Is the Sympathetic System Detrimental in the Setting of Septic Shock, with Antihypertensive Agents as a Counterintuitive Approach? A Clinical Proposition

Abstract

Mortality in the setting of septic shock varies between 20% and 100%. Refractory septic shock leads to early circulatory failure and carries the worst prognosis. The pathophysiology is poorly understood despite studies of the microcirculatory defects and the immuno-paralysis. The acute circulatory distress is treated with volume expansion, administration of vasopressors (usually noradrenaline: NA), and inotropes. Ventilation and anti-infectious strategy shall not be discussed here. When circulation is considered, the literature is segregated between interventions directed to the systemic circulation vs. interventions directed to the micro-circulation. Our thesis is that, after stabilization of the acute cardioventilatory distress, the prolonged sympathetic hyperactivity is detrimental in the setting of septic shock. Our hypothesis is that the sympathetic hyperactivity observed in septic shock being normalized towards baseline activity will improve the microcirculation by recoupling the capillaries and the systemic circulation. Therefore, counterintuitively, antihypertensive agents such as beta-blockers or alpha-2 adrenergic agonists (clonidine, dexmedetomidine) are useful. They would reduce the noradrenaline requirements. Adjuncts (vitamins, steroids, NO donors/inhibitors, etc.) proposed to normalize the sepsis-evoked vasodilation are not reviewed. This itemized approach (systemic vs. microcirculation) requires physiological and epidemiological studies to look for reduced mortality.

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“…An alternative therapeutic intervention, reported by Pititjeans et al. 36 and Lankadeva et al. 37 in which sympathetic outflow is inhibited, has produced encouraging preclinical experiments and preliminary clinical observations.…”

Dexmedetomidine only regimen for long-term sedation is associated with reduced vasopressor requirements in septic shock patients: A retrospective cohort study from MIMIC-IV database

“…Theoretically, the sympathetic nervous system (SNS) plays a vital role in septic shock by enabling patients to maintain smooth muscle cell contraction (6). However, prolonged activation of the SNS in septic shock patients may elevate levels of circulating catecholamines (7), causing down-regulation and desensitization of α-adrenergic receptors on the surface of smooth muscle cells (8). This can make patients hyposensitive or insensitive to exogenous catecholamines, leading to deterioration due to refractory shock (9).…”

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“…Adequate iterative circulatory optimization combined to the sympatholysis evoked by alpha-2 agonists normalizes the microcirculation, systemic pH, lactate concentration, CO 2 gap and venous O 2 saturation. Alpha-2 agonists present anti-inflammatory properties [ 11 ], either at the systemic or central nervous system or lung (tissue or receptors) level. In turn, normalized microcirculation eases diapedesis and improves the innate immune function: a return to normal functioning of the adrenergic receptors of immune cells possibly occurs (“upregulation”).…”