What happens to the autonomic nervous system in critical illness?

SECTION 7  Persistent Critical Illness

40 What Happens to the Autonomic Nervous System in Critical Illness? Gareth L. Ackland

INTRODUCTION The term autonomic dysfunction is frequently associated with critical illness. Numerous studies have reported a striking association between depressed autonomic activity (usually measured as reduced heart rate variability), disease severity, and outcome.1,2 More sophisticated interrogation of various components of the autonomic nervous system also reveals that the loss of chemoreflex3 or baroreflex4 responses is associated with higher mortality in critically ill patients. However, the debate over the significance of these findings is difficult to disentangle—at least from clinical studies. Moreover, much of the literature that seeks to associate the development of critical illness with autonomic dysfunction is limited by (1) the variety of techniques used to detect alterations in autonomic control, (2) the lack of population norms, (3) variable analysis techniques, and (4) lack of suitable controls and follow-up.5 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 that primes pathophysiologic responses that subsequently result in multiorgan 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 an uncoupling of cellular and integrative physiologic control.6 In other words, autonomic dysfunction is characterized by changes in afferent, integrative (central nervous system [CNS]), or efferent components of sympathetic or parasympathetic neural control that are associated with pathologic states. These criteria broaden the potential impact of autonomic dysfunction on our understanding of 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 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 appears to be prognostically linked to outcome. From a neuropathologic viewpoint, postmortem samples of tissue obtained from the brains of septic patients show evidence of neuronal death in autonomic centers.7 At the molecular level, disruption of normal G-protein-coupled receptor (GPCR) recycling8 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 to the consequences of autonomic dysfunction alone (Table 40.1).

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.9 Subclinical changes in autonomic function precede the onset of diabetes and hypertension.10 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 279

280

SECTION 7 

Persistent Critical Illness

TABLE 40.1  Common Symptoms/Signs in Critically Ill Patients Mimicked by Features

of Aberrant Autonomic Control. Symptom of Critical Illness

Conventional Explanation

Alternative “Dysautonomia” Hypothesis

Tachycardia

Agitation58/fever59

Loss of baroreflex diminution of heart rate Cytokine stimulation of peripheral chemoreceptors

Cardiac ischemia

Underlying or acquired coronary disease60/hypercoaguability61

Loss of cardioprotective vagal innervation

Loss of inotropic performance

Cardiac ischemic damage

Neurohormonal downregulation of b-adrenoreceptors 6 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

anaerobic threshold yet no formal diagnosis of heart failure.11 Cardiac failure is characterized by increased sympathetic drive, high levels of circulating catecholamines and cortisol, and withdrawal of parasympathetic activity.12 Elevated plasma levels of proinflammatory cytokines and deficient immune function are also common features of chronic heart failure.13 Restoration toward normal autonomic function with conventional or experimental therapies improves cardiac function, as well as reducing excess neurohormonal and inflammatory activation.13 A growing body of accumulating evidence in both chronic heart failure14 and critically ill patients indicates that sympatholysis is associated with an apparently counterintuitive improvement in left ventricular function15 in addition to reductions in left ventricular remodeling and reduced plasma levels of inflammatory cytokines.16 Loss of vagal activity in chronic heart failure is a predictor of high mortality.17 Beyond overt cardiovascular disease, patients with extracardiac disease also show features of established autonomic dysfunction. For example, end-stage renal disease18 and obstructive jaundice19 are characterized by impaired baroreflex sensitivity and increased levels of plasma atrial natriuretic peptide. Moreover, patients at substantially higher risk of becoming critically ill after major surgery share many of these dysautonomic features, even though only a small fraction of these patients have a clinical diagnosis of cardiac failure as part of their preoperative workup.20

AUTONOMIC DYSFUNCTION AT THE VERY ONSET OF CRITICAL ILLNESS The hallmark of the onset of critical illness is tachycardia, frequently accompanied by tachypnea.21,22 Sepsis, hypoxia, and acidosis are all major stimuli for driving tachypnea/tachycardia through peripheral chemoreceptor-driven autonomic reflexes.23 Similarly, sterile inflammation, or danger-associated molecular patterns, may also be an important—although underrecognized—additional driver for this physiologic response.23 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. 40.1). Experi-

mental 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.24,25 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.26 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.27

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, central autonomic, baroreflex, and chemoreceptor control. Sedation inhibits parasympathetic neuronal activity while reducing sympathetic drive.28 Neuromuscular blockade agents inhibit peripheral chemoreceptor sensitivity29 and conceivably produce immunosuppression through nicotinic receptor blockade.30 Inotropes dramatically reduce baroreflex control and inhibit parasympathetic activity, as reflected by changes in heart rate variability.31,32 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.33 Perhaps most strikingly, models of enforced bed rest in healthy volunteers are associated with the rapid onset of autonomic dysfunction appearing well before other features of deconditioning. Typically, these changes involve sympathetic activation and parasympathetic withdrawal.34

281

sin us

ne rv e

CHAPTER 40

ATP

Ca ro tid

TLR-2 (e.g., zymosan) ATP ATP ATP ATP ATP

MyD-88

Inflammasome

Hypoxic sensing

NF-κβ

Hypoxia

Caspase-1

pro-IL-1β

IL-1β

Fig. 40.1  ​Peripheral autonomic sensing of inflammation by the carotid body chemoreceptors. Hypoxic sensing is transduced by the release of adenosine triphosphate (ATP) as a neurotransmitter at the carotid sinus nerve; ATP is also required for activation of inflammation (NLRP3 inflammasome by the toll-like receptor 2 [TLR-2] agonist zymosan). TLR-2 activation increases production of prointerleukin-1b (pro-IL-1b) in a myeloid differentiation primary response gene 88 (MyD-88), nuclear factor-kB (NF-kB)–dependent fashion. In turn, concomitant NLRP3 activation by extracellular ATP causes caspase-1 upregulation and cleavage of pro-IL-1b, which mimics hypoxia through the induction of hypoxia-inducible factor 1-a (HIF-1a). IL-1b, Interleukin 1b.

Decreased activity and/or gradual loss of neurons within the dorsal vagal motor nucleus provides a neurophysiological basis for the progressive decline of exercise capacity in critical illness, because parasympathetic vagal drive determines optimal exercise capacity.35 The increasingly recognized, though seldom detected, problem of psychological stress induced by the critical care environment reduces baroreflex sensitivity and promotes tachycardia.36 Experimental models of enforced bed rest demonstrate a mechanistic interaction between dysautonomia and anhedonia (loss of the capacity to experience pleasure),37 which may relate to depression being a negative prognosticator of outcome in critical illness.38 Given the current vogue for early physical, occupational, or behavioral therapy,39 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.40 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.41 Acute stress, whether it be psychological or hemodynamic in origin, triggers coagulation and endothelial cell dysfunction through sustained increases in sympathetic activity.42 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.43 The carefully targeted use of a-2 agonists44 and beta blockers45 may contribute a useful therapeutic role in this context. In the absence of direct myocardial injury, prolonged sympathetic activation results in b-adrenoreceptor downregulation and desensitization. Circulating inflammatory mediators directly disrupt effective coupling of adrenergic

282

SECTION 7 

Persistent Critical Illness

receptors from their downstream signaling kinases.46 As a result, the pathologic failure to recycle GPCRs may explain the impaired cardiometabolic response to exogenous b-adrenoreceptor stimulation. Several clinical studies have repeatedly shown that increased mortality is associated with the loss of the typical cardiometabolic response to exogenous b-adrenergic agonists in established critical illness.47 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. Activity of a subpopulation of vagal motor neurons tonically inhibit left ventricular contractility.48 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.49 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.50

IMMUNE DYSFUNCTION IN CRITICAL ILLNESS AS A RESULT OF AUTONOMIC DYSFUNCTION Experimental data show that multiple autonomic mechanisms contribute to immunoparesis and immunosuppression, key features of established critical illness. Monocyte deactivation is associated with increased risk of infection and higher mortality, accompanied by b-adrenergic desensitization.51 Catecholamines exacerbate the hepatic dysfunction observed during sepsis,52 which may be reversed by targeted beta-blockade.53 The parasympathetic nervous system, acting through the vagus nerve, can sense inflammation in the periphery and relay this information to the brain, resulting in fever and activation of the hypothalamic-pituitary-adrenal axis and sympathetic activation.54 Enhancing efferent vagal activity, at least in animal models, attenuates macrophage release of inflammatory cytokines through nicotinic a-7 agonism.55 Other parasympathetic neurotransmitters56 and pathways57 may also contribute to neuroimmunomodulation.

CONCLUSIONS An abnormal cardiometabolic response to sympathoexcitation is robustly associated with key features of chronic critical illness and paralleled by the loss of parasympathetic activity. Emerging clinical data support these largely experimental concepts. Precedents from the clinical cardiac failure literature suggest that autonomic modulation provides a rational target for preventing/reversing critical illness.

AUTHORS’ RECOMMENDATIONS • Persistent tachycardia should not automatically be attributed to conventionally thought-of triggers of excess sympathetic activity, such as hypovolemia or pain. • Treating dysautonomic features such as hypotension and/or tachycardia without detailed hemodynamic scrutiny may result in inappropriate therapy, including excess fluid administration. • Early efforts to minimize prolonged immobility may be beneficial through preventing associated autonomic dysfunction. • Targeted treatments to ameliorate tachycardia, using a2 adrenoceptor agonists, such as dexmedetomidine or clonidine, or titratable beta-blockers, such as esmolol, may also be beneficial.

REFERENCES 1. Hoyer D, Friedrich H, Zwiener U, et al. Prognostic impact of autonomic information flow in multiple organ dysfunction syndrome patients. Int J Cardiol. 2006;108:359-369. 2. Schmidt H, Müller-Werdan U, Hoffmann T, et al. Attenuated autonomic function in multiple organ dysfunction syndrome across three age groups. Biomed Tech (Berl). 2006;51:264-267. 3. Schmidt H, Müller-Werdan U, Nuding S, et al. Impaired chemoreflex sensitivity in adult patients with multiple organ dysfunction syndrome—the potential role of disease severity. Intensive Care Med. 2004;30:665-672. 4. Schmidt H, Müller-Werdan U, Hoffmann T, et al. Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups. Crit Care Med. 2005;33:1994-2002. 5. Stein PK. Challenges of heart rate variability research in the ICU. Crit Care Med. 2013;41:666-667. 6. Godin PJ, Buchman TG. Uncoupling of biological oscillators: a complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med. 1996; 24:1107-1116. 7. Sharshar T, Gray F, Lorin de la Grandmaison G, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet. 2003;362:1799-1805. 8. Hupfeld CJ, Olefsky JM. Regulation of receptor tyrosine kinase signaling by GRKs and beta-arrestins. Annu Rev Physiol. 2007; 69:561-577. 9. Phillips JK. Autonomic dysfunction in heart failure and renal disease. Front Physiol. 2012;3:219. 10. Davis JT, Rao F, Naqshbandi D, et al. Autonomic and hemodynamic origins of pre-hypertension: central role of heredity. J Am Coll Cardiol. 2012;59:2206-2216. 11. Sultan P, Edwards MR, Gutierrez del Arroyo A, et al. Cardiopulmonary exercise capacity and preoperative markers of inflammation. Mediators Inflamm. 2014;2014:727451. 12. Schwartz PJ, De Ferrari GM. Sympathetic-parasympathetic interaction in health and disease: abnormalities and relevance in heart failure. Heart Fail Rev. 2011;16:101-107. 13. Maisel AS. Beneficial effects of metoprolol treatment in congestive heart failure. Reversal of sympathetic-induced alterations of immunologic function. Circulation. 1994;90:1774-1780.

CHAPTER 40 14. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150:784-794. 15. Gore DC, Wolfe RR. Hemodynamic and metabolic effects of selective beta1 adrenergic blockade during sepsis. Surgery. 2006;139:686-694. 16. Felder RB, Yu Y, Zhang ZH, Wei SG. Pharmacological treatment for heart failure: a view from the brain. Clin Pharmacol Ther. 2009;86:216-220. 17. Van Wagoner DR. Chronic vagal nerve stimulation for the treatment of human heart failure: progress in translating a vision into reality. Eur Heart J. 2011;32:788-790. 18. Chesterton LJ, McIntyre CW. The assessment of baroreflex sensitivity in patients with chronic kidney disease: implications for vasomotor instability. Curr Opin Nephrol Hypertens. 2005; 14:586-591. 19. Song JG, Cao YF, Sun YM, et al. Baroreflex sensitivity is impaired in patients with obstructive jaundice. Anesthesiology. 2009; 111:561-565. 20. Abbott TEF, Minto G, Lee AM, et al. Elevated preoperative heart rate is associated with cardiopulmonary and autonomic impairment in high-risk surgical patients. Br J Anaesth. 2017;119:87-94. 21. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995; 273:117-123. 22. Annane D, Trabold F, Sharshar T, et al. Inappropriate sympathetic activation at onset of septic shock: a spectral analysis approach. Am J Respir Crit Care Med. 1999;160:458-465. 23. Ackland GL, Kazymov V, Marina N, Singer M, Gourine AV. Peripheral neural detection of danger-associated and pathogenassociated molecular patterns. Crit Care Med. 2013;41:e85-e92. 24. Godin PJ, Fleisher LA, Eidsath A, et al. Experimental human endotoxemia increases cardiac regularity: results from a prospective, randomized, crossover trial. Crit Care Med. 1996; 24:1117-1124. 25. Taylor EW, Jordan D, Coote JH. Central control of the cardiovascular and respiratory systems and their interactions in vertebrates. Physiol Rev. 1999;79:855-916. 26. Tang GJ, Kou YR, Lin YS. Peripheral neural modulation of endotoxin-induced hyperventilation. Crit Care Med. 1998; 26:1558-1563. 27. Koyama S, Terada N, Shiojima Y, Takeuchi T. Baroreflex participation of cardiovascular response to E. coli endotoxin. Jpn J Physiol. 1986;36:267-275. 28. Bradley BD, Green G, Ramsay T, Seely AJ. Impact of sedation and organ failure on continuous heart and respiratory rate variability monitoring in critically ill patients: a pilot study. Crit Care Med. 2013;41:433-444. 29. Eriksson LI, Sato M, Severinghaus JW. Effect of a vecuroniuminduced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology. 1993;78:693-699. 30. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384-388. 31. Hogue Jr CW, Dávila-Román VG, Stein PK, Feinberg M, Lappas DG, Pérez JE. Alterations in heart rate variability in patients undergoing dobutamine stress echocardiography, including patients with neurocardiogenic hypotension. Am Heart J. 1995;130:1203-1209.

283

32. van de Borne P, Heron S, Nguyen H, et al. Arterial baroreflex control of the sinus node during dobutamine exercise stress testing. Hypertension. 1999;33:987-991. 33. Lyte M, Freestone PP, Neal CP, et al. Stimulation of Staphylococcus epidermidis growth and biofilm formation by catecholamine inotropes. Lancet. 2003;361:130-135. 34. Hughson RL, Yamamoto Y, Maillet A, et al. Altered autonomic regulation of cardiac function during head-up tilt after 28-day head-down bed-rest with counter-measures. Clin Physiol. 1994; 14:291-304. 35. Machhada A, Trapp S, Marina N, et al. Vagal determinants of exercise capacity. Nat Commun. 2017;8:15097. 36. Truijen J, Davis SC, Stok WJ, et al. Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under b-adrenergic blockade. Clin Sci (Lond). 2011;120:161-167. 37. Moffitt JA, Grippo AJ, Beltz TG, Johnson AK. Hindlimb unloading elicits anhedonia and sympathovagal imbalance. J Appl Physiol (1985). 2008;105:1049-1059. 38. Desai SV, Law TJ, Needham DM. Long-term complications of critical care. Crit Care Med. 2011;39:371-379. 39. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009;373:1874-1882. 40. Lara TM, Hajjar LA, de Almeida JP, et al. High levels of B-type natriuretic peptide predict weaning failure from mechanical ventilation in adult patients after cardiac surgery. Clinics (Sao Paulo). 2013;68:33-38. 41. Ellison GM, Torella D, Karakikes I, et al. Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. J Biol Chem. 2007;282:11397-11409. 42. Bruno RM, Ghiadoni L, Seravalle G, Dell’oro R, Taddei S, Grassi G. Sympathetic regulation of vascular function in health and disease. Front Physiol. 2012;3:284. 43. Weekers F, Giulietti AP, Michalaki M, et al. Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology. 2003;144:5329-5338. 44. MacLaren R. Immunosedation: a consideration for sepsis. Crit Care. 2009;13:191. 45. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310:1683-1691. 46. Coggins M, Rosenzweig A. The fire within: cardiac inflammatory signaling in health and disease. Circ Res. 2012;110:116-125. 47. Collin S, Sennoun N, Levy B. Cardiovascular and metabolic responses to catecholamine and sepsis prognosis: a ubiquitous phenomenon? Crit Care. 2008;12:118. 48. Machhada A, Marina N, Korsak A, Stuckey DJ, Lythgoe MF, Gourine AV. Origins of the vagal drive controlling left ventricular contractility. J Physiol. 2016;594:4017-4030. 49. Mastitskaya S, Marina N, Gourine A, et al. Cardioprotection evoked by remote ischaemic preconditioning is critically dependent on the activity of vagal pre-ganglionic neurones. Cardiovasc Res. 2012;95:487-494. 50. Leib C, Göser S, Lüthje D, et al. Role of the cholinergic antiinflammatory pathway in murine autoimmune myocarditis. Circ Res. 2011;109:130-140. 51. Link A, Selejan S, Maack C, Lenz M, Böhm M. Phosphodiesterase 4 inhibition but not beta-adrenergic stimulation suppresses

284

SECTION 7 

Persistent Critical Illness

tumor necrosis factor-alpha release in peripheral blood mononuclear cells in septic shock. Crit Care. 2008;12:R159. 52. Aninat C, Seguin P, Descheemaeker PN, Morel F, Malledant Y, Guillouzo A. Catecholamines induce an inflammatory response in human hepatocytes. Crit Care Med. 2008;36:848-854. 53. Ackland GL, Yao ST, Rudiger A, et al. Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1adrenoceptor blockade in severe sepsis in rats. Crit Care Med. 2010;38:388–394. 54. Goehler LE, Gaykema RP, Hansen MK, Anderson K, Maier SF, Watkins LR. Vagal immune-to-brain communication: a visceral chemosensory pathway. Auton Neurosci. 2000;85:49–59. 55. Tracey KJ. Understanding immunity requires more than immunology. Nat Immunol. 2010;11:561–564. 56. Smalley SG, Barrow PA, Foster N. Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its therapeutic potential in inflammatory disease. Clin Exp Immunol. 2009;157:225–234.

57. Cailotto C, Gomez-Pinilla PJ, Costes LM, et al. Neuro-anatomical evidence indicating indirect modulation of macrophages by vagal efferents in the intestine but not in the spleen. PLoS One. 2014; 9:e87785. 58. Chevrolet JC, Jolliet P. Clinical review: agitation and delirium in the critically ill-significance and management. Crit Care. 2007;11:214. 59. Launey Y, Nesseler N, Mallédant Y, Seguin P. Clinical review: fever in septic ICU patients-friend or foe? Crit Care. 2011;15:222. 60. Lim W, Qushmaq I, Devereaux PJ, et al. Elevated cardiac troponin measurements in critically ill patients. Arch Intern Med. 2006;166:2446–2454. 61. Alhazzani W, Lim W, Jaeschke RZ, Murad MH, Cade J, Cook DJ. Heparin thromboprophylaxis in medical-surgical critically ill patients: a systematic review and meta-analysis of randomized trials. Crit Care Med. 2013;41:2088–2098.

e1 Abstract: 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. Keywords: adrenoceptor, autonomic dysfunction, parasympathetic, sympathetic, vagus nerve