The term autonomic dysfunction is frequently associated with the syndrome of critical illness. Numerous studies have reported a striking association among depressed autonomic activity (usually measured as reduced heart rate variability), disease severity, and outcome. More sophisticated interrogation of various components of the autonomic nervous system also reveals that the loss of chemoreflex or baroreflex responses is associated with higher mortality in critically ill patients. However, the marker versus mediator debate over the significance of these findings is difficult to disentangle—at least from clinical studies. Moreover, much of the literature making an association between the development of critical illness and the autonomic dysfunction is hampered by the variety of techniques used to detect alterations in autonomic control, the lack of population norms, variable analysis techniques, and lack of suitable controls and follow-up. Nevertheless, emerging laboratory and trial data suggest that autonomic dysfunction may be a clinically underappreciated driver of established critical illness. Specifically, the argument put forward here is that critical illness occurs as a direct result of autonomic dysfunction, which also serves as an essential biological precursor for priming pathophysiologic responses that subsequently result in multiorgan failure/dysfunction. As a complementary hypothesis, acquired autonomic dysfunction may also portend worse outcomes following disparate triggers of critical illness.
What Is Autonomic Dysfunction?
From a basic biological perspective, autonomic dysfunction should be considered as the uncoupling of cellular and integrative physiologic control. In other words, autonomic dysfunction may be defined as changes in afferent, integrative (central nervous system [CNS]), or efferent components of sympathetic or parasympathetic neural control, associated with pathologic states. This broadens the scope of its potential impact on understanding the pathophysiology of critical illness. Coordinated and self-limiting sympathetic activation, coupled with the maintenance of parasympathetic tone, appears to be associated with a favorable physiologic response to tissue injury and sepsis. The “uncoupling” of these autonomic control mechanisms, and consequent loss of neurally mediated interorgan feedback pathways, is a feature of the development of multiorgan dysfunction syndrome. In established critical illness, there is a temporally related association between autonomic dysfunction and derangements in immune, metabolic, and bioenergetic mechanisms that appear to be prognostically linked to outcome. From a neuropathologic viewpoint, postmortem samples of brain tissue, obtained from septic patients, show evidence for neuronal death in autonomic centers. At the molecular level, disruption of normal G-protein–coupled receptor (GPCR) recycling is a feature of neurohormonal dysregulation in disease states where biological variability is disrupted. In many respects, core features of established critical illness may be erroneously attributed to conventional clinical explanations rather than the consequences of autonomic dysfunction alone ( Table 48-1 ).
| Symptom of Critical Illness | Conventional Explanation | Alternative “Dysautonomia” Hypothesis |
|---|---|---|
| Tachycardia | Agitation /fever | Loss of baroreflex diminution of heart rate Cytokine stimulation of peripheral chemoreceptors |
| Cardiac ischemia | Underlying or acquired coronary disease /hypercoaguability | Loss of cardioprotective vagal innervation |
| Loss of inotropic performance | Cardiac ischemic damage | Neurohormonal downregulation of β-adrenoreceptors ± cardiac receptors |
| Failure to wean | Cardiac failure | All above |
| Fever of uncertain origin | Undeclared infectious source | Cytokinemia derived from neurohormonal activation of immune cells |
| Persistently raised inflammatory markers | Undeclared infectious source | Cytokinemia derived from neurohormonal activation of immune cells |
| Bacterial colonization | Immunosuppression | Adrenergic fuel for microorganism growth |
At What Point Does Autonomic Dysfunction Influence the Development of Critical Illness?
Many patients who ultimately require critical care have established features of autonomic dysfunction well before the clinical manifestation of critical illness, as a result of various established chronic disease states. The striking observation that several chronic diseases such as cardiac and renal failure confer increased risk for sepsis suggests that an underlying common mechanism contributes to this increased propensity for multiorgan dysfunction. Subclinical changes in autonomic function precede the onset of diabetes and hypertension. Patients with overt or occult heart failure are at particularly high risk of having critical illness, including acquiring infection or sustaining excess postoperative morbidity following cardiac or noncardiac surgery. It has become increasingly apparent that many of the pathophysiologic features of cardiac failure are present in deconditioned patients, with poor aerobic capacity and low anaerobic threshold, yet no formal diagnosis of heart failure. Cardiac failure is characterized by increased sympathetic drive, high levels of circulating catecholamines and cortisol, and withdrawal of parasympathetic activity. Elevated plasma levels of proinflammatory cytokines and deficient immune function are also common features of chronic heart failure. Restoration toward normal autonomic function with conventional or experimental therapies improves cardiac function, as well as reduces excess neurohormonal and inflammatory activation. A growing body of evidence in both chronic heart failure and critically ill patients is accumulating, indicating that sympatholysis is associated with a counterintuitive improvement in left ventricular function in addition to reductions in left ventricular remodeling and reduced plasma levels of inflammatory cytokines. Loss of vagal activity in chronic heart failure is a predictor of high mortality. Beyond overt cardiovascular disease, patients with extracardiac disease also show features of established autonomic dysfunction. For example, end-stage renal disease and obstructive jaundice are characterized by impaired baroreflex sensitivity and increased levels of plasma atrial natriuretic peptide.
Autonomic Dysfunction at the Very Onset of Critical Illness
The hallmark of the onset of critical illness is tachycardia, frequently accompanied by tachypnea. Sepsis, hypoxia, and acidosis are all major stimuli for driving tachypnea/tachycardia through peripheral chemoreceptor-driven autonomic reflexes. Similarly, sterile inflammation, or danger-associated molecular patterns, may also be an important—though underrecognized—additional driver for this physiologic response. Thus, afferent sensors of the autonomic nervous system are hardwired to detect pathologic changes in oxygen, carbon dioxide, acidosis, glucose, electrolytes, neurohormones, and inflammatory mediators ( Fig. 48-1 ). Experimental models of endotoxin infusion illustrate the speed with which neural afferents detect inflammatory changes, in parallel with the rapid and dramatic pathophysiologic features that can appear in otherwise previously well, healthy individuals. Typical pathophysiologic changes in respiratory function—beyond tachypnea—include increased airway resistance and secretions. Discrete activation of the peripheral chemoreflex triggers the release of cortisol and vasopressin, prototypical neurohormones of critical illness. These responses may form part of the protective autonomic response to triggers of critical illness because acute carotid sinus denervation hastens mortality after lethal experimental endotoxemia. Loss of baroreflex control through denervation of the carotid sinus and aortic baroreceptor nerves appears to compromise the compensatory response to hypotension induced by acute sepsis, with lower mean blood pressure, cardiac output, total peripheral resistance, and central venous pressure.
Is Autonomic Dysfunction in Critical Illness Induced by Modern Critical Care Strategies?
By most accounts, many of the therapies used in critically ill patients profoundly alter, if not ablate, autonomic, baroreflex, and chemoreceptor control. Sedation inhibits parasympathetic neuronal activity while reducing sympathetic drive. Neuromuscular blockade agents such as vecuronium inhibit peripheral chemoreceptor sensitivity and conceivably produce immunosuppression through nicotinic receptor blockade. Inotropes dramatically reduce baroreflex control and inhibit parasympathetic activity, as reflected by changes in heart rate variability. Furthermore, catecholamines directly fuel infection by promoting bacterial acquisition of normally inaccessible sequestered host iron, which is released by transferrin as a result of catecholamines forming protein complexes with ferric iron.
Perhaps most strikingly, models of enforced bed rest in healthy volunteers show the rapid onset of autonomic dysfunction appearing well before other features of deconditioning. Typically, these changes involve sympathetic activation and parasympathetic withdrawal. The increasingly recognized, though seldom detected, problem of psychological stress induced by the critical care environment reduces baroreflex sensitivity and promotes tachycardia. Experimental models of enforced bed rest demonstrate a mechanistic interaction between dysautonomia and anhedonia (loss of the capacity to experience pleasure), which may relate to depression being a negative prognosticator of outcome in critical illness. Given the current vogue for early physical, occupational, or behavioral therapy, it is tempting to speculate that restoring autonomic control may be an underappreciated feature of the apparent success of this strategy.
Cardiovascular Dysfunction in Critical Illness as a Direct Result of Autonomic Dysfunction
Cardiovascular dysfunction, a hallmark of critical illness, frequently prevents successful liberation from mechanical ventilation. The etiology of cardiac injury during critical illness remains unclear and appears unlikely to be merely attributable to coronary artery disease given the strikingly broad demographic associated with abnormal levels of circulating troponin. Excessive sympathetic activity alone leads to accumulation of intracellular calcium, triggering myocardial necrosis. Acute stress, whether it be psychological or hemodynamic in origin, triggers coagulation and endothelial cell dysfunction through sustained increases in sympathetic activity. Together with persistent tachycardia, endothelial dysfunction and a sympathetic-mediated prothrombotic state may explain in part elevations in troponin frequently seen in critically ill patients. Catecholamine-associated metabolic dysregulation, typified by “stress” hyperglycemia, may further exacerbate myocardial injury. The carefully targeted use of alpha-2 agonists and beta blockers may contribute to a useful therapeutic role in this context.
In the absence of direct myocardial injury, prolonged sympathetic activation results in β-adrenoreceptor downregulation and desensitization. Circulating inflammatory mediators directly disrupt effective coupling of adrenergic receptors from their downstream signaling kinases. As a result, the pathologic failure to recycle GPCRs may explain the impaired cardiometabolic response to exogenous β-adrenoreceptor stimulation. Several clinical studies have repeatedly shown that increased mortality is associated with the loss of the typical cardiometabolic response to exogenous β-adrenergic agonists in established critical illness.
The parasympathetic limb of the autonomic nervous system also plays an important cardioprotective role, through several disparate mechanisms. In addition to the well-recognized hemodynamic effects of increasing diastolic filling time, recent experimental data add important new mechanisms of direct relevance to established critical illness. Remote preconditioning is activated by numerous afferent inputs, including pain and transient ischemia in distant organs. Cardioprotective remote ischemic preconditioning is dependent on intact vagal efferent innervations of the myocardium. Some of these cardioprotective effects may further be mediated through a parasympathetic-mediated anti-inflammatory mechanism, at least in the context of myocardial dysfunction triggered by inflammatory myocarditis.
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