate whether common nonsynonymous variants [single-nucleotide polymorphisms (SNPs) or SNP haplotypes] in the β2-adrenergic receptor render subjects more susceptible to norepinephrine-induced immunosuppression and whether they are associated with dysregulated ex vivo and in vivo inflammatory responses. Methods: Peripheral blood mononuclear cells from healthy volunteers (main cohort: n = 106, secondary cohort: n = 408) were ex vivo stimulated with various stimuli and production of cytokines was assessed. Additionally, ex vivo modulation of cytokine production by norepinephrine was evaluated in the main cohort. Volunteers from the main cohort also underwent experimental endotoxemia (administration of 1 ng/kg lipopolysaccharide), during which in vivo plasma cytokine concentrations and clinical inflammatory parameters were measured. Subjects were genotyped, common SNPs in the ADRB2 gene were extracted (rs1042711, rs1042713, and rs1042714), and the presence of haplotypes was identified (CysGlyGln, CysArgGln, and ArgGlyGlu). Results: In both cohorts, presence of ADRB2 SNPs or haplotypes was not associated with altered ex vivo cytokine responses. Norepinephrine attenuated production of the proinflammatory cytokines TNF and IL-6 [-26% (-22% to -30%) and -14% (-9% to -18%), respectively, both P 0.37). In addition, no influence of SNPs or haplotypes on in vivo cytokine concentrations or clinical inflammatory parameters was observed (P values >0.14). Conclusions: Common nonsynonymous variants in the ADRB2 gene influence neither ex vivo cytokine production or norepinephrine-mediated immunosuppression nor the systemic in vivo inflammatory response induced by lipopolysaccharide administration in healthy volunteers

Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study

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Observation of strongly deformed shapes in 154-152 Dy nuclei at medium temperatures

The γ-decay of the giant dipole resonance (GDR) built on excited states of 154-152 Dy nuclei is studied. The selection of GDR decay from high spin states leading to specific exit channels was made possible by triggering on high spin isomers. The deduced energy splitting of the GDR implies large deformations (|β|{all equal to}0.4-0.5). The resonance widths of the components are comparable to those of the GDR built on the ground state indicating small shape fluctuations

Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis

Rationale: Sepsis is characterized by a dysregulated immune response to infection. Norepinephrine, the cornerstone vasopressor used in septic shock, may contribute to immune dysregulation and impact host defense.Objectives: To investigate effects of norepinephrine and the alternative vasopressor vasopressin on the immune response and host defense.Methods: Leukocytes from six to nine donors were stimulated in the presence or absence of norepinephrine and vasopressin. A total of 190 C57BL/6J mice received a continuous infusion of norepinephrine or vasopressin via microosmotic pumps and were challenged with LPS or underwent cecal ligation and puncture. Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin, or saline and intravenously challenged with LPS. The relationship between the norepinephrine infusion rate and the use of β-blockers and plasma cytokines was assessed in 195 patients with septic shock.Measurements and Main Results: Norepinephrine attenuated the production of proinflammatory mediators and reactive oxygen species and augmented antiinflammatory IL-10 production both in vitro and in LPS-challenged mice. Norepinephrine infusion during cecal ligation and puncture resulted in increased bacterial dissemination to the spleen, liver, and blood. In LPS-challenged volunteers, norepinephrine enhanced plasma IL-10 concentrations and attenuated the release of the proinflammatory cytokine IFN-γ-induced protein 10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more antiinflammatory cytokine balance, whereas β-blocker use was associated with a more proinflammatory cytokine balance.Conclusions: Norepinephrine dysregulates the immune response in mice and humans and compromises host defense. Therefore, it may significantly contribute to sepsis-induced immunoparalysis, whereas vasopressin does not have untoward immunologic effects