Bench-to-bedside review: β-Adrenergic modulation in sepsis

Abstract

Sepsis, despite recent therapeutic progress, still carries unacceptably high mortality rates. The adrenergic system, a key modulator of organ function and cardiovascular homeostasis, could be an interesting new therapeutic target for septic shock. β-Adrenergic regulation of the immune function in sepsis is complex and is time dependent. However, β2 activation as well as β1 blockade seems to downregulate proinflammatory response by modulating the cytokine production profile. β1 blockade improves cardiovascular homeostasis in septic animals, by lowering myocardial oxygen consumption without altering organ perfusion, and perhaps by restoring normal cardiovascular variability. β-Blockers could also be of interest in the systemic catabolic response to sepsis, as they oppose epinephrine which is known to promote hyperglycemia, lipid and protein catabolism. The role of β-blockers in coagulation is less clear cut. They could have a favorable role in the septic pro-coagulant state, as β1 blockade may reduce platelet aggregation and normalize the depressed fibrinolytic status induced by adre-nergic stimulation. Therefore, β1 blockade as well as β2 activation improves sepsis-induced immune, cardiovascular and coagulation dysfunctions. β2 blocking, however, seems beneficial in the metabolic field. Enough evidence has been accumulated in the literature to propose β- adrenergic modulation, β1 blockade and β2 activation in particular, as new promising therapeutic targets for septic dyshomeostasis, modulating favorably immune, cardiovascular, metabolic and coagulation systems.

Shock Management For Cardio-Surgical ICU Patients — The Golden Hours

“…In comparison to dobutamine, milrinone is considered to be more effective in patients under β-blockade. 80,90 The effects of milrinone on right ventricular ejection fraction were comparable with the inhalational nitric oxide at 20 ppm. …”

“…Although improving oxygen delivery was beneficial perioperatively 4,75 and during the early phase of shock, 8 circulatory stimulation with dobutamine to supra-normal values (cardiac index > 4.5 l/min/m 2 , oxygen delivery >600 ml/min/m 2 ) was associated with an adverse outcome in patients with established multi-organ failure. 78,79 This might be due to the fact that excessive adrenergic stimulation has adverse metabolic effects (augmented energy demands, hyperglycaemia, lipolysis, muscle wasting), [80][81][82] impairs splanchnic haemodynamics, 83,84 causes arrhythmia, 85 stimulates inflammation 86,87 and promotes stress cardiomyopathy. 88,89 Dobutamine is also associated with eosinophilia and fever, 90 and its use for longer than 72 hours may lead to tolerance.…”

Role of I-123 MIBG in sepsis-induced cardiomyopathy

“…Although there are no randomized trials on this subject, several small studies suggest a controversial but potentially beneficial role of adrenergic blocker therapies in septic patients. 28,29 The role of adrenergic overstimulation in development of myocardial dysfunction in septic patients and the potential role of autonomic modulation in its treatment and prevention require further investigation.…”

Beta-blockers in patients with septic shock: plenty of promise, but no hard evidence yet

“…In patients with similar cardiac outputs, a hemodynamic profile characterized by a relatively slow HR and concomitantly high SV can be interpreted as an improvement in cardiac efficiency, or V-A coupling. Sepsis induces substantial pro-inflammatory and anti-inflammatory cascades, and the administration of beta-blockers downregulates the pro-inflammatory response (including the release of TNF-α, IL-1β, and IL-6) and up-regulates the antiCommentary Beta-blockers in patients with septic shock: plenty of promise, but no hard evidence yet inflammatory pathway (including IL-10) (15). Along with reduction of vascular oxidative stress and modulation of nitric oxide pathways, beta-blockers may improve endotheliumdependent relaxation by exerting anti-inflammatory effects (16)…”