Pressor Response to Noradrenaline in the Setting of Septic Shock: Anything New under the Sun—Dexmedetomidine, Clonidine? A Minireview

Abstract

Progress over the last 50 years has led to a decline in mortality from ≈70% to ≈20% in the best series of patients with septic shock. Nevertheless, refractory septic shock still carries a mortality close to 100%. In the best series, the mortality appears related to multiple organ failure linked to comorbidities and/or an intense inflammatory response: shortening the period that the subject is exposed to circulatory instability may further lower mortality. Treatment aims at reestablishing circulation within a “central” compartment (i.e., brain, heart, and lung) but fails to reestablish a disorganized microcirculation or an adequate response to noradrenaline, the most widely used vasopressor. Indeed, steroids, nitric oxide synthase inhibitors, or donors have not achieved overwhelming acceptance in the setting of septic shock. Counterintuitively, α 2-adrenoceptor agonists were shown to reduce noradrenaline requirements in two cases of human septic shock. This has been replicated in rat and sheep models of sepsis. In addition, some data show that α 2-adrenoceptor agonists lead to an improvement in the microcirculation. Evidence-based documentation of the effects of alpha-2 agonists is needed in the setting of human septic shock.

Renal sympathetic nerve activity and vascular reactivity to phenylephrine after lipopolysaccharide administration in conscious rats

“…; Geloën et al. ). Nevertheless, dexmedetomidine improved vascular reactivity to phenylephrine, through a mechanism that largely remains to be determined.…”

“…; Geloën et al. ). Geloën and coworkers reported that rats challenged with lipopolysaccharide (LPS) had decreased pressor responses to noradrenaline that could be entirely restored by clonidine and dexmedetomidine (Geloën et al.…”

Updates in the function and regulation of α1‐adrenoceptors

“…In septic shock, reversal of hypotension with the currently available vasoconstrictors is limited by tachyphylaxis because vasoconstriction diminishes as treatment continues, resulting in inadequate blood perfusion and vital organ failure. It has been proposed that the loss of vasoconstriction due to α 1 -adrenoceptor agonists in septic patients might result from receptor desensitization (Geloen et al, 2015;Hwang, Lau, Huang, Chen, & Liu, 1994), and again, the development of ligands that are less tachyphylactic than the natural catecholamines and phenylephrine would be a significant improvement in the emergency treatment of hypotension by providing more sustained elevation of BP. through Gq proteins and, probably, through β-arrestins, leading to the activation of MAPKs, modulation of transcription factors, and ultimately to hypertrophy (Cotecchia et al, 2015;O'Connell et al, 2014;Woodcock et al, 2008).…”

Protective Effect of Dexmedetomidine on Acute Lung Injury via the Upregulation of Tumour Necrosis Factor-α-Induced Protein-8-like 2 in Septic Mice

“…Recently, studies have shown that DEX has potent anti-inflammatory, antioxidant and anti-apoptotic effects [11][12][13]. Animal studies have suggested that DEX plays a protective role in a number of lung diseases, including ALI [14][15][16].…”