The autonomic nervous system in septic shock and its role as a future therapeutic target: a narrative review

Abstract

The autonomic nervous system (ANS) regulates the cardiovascular system. A growing body of experimental and clinical evidence confirms significant dysfunction of this regulation during sepsis and septic shock. Clinical guidelines do not currently include any evaluation of ANS function during the resuscitation phase of septic shock despite the fact that the severity and persistence of ANS dysfunction are correlated with worse clinical outcomes. In the critical care setting, the clinical use of ANS-related hemodynamic indices is currently limited to preliminary investigations trying to predict and anticipate imminent clinical deterioration. In this review, we discuss the evidence supporting the concept that, in septic shock, restoration of ANS-mediated control of the cardiovascular system or alleviation of the clinical consequences induced by its dysfunction (e.g., excessive tachycardia, etc.), may be an important therapeutic goal, in combination with traditional resuscitation targets. Recent studies, which have used standard and advanced monitoring methods and mathematical models to investigate the ANS-mediated mechanisms of physiological regulation, have shown the feasibility and importance of monitoring ANS hemodynamic indices at the bedside, based on the acquisition of simple signals, such as heart rate and arterial blood pressure fluctuations. During the early phase of septic shock, experimental and/or clinical studies have shown the efficacy of negative-chronotropic agents (i.e., beta-blockers or ivabradine) in controlling persistent tachycardia despite adequate resuscitation. Central α-2 agonists have been shown to prevent peripheral adrenergic receptor desensitization by reducing catecholamine exposure. Whether these new therapeutic approaches can safely improve clinical outcomes remains to be confirmed in larger clinical trials. New technological solutions are now available to non-invasively modulate ANS outflow, such as transcutaneous vagal stimulation, with initial pre-clinical studies showing promising results and paving the way for ANS modulation to be considered as a new potential therapeutic target in patients with septic shock.

Keywords: Autonomic dysfunction; Autonomic nervous system; Baroreflex; Desensitization; Dysautonomia; Sepsis; Septic shock; Sympathetic overstimulation; Tachycardia; Vagal stimulation.

Fig. 1

Illustration of the short-term ANS regulatory mechanisms of the cardiovascular system. The arterial baroreceptors, usually known as high-pressure baroreceptors, are mainly located in the aortic arch and carotid sinuses. Cardiopulmonary baroreceptors—also known as volume-receptors or low-pressure baroreceptors—are located in the atria, ventricles, vena cava, and pulmonary vessels. The chemoreceptors are located both peripherally (carotid bodies and aortic arch) and centrally. The vasomotor center hosts the circulatory regulation and is part of the medulla oblongata located in the brainstem, next to the nucleus of the solitary tract that receives sensory nerves signals through the glossopharyngeal and the vagus nerves (green lines). The SNS fibers (blue lines) originate from the medulla oblongata and emerge from the spinal cord's upper thoracic segments as pre-ganglionic neurons, ending inside the sympathetic chain ganglia located next to the vertebral column. SNS post-ganglionic neurons leave the sympathetic chain ganglia towards their target organs, namely the heart, the vessels, and the adrenal glands. Note that adrenal medulla sympathetic activation also induces epinephrine and norepinephrine release (dashed light blue lines) into the bloodstream. The PNS fibers (red lines) also originate from the brain stem and are incorporated as pre-ganglionic neurons in the vagal nerve, ending on the parasympathetic cardiac ganglia lying in the heart fat pad. Very short post-ganglionic neurons arise from these parasympathetic cardiac ganglia towards the right and left atrium, the atrioventricular node, the interatrial septum, the ascending aorta, and the pulmonary trunk. During septic shock, hypotension and the inflammatory reaction inhibit the vagal centers—inducing vagal outflow reduction—whereas the sympathetic pathway is stimulated. Sepsis, therefore, provokes a striking imbalance in ANS activity with a shift towards the SNS

Fig. 2

Mechanisms of adrenergic receptor activation and desensitization (here, β-adrenergic receptor). When catecholamines bind to G protein-coupled receptors (GPCR), there is a conformational change leading to dissociation of the receptors’ G protein subunits and transformation of ATP into cyclic adenosine monophosphate (cAMP). GPCR kinases (GRK) phosphorylate GPCR but only in their agonist-occupied receptor configuration. This GPCR phosphorylation by GRK enhances GPCR interaction with cytosolic proteins known as β-arrestins. These later bind to the GPCR and prevent further intracellular G-protein signaling, preventing the subsequent production of more cAMP. Increased GRK activity forces the equilibrium of β-receptors towards an inactive state. Moreover, β-arrestins promote GPCR internalization and their subsequent degradation in lysosomes. Resensitization is the process that restores the responsiveness of the desensitized receptors, through dephosphorylation by specific phosphatases and receptor recycling back to the cell membrane. Downregulation of genes encoding GPCRs also leads to reduced catecholamine efficacy, through a net loss of receptors. Of note, catecholamine binding modulates a complex cascade of enzymes and transmembrane ion channel activation, all of which are also prone to acute alteration and dysregulation due to sepsis [–110]

Fig. 3

Illustration of the inflammatory reflex (here, in the spleen). Efferent signals from the brain stem travel through the efferent vagus nerve to the celiac plexus, which also receives input from the sympathetic branch. The catecholaminergic splenic nerve arises in this celiac plexus and projects inside the spleen, where its terminal fibers reach T and B lymphocytes. Efferent signals in the vagus nerve activate the splenic nerve, which releases norepinephrine in the spleen, activating the choline acetyltransferase‐expressing T-lymphocytes (ChAT) through their adrenergic receptors (AR). ChAT then release acetylcholine (ACh), which acts on α7 subunits (α7) of the nicotinic acetylcholine receptor on macrophages (M_Φ), suppressing further release of tumor necrosis factors (TNF). Activation of the splenic nerve also stops B‐lymphocyte migration and inhibits their antibody production. Adapted from [111]

Fig. 4

Basic concepts to estimate heart rate and blood pressure variabilities. a Identification of R peaks in the ECG signal—in sinus rhythm—permits assessment of the RR interval duration for consecutive beats. b The tachogram displays RR intervals for each beat; this time series analysis permits a first visual inspection of the variability in RR interval duration, computed as the mean RR interval and its standard deviation. c Before the spectral analysis, the time series needs to be resampled at evenly spaced time intervals (T_c = sampling interval which corresponds to f_c = 1/T_c sampling frequency). d Power spectrum density (PSD) computation and spectral analysis: as the parasympathetic nervous system (PNS) acts at higher frequencies than the sympathetic nervous system (SNS), the region associated with high frequency (HF, 0.15–0.4 Hz) estimates the PNS contribution to RR interval modulation, whereas the low frequency (LF, 0.04–0.15 Hz) represents mainly the SNS contribution; LF and HF indexes represent the PSD areas in those bands. e Similar to HRV, beat-to-beat series of systolic (SBP) and diastolic (DBP) blood pressure values lead first to the time domain analysis and, after resampling, to PSD computation and spectral analysis (NB: in case of blood pressure, HF variations are not related to the PNS, but mainly to the respiratory activity). The simplest way to assess the baroreflex sensitivity consists of calculating the ratio between LF components of both SBP and RR series, in their respective PSD computation. f The spectral analysis permits to disentangle the individual contributions of several modulators (in this example, the signal y(t) is composed of three harmonics and the PSD can clearly identify those harmonics with the low-frequency signal, y1(t), contributing more than the other two)