SciELO - Scientific Electronic Library Online

 
vol.36 issue3Sensorimotor performance in euthymic bipolar disorder: the MPraxis (PennCNP) analysisIndustry withdrawal from psychiatric medication development author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

Share


Brazilian Journal of Psychiatry

Print version ISSN 1516-4446

Rev. Bras. Psiquiatr. vol.36 no.3 São Paulo July/Sept. 2014  Epub June 11, 2014

http://dx.doi.org/10.1590/1516-4446-2013-1233 

UPDATE ARTICLES

Septic encephalopathy: does inflammation drive the brain crazy?

Felipe Dal-Pizzol1 

Cristiane D. Tomasi1 

Cristiane Ritter1 

1Laboratory of Experimental Pathophysiology and National Science and Technology Institute for Translational Medicine (INCT-TM), Graduate Program in Health Sciences, Health Sciences Research Center, Universidade do Extremo Sul Catarinense (UNESC), Criciúma - SC - Brazil

ABSTRACT

Sepsis and the multiorgan dysfunction syndrome are among the most common reasons for admission to an intensive care unit, and are a leading cause of death. During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as sepsis-associated encephalopathy (SAE). It is postulated that the common final pathway that leads to SAE symptoms is the deregulation of neurotransmitters, mainly acetylcholine. Thus, it is supposed that inflammation can affect neurotransmitters, which is associated with SAE development. In this review, we will cover the current evidence (or lack thereof) for the mechanisms by which systemic inflammation interferes with the metabolism of major CNS neurotransmitters, trying to explain how systemic inflammation drives the brain crazy.

Key words: Sepsis-associated encephalopathy; acetylcholine; amines; GABA; inflammation

Introduction

Sepsis and the multiorgan dysfunction syndrome are among the most common reasons for admission to an intensive care unit, and are a leading cause of death.1-4 During the last decades, advances have been made in our understanding of sepsis, but currently there is no target-directed, FDA-approved treatment for sepsis.

The pathophysiology of sepsis has been partially elucidated; it is a dynamic process, which involves components of the immune system, the coagulation pathway, parenchymal cells, and the endocrine and metabolic pathways.5 Many factors have been postulated to trigger sepsis, including products released from bacteria as well as products from damaged cells. Toll-like receptor (TLR) signaling has been suggested to be a key pathway in sepsis pathophysiology, leading to the production of inflammatory mediators.6 The activation of this pathway depends on the interaction between TLR and TLR ligands, which include those derived from bacteria in addition to host-derived products such as intracellular proteins, extracellular matrix components, and oxidized lipids.7

During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as septic encephalopathy (SE) or sepsis-associated delirium (SAD).8-9 SE has been reported to occur in 8-70% of septic patients, with the wide variation attributable mainly to diagnostic criteria.10 Reciprocal interactions between the immune system and the CNS are considered to be major components of the host response in sepsis (Figure 1). In addition, brain injury occurs during sepsis development, and proposed mechanisms to explain it include alterations in the blood-brain barrier (BBB), local generation of pro- and anti-inflammatory cytokines, amino acid metabolism disruption, brain ischemia, and imbalance of neurotransmitters11 (Figure 2). Additionally, once inflammation persists, excitotoxicity and oxidative stress may further aggravate SE and contribute to neuronal dysfunction.12 In animal models of sepsis, acute encephalopathy occurs, and survivors exhibit cognitive impairment that could be secondary to CNS damage.13 Likewise, survivors from critical care, including septic patients, have well-documented persistent neurocognitive deficits and develop psychiatric disorders.14-23

Figure 1 During sepsis, inflammatory mediators (e.g., TNF-α, IL-1β) are released peripherally and can drive alterations in several organs, such as the liver, lung, kidney, cardiovascular system, and central nervous system. An imbalance between pro- and anti-inflammatory mediators interferes with the normal function of neurotransmitters. Furthermore, alterations in neurotransmitters can modulate the inflammatory balance, and are probably involved in the pathophysiology of brain dysfunction. CNS = central nervous system; IL-1β = interleukin 1β; SAE = sepsis-associated encephalopathy; TNF-α = tumor necrosis factor alpha. 

Figure 2 Cytokines produced in the infection site activate afferent signals to the brain, and the subsequent vagal activation inhibits cytokine synthesis through the “inflammatory reflex” of the cholinergic pathway. Inflammation changes the structure and function of the blood-brain barrier (BBB), increasing microvascular permeability, impairing microcirculatory blood flow, and producing brain inflammation. During sepsis, alterations in the coagulation system results in microthrombus formation and microinfarcts. Endothelial activation also impairs the microcirculation and worsens brain inflammation, which in turn is related to brain dysfunction. Ach = acetylcholine; BBB = blood-brain barrier; SAE = sepsis-associated encephalopathy. 

The interaction between sepsis and the brain is an opportunity to study how systemic inflammation affects brain function. Most studies about the mechanisms of SE have used animals or cell cultures, and improved our understanding of how the CNS is affected by endotoxins and cytokines, but whether this is related to clinical SE remains unclear. It is postulated that the common final pathway that drives SE symptoms is the deregulation of neurotransmitters, mainly acetylcholine.24 In this review, we will cover the current evidence (or lack thereof) for the mechanisms by which systemic inflammation interferes with the metabolism of the major CNS neurotransmitters, trying to explain how systemic inflammation drives the brain crazy.

Evidence that systemic inflammation is associated with brain dysfunction

Theoretically, systemic inflammation can reach the brain through at least four different routes: 1) peripheral organs synthesize and release cytokines that act on their receptors present in nerve fibers of the autonomic nervous system to modulate brain function; 2) circulating cytokines diffuse through the BBB; 3) cytokines might signal into the brain through specific areas that lack the BBB, such as the circumventricular organs; or 4) cytokines might enter the brain through a saturable transport mechanism.25 There is no clear evidence to explain in detail how inflammation reaches the brain during sepsis, but both in animals and in humans, inflammation occurs in the CNS early and late after sepsis.26-29

The immune system is a complex, highly adaptive system,29 and it is integrated with the CNS at several levels to maintain homeostasis.30-32 However, it is possible that activation of the immune system may induce brain dysfunction, and, in fact, sepsis is a major risk factor for occurrence of delirium.33 It is believed that pro-inflammatory cytokines, particularly interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α), are generated in the periphery, communicate with the brain, and initiate cytokine synthesis in the CNS.24 Fever and changes in behavior - such as anorexia, lethargy, and depression, collectively named sickness behavior - are observed as a response of neurons to cytokines in several different animal models.34-38 In addition, studies in healthy volunteers have demonstrated that systemic inflammatory challenges impact the human brain.39-41 A postmortem investigation found an association between brain dysfunction and astrocyte, microglia, and IL-6 activity in the human brain.42

However, excluding postmortem studies, a direct relation between inflammation and brain dysfunction in humans is limited because of the inaccessibility of the CNS. Thus, in general, investigations are limited to searching for a correlation between systemic inflammation markers and brain dysfunction.

High levels of procalcitonin and C-reactive protein (CRP) at intensive care unit (ICU) admission correlate with the duration of brain dysfunction, both in septic and non-septic patients.43 Krabbe et al.,41 using a human endotoxemia model, showed that a low-grade increase in the concentrations of TNF-α, its soluble receptor (sTNF-R), IL-6, and IL-1 receptor antagonist (IL-1RA) was inversely associated with declarative memory performance. This was independent of physical stress symptoms or activation of the hypothalamic-pituitary-adrenal (HPA) axis, suggesting that low-level systemic inflammation had a negative effect on some areas related to cognitive function. A recent study demonstrated that sTNFR was independently associated with delirium in general ICU patients.44

Pfister et al.45 found a correlation between high plasma CRP levels, alterations in cerebrovascular autoregulation, and SE. The cerebral arterioles of patients with SE were less reactive to vasodilatory stimuli,46 and this was independently associated with acute brain dysfunction.47 Healthy volunteers injected with endotoxin had decreased cerebral blood flow, and this was associated with peak serum concentrations of TNF-α.48 Recently, it was demonstrated that patients with lower vascular reactivity had increased duration of brain dysfunction.47 The mechanisms behind endothelial dysfunction and acute brain dysfunction remain unclear, but inflammation could drive structural and functional alterations in the BBB, increasing microvascular permeability and impairing microcirculatory blood flow.49-52 These alterations could be secondary to a decrease in the activity of endothelial nitric oxide synthase induced by inflammation53 or to alterations in the coagulation system, resulting in microthromboses and microinfarcts.54 Endothelial activation in the brain microvasculature has been observed after sepsis in animal models, and this was associated with leukocyte adhesion and brain inflammation.26 In addition, BBB dysfunction induced by metalloproteinase (MMP) activation was also associated with brain inflammation and cognitive impairment in an animal model of sepsis.55 This is supported by the fact that MMP-9 content was associated with delirium in the general ICU patient.44

It is supposed that systemic inflammation can lead to neuronal or glial damage; however, at least in experimental endotoxemia in humans, there is no correlation between acute systemic inflammation and plasma levels of brain specific proteins (S-100β, neuronal enolase [NSE], glial fibrillary acidic protein [GFAP]) nor deterioration of cognitive function.56 In contrast, S-100β <1?show=[to]?>is associated with SE,45 and NSE is associated with delirium in general ICU patients.57 Sharshar et al.27 demonstrated that septic shock is associated with neuronal and glial apoptosis in autonomic centers in humans, but brain TNF-α expression did not differ between septic shock and control patients. Whether neuronal and glial apoptosis is sufficient to induce clinically relevant brain dysfunction remains unknown.

Thus, to date, there is evidence that brain inflammation occurs during sepsis both in animals and in humans. Inflammation is probably related to alterations in cerebral blood flow and neuronal/glial cell damage, but a direct link between these and SE is still lacking.

Evidence linking systemic inflammation and deregulation of neurotransmitters

Since inflammation and alterations in neurotransmitters are the major theories trying to explain brain dysfunction we explore the evidences that links inflammation and major neurotransmitters system deregulation (Figure 3).

Figure 3 Facts that favors or are against the theory of neurotransmitters imbalance in the genesis of sepsis-associated encephalopathy. LPS = lipopolysaccharide; Trp = tryptophan; ICU = intensive care unit; BZ = benzodiazepines; NRI = norepinephrine reuptake inhibitors; GABA = gamma-aminobutyric acid; SAE = sepsis-associated encephalopathy. 

Acetylcholine (Ach)

A widely postulated mechanism to explain delirium is cholinergic failure.83 The first evidence for this hypothesis came from case reports linking delirium to acute poisoning with anticholinergic drugs and the reversal of delirium with cholinergic drugs. Cholinergic signaling by both nicotinic and muscarinic receptors modulates cognitive function, arousal, learning, and memory, the major brain functions affected in delirium. Thus, sepsis-induced inflammation is presumed to affect cholinergic signaling and contribute to the genesis of SE.

In an animal model of LPS-induced long-term cognitive deficits, neuronal loss in the hippocampus and the prefrontal cortex occurs mainly due to reduced cholinergic innervation at postrolandic cortical areas. This is consistent with the fact that the hippocampus is particularly sensitive to systemic inflammation.84 We demonstrated that the use of cholinergic agonists improves cognitive performance in septic animals,58 and that endotoxin is able to reduce brain choline acetyltransferase activity.59 Thus, it is possible that cholinergic neurons are particularly sensitive to systemic inflammation. This is the major theory behind SE, but to date there is no direct evidence to support it.

Endotoxin administration to healthy individuals increases plasma acetylcholinesterase (AChE) activity, which is associated with better performance in evocative memory tasks, but worse performance in working memory.60 In addition, patients that respond to endotoxin by suppressing the cholinergic system have a better working memory performance as compared with patients that enhance cholinergic activity, indicating that limited cholinergic activation may be beneficial for cognition.60 To date, human trials of cholinesterase inhibitors have not demonstrated benefit to prevent or treat delirium.71

The cholinergic pathway may be involved indirectly in the pathogenesis of delirium. The cholinergic pathway acts as a predictor of individual variation in systemic inflammatory response to infection; thus, by modulating systemic inflammation, the cholinergic system can indirectly affect brain function.60 High plasma levels of an alpha-7 nicotinic Ach receptor agonist correlated with lower cytokine levels in endotoxin-treated volunteers.72 Cholinergic signaling protects striatal, hippocampal, and cortical neurons against neurotoxicity induced by excitotoxic amino acids as well as other toxic insults. Several mechanisms have been postulated to explain these effects, from the production of growth factors61,85 to a decrease in superoxide anion generation62 to antioxidant actions.63,64 In addition, resembling the peripheral cholinergic anti-inflammatory pathway, ACh and nicotine65 have been reported to modulate LPS-induced TNF-α release from microglia through activation of α-nAChR. Thus, it is possible that the decrease in cholinergic neurons during systemic inflammation decreases the availability of an “anti-inflammatory” signal in the brain. This is consistent with the decrease of cholinergic neurons observed with aging86 that occurs in parallel to microglia activation.87

Amines

Dopamine, norepinephrine, and serotonin have a role in arousal and the sleep-wake cycle.83 In addition, the D2 dopamine receptor subtype has been associated with hallucinations, stereotypic behavior, and thought disturbances,88 and norepinephrine plays an important role in modulating attention, anxiety, and mood.89 Thus, amines could be involved in several different symptoms associated with brain dysfunction. In fact, excess dopamine and norepinephrine has been associated with hyperactive delirium.89 Experimentally, this is supported by the fact that the administration of dopamine agonists results in frontostriatal abnormalities that correlate with delirium, and dopamine antagonists are classically used to treat hyperactive delirium.90,91 Furthermore, elevated CNS serotonin activity is postulated to occur in hepatic encephalopathy, and serotonin syndrome secondary to the withdrawal of serotonin reuptake inhibitors resembles the clinical picture of SE.92,93

Brain serotonin synthesis depends on the availability of tryptophan (Trp), and dopamine and norepinephrine production requires tyrosine (Tyr) and phenylalanine (Phe).94 Despite the fact that most delirium theories suggest that an increase in amines drives delirium, in healthy volunteers the administration of LPS increases the cerebral delivery and influx of Phe.95 This can be associated with the synthesis of “false” neurotransmitters, such as phenylethanolamine, which in turn can decrease central noradrenergic pathways.73,96 An elevated Phe/large neutral amino acids (LNAA) ratio during acute febrile illness is associated with delirium in hospitalized elderly patients.74 The systemic inflammatory response is associated with a decrease in the ratio of branched-chain (valine and isoleucine) and aromatic amino acids (mainly phenylalanine). This is associated with an increase in the cerebral delivery and unidirectional cerebral influx of phenylalanine, an abolished influx of leucine and isoleucine, and an ammonia-independent cerebral efflux of glutamine.95 In this context, both low and high levels of Trp/LNAA are associated with delirium in the general ICU patient.94 Alterations in Trp concentrations could lead to delirium due to the production of neurotoxic metabolites or alterations in serotonin/melatonin synthesis. In fact, increased activation of the kynurenine pathway (a neurotoxic metabolite of Trp) is associated with mortality and brain dysfunction in ICU patients.97 Besides its neurotoxic effect, the accumulation of kynurenine or quinolinic acid can compromise immune functions.66 In addition, the excessive degradation of tryptophan, as seen in septic patients, could lead to NAD+ depletion.67 In this context, neurons may become functionally hypoxic (due to Krebs cycle impairment) even in the presence of oxygen, and cellular hibernation may, in part, reflect an underlying tryptophan shortage.

Plasma levels of Tyr/LNAA are also associated with delirium. Patients with high levels of tyrosine could have excess dopamine or norepinephrine, which is consistent with a neurotoxic effect of norepinephrine.68 Despite this, the use of dopamine antagonists in critically ill patients does not consistently improve delirium severity and duration,75,98 and the use of vasoactive drugs is not independently associated with increased incidence of delirium.76 Furthermore, as described with Ach, norepinephrine seems to have anti-inflammatory properties. The administration of norepinephrine reuptake inhibitors (NRIs) inhibits LPS-induced expression of cytokines, chemokines and endothelial activation,99 probably increasing norepinephrine availability to glial cells. In addition, α2-adrenoceptor stimulation decreases vascular endothelial cell permeability77 and reduces production of inflammatory mediators.78 Supporting this view, dopexamine, an α2-adrenoceptor and dopamine 1 and 2 receptor agonist, protects against cerebral edema induced by sepsis, and the co-administration of an α2-adrenoceptor antagonist blunted this effect.79 In humans, there is preliminary evidence that dexmedetomidine, an α-agonist, exerts protective effects in septic patients,80 but this is not supported by animal models of primary brain injury.100 The lack of a consistent effect is also observed with the β-adrenergic receptor; β2-adrenoceptor activation can induce101 or protect against brain inflammation.102,103

Gamma-aminobutyric acid (GABA)

The most compelling evidence about delirium prevention in ICU patients comes from sedation strategies aimed to reduce benzodiazepine (BZ) use.104 Despite this, little is known about GABA neurotransmission under inflammatory conditions, or of the exact mechanisms whereby increased GABA signaling drives delirium. The cortical type A GABA (GABA-A) and corticotrophin-releasing factor systems are major regulatory factors of the behavioral response to stress.69 Acute stressors such as restraint, infection, hypoxia or combined mild stressors influence the GABA-A complex at two different levels: by altering BZ-1 binding sites and modulating the expression of selective GABA-A receptor subunits.105 Inflammatory mediators increase the insertion of GABA-A receptors in the neuron membrane,106 and an increase in GABA-A receptor activity has been observed in septic rats.107,108 Thus, it could be presumed that increased sensitivity to BZ occurs during systemic inflammation. In fact, GABA-A agonists worsen postoperative pain only in the presence of inflammation.109 Cerebral synaptic activity is decreased in SE, and because GABA-A receptor regulates synaptic transmission in most cerebral inhibitory synapses, it is possible that GABA-A could be a target for new therapeutic strategies aimed to treat or prevent delirium. Indeed, increased GABAergic neurotransmission has been reported in patients with hepatic encephalopathy.70

On the other hand, while the expression of GABA-A receptors is found normally in glial cells, BZ receptor non-associated with GABA-A expression, which is low in normal glial cells, is increased during inflammatory conditions.110 In this context, the BZ midazolam improves neural recovery after anoxia and ischemia.111 Midazolam decreases LPS-induced cytokine release from microglia via non-GABA-A BZ receptors.81 This seems to be a specific effect, as propofol has no such protective effect in vitro.82 Thus, if systemic and brain inflammation leads to delirium, it is expected that BZ could improve delirium in the critically ill patient.

Concluding remarks

Despite the fact that SE and brain dysfunction are highly prevalent in ICU patients and are associated with worse prognosis, surprisingly little is known about their pathophysiology. The most cited theory - neurotransmitter deregulation - lacks solid evidence to be widely accepted, and this may partly account for the lack of effect of clinical interventions designed to treat acute brain dysfunction, mainly strategies based on cholinergic drugs. Thus, the hypothesis that neurotransmission and inflammation are connected and are major players in brain dysfunction pathophysiology requires further critical assessment in the future.

Acknowledgements

This study received financial support from the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC), Program of Support to Centers of Excellence (PRONEX), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo è Pesquisa e Inovação do Estado de Santa Catarina (FAPESC); from the National Science and Technology Institute for Translational Medicine (INCT-TM); and from Programa de Cooperação Acadêmica (PROCAD) - Sepse.

References

1. Perl TM, Dvorak L, Hwang T, Wenzel RP. Long-term survival and function after suspected gram-negative sepsis. JAMA. 1995;274:338-45. [ Links ]

2. Quartin AA, Schein RM, Kett DH, Peduzzi PN. Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA. 1997;277:1058-63. [ Links ]

3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303-10. [ Links ]

4. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304:1787-94. [ Links ]

5. Vincent JL, Opal SM, Marshall JC, Tracey K. Sepsis definitions: time for change. Lancet. 2013;381:774-5. [ Links ]

6. Tsung A, McCoy SL, Klune JR, Geller DA, Billiar TR, Hefeneider SH. A novel inhibitory peptide of Toll-like receptor signaling limitslipopolysaccharide-induced production of inflammatory mediators andenhances survival in mice. Shock. 2007;27:364-9. [ Links ]

7. Song DH, Lee JO. Sensing of microbial molecular patterns by toll-like receptors. Immunol Rev. 2012;250:216-29. [ Links ]

8. Sprung CL, Peduzzi PN, Shatney CH, Schein RM, Wilson MF, Sheagren JN, et al. Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group. Crit Care Med. 1990;18:801-6. [ Links ]

9. Ebersoldt M, Sharshar T, Annane D. Sepsis-associated delirium. Intensive Care Med. 2007;33:941-50. [ Links ]

10. Kafa IM, Bakirci S, Uysal M, Kurt MA. Alterations in the brain electrical activity in a rat model of sepsis-associated encephalopathy. Brain Res. 2010;1354:217-26. [ Links ]

11. Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED. Pathophysiology of septic encephalopathy: a review. Crit Care Med. 2000;28:3019-24. [ Links ]

12. Wilson JX, Young GB. Progress in clinical neurosciences: sepsis-associated encephalopathy: evolving concepts. Can J Neurol Sci. 2003;30:98-105. [ Links ]

13. Barichello T, Martins MR, Reinke A, Feier G, Ritter C, Quevedo J, et al. Cognitive impairment in sepsis survivors from cecal ligation and perforation. Crit Care Med. 2005;33:221-3. [ Links ]

14. Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson-LOHR V. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160:50-6. [ Links ]

15. Heyland DK, Hopman W, Coo H, Tranmer J, McColl MA. Long-term healthrelated quality of life in survivors of sepsis. Short Form 36: a valid and reliable measure of health-related quality of life. Crit Care Med. 2000;28:3599-605. [ Links ]

16. Angus DC, Musthafa AA, Clermont G, Griffin MF, Linde-Zwirble WT, Dremsizov TT, et al. Quality adjusted survival in the first year after the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163:1389-94. [ Links ]

17. Granja C, Dias C, Costa-Pereira A, Sarmento A. Quality of life of survivors from severe sepsis and septic shock may be similar to that of others who survive critical illness. Crit Care. 2004;8:R91-8. [ Links ]

18. Jackson JC, Gordon SM, Ely EW, Burger C, Hopkins RO. Research issues in the evaluation of cognitive impairment in intensive care unit survivors. Intensive Care Med. 2004;30:2009-16. [ Links ]

19. Granja C, Lopes A, Moreira S, Dias C, Costa-Pereira A, Carneiro A, et al. Patients' recollectionsof experiences in the intensive care unit may affect their quality of life. Crit Care. 2005;9:R96-109. [ Links ]

20. Hopkins RO, Weaver LK, Collingridge D, Parkinson RB, Chan KJ, Orme JF Jr. Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2005;171:340-7. [ Links ]

21. Hough CL, Curtis JR. Long-term sequelae of critical illness: memories and health-related quality of life. Crit Care. 2005;9:145-6. [ Links ]

22. Hopkins RO. Sepsis, oxidative stress, and brain injury. Crit Care Med. 2007;35:2233-4. [ Links ]

23. Gordon SM, Jackson JC, Ely EW, Burger C, Hopkins RO. Clinical identification of cognitive impairment in ICU survivors: insights for intensivists. Intensive Care Med. 2004;30:1997-2008. [ Links ]

24. van Gool WA, van de Beek D, Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide. Lancet. 2010;375:773-5. [ Links ]

25. Licinio J, Mastronardi C, Wong M. Pharmacogenomics of neuroimmune interactions in human psychiatric disorders. Exp Physiol. 2008;92:807-11. [ Links ]

26. Comim CM, Vilela MC, Constantino LS, Petronilho F, Vuolo F, Lacerda-Queiroz N, et al. Traffic of leukocytes and cytokine up-regulation in the central nervous system in sepsis. Intensive Care Med. 2011;37:711-8. [ Links ]

27. Sharshar T, Gray F, Lorin de la Grandmaison G, Hopkinson NS, Ross E, Dorandeu A, et al. Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet. 2003;362:1799-805. [ Links ]

28. Weberpals M, Hermes M, Hermann S, Kummer MP, Terwel D, Semmler A, et al. NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J Neurosci. 2009;29:14177-84. [ Links ]

29. Teeling JL, Perry VH. Systemic infection and inflammation in acute cns injury and chronic neurodegeneration: underlying mechanisms. Neuroscience. 2009;158:1062-73. [ Links ]

30. Dantzer R, Bluthe RM, Gheusi G, Cremona S, Laye S, Parnet P, et al. Molecular basis of sickness behavior. Ann N Y Acad Sci. 1998;856:132-8. [ Links ]

31. Dantzer R, Aubert A, Bluthe RM, Gheusi G, Cremona S, Laye S, et al. Mechanisms of the behavioural effects of cytokines. Adv Exp Med Biol. 1999;461:83-105. [ Links ]

32. Dantzer R, Konsman JP, Bluthe RM, Kelley KW. Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent? Auton Neurosci. 2000;85:60-5. [ Links ]

33. Khurana V, Gambhir IS, Kishore D. Evaluation of delirium in elderly: a hospital-based study. Geriatr Gerontol Int. 2011;11:467-73. [ Links ]

34. Ek M, Kurosawa M, Lundeberg T, Ericsson A. Activation of vagal afferents after intravenous injection of interleukin-1beta: role of endogenous prostaglandins. J Neurosci. 1998;18:9471-79. [ Links ]

35. Bluthe RM, Laye S, Michaud B, Combe C, Dantzer R, Parnet P. Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci. 2000;12:4447-56. [ Links ]

36. Bluthe RM, Michaud B, Poli V, Dantzer R. Role of IL-6 in cytokine-induced sickness behavior: a study with IL-6 deficient mice. Physiol Behav. 2000;70:367-73. [ Links ]

37. Cartmell T, Poole S, Turnbull AV, Rothwell NJ, Luheshi GN. Circulating interleukin-6 mediates the febrile response to localized inflammation in rats. J Physiol. 2000;526:653-61. [ Links ]

38. Konsman JP, Blond D, Vigues S. Neurobiology of interleukin-1 receptors: getting the message. Eur Cytokine Netw. 2000;11:699-702. [ Links ]

39. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445-52. [ Links ]

40. Cohen O, Reichenberg A, Perry C, Ginzberg D, Pollmacher T, Soreq H, et al. Endotoxin-induced changes in human working and declarative memory associate with cleavage of plasma “readthrough” acetylcholinesterase. J Mol Neurosci. 2003;21:199-212. [ Links ]

41. Krabbe KS, Reichenberg A, Yirmiya R, Smed A, Pedersen BK, Bruunsgaard H. Low-dose endotoxemia and human neuropsychological functions. Brain Behav Immun. 2005;19:453-60. [ Links ]

42. Munster BC, Aronica E, Zwinderman AH, Eikelenboom P, Cunningham C, Rooij SE. Neuroinflammation in delirium: a postmortem case-control study. Rejuvenation Res. 2011;14:615-22. [ Links ]

43. McGrane S, Girard TD, Thompson JL, Shintani AK, Woodworth A, Ely W, et al. Procalcitonin and C-reactive protein levels at admission as predictors of duration of acute brain dysfunction in critically ill patients. Crit Care. 2011;15:R78. [ Links ]

44. Girard TD, Ware LB, Bernard GR, Pandharipande PP, Thompson JL, Shintani AK, et al. Associations of markers of inflammation and coagulation with delirium during critical illness. Intensive Care Med. 2012;38: 1965-73. [ Links ]

45. Pfister D, Siegemund M, Dell-Kuster S, Smielewiski P, Rüegg S, Strebel SP, et al. Cerebral perfusion in sepsis-associated delirium. Crit Care. 2008;12:R63. [ Links ]

46. Szatmári S, Végh T, Csomós A, Hallay J, Takács I, Molnár C, et al. Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test. Crit Care. 2010;14:R50. [ Links ]

47. Hughes CG, Morandi A, Girard TD, Riedel B, Thompson JL, Shintani AK, et al. Association between endothelial dysfunction and acute brain dysfunction during critical illness. Anesthesiology. 2013;118:631-9. [ Links ]

48. Møller K, Strauss GI, Qvist J, Fonsmark L, Knudsen GM, Larsen FS, et al. Cerebral Blood Flow and Oxidative Metabolism During Human Endotoxemia. J Cereb Blood Flow Metab. 2002;22:1262-70. [ Links ]

49. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7:41-53. [ Links ]

50. Gavins F, Yilmaz G, Granger DN. The evolving paradigm for blood cell-endothelial cell interactions in the cerebral microcirculation. Microcirculation. 2007;14:667-81. [ Links ]

51. Taccone FS, Su F, Pierrakos C, He X, James S, Dewitte O, et al. Cerebral microcirculation is impaired during sepsis: an experimental study. Crit Care. 2010;14:R140. [ Links ]

52. He F, Peng J, Deng XL, Yang LF, Wu LW, Zhang CL, et al. RhoA and NF-κB are involved in lipopolysaccharideinduced brain microvascular cell line hyperpermeability. Neuroscience. 2011;188:35-47. [ Links ]

53. Wilson JX, Young GB. Sepsis-associated encephalopathy: evolving concepts. Can J Neurol Sci. 2003;30:98-105. [ Links ]

54. Vincent JL. Microvascular endothelial dysfunction: a renewed appreciation of sepsis pathophysiology. Crit Care. 2001;5:S1-5. [ Links ]

55. Dal-Pizzol F, Rojas HA, dos Santos EM, Vuolo F, Constantino L, Feier G, et al. Matrix Metalloproteinase-2 and Metalloproteinase-9 Activities are Associated with Blood-Brain Barrier Dysfunction in an Animal Model of Severe Sepsis. Mol Neurobiol. 2013;48:62-70. [ Links ]

56. van den Boogaard M, Ramakers B, van Alfen N, van der Werf SP, Fick WF, Hoedemaekers CW, et al. Endotoxemia-induced inflammation and the effect on the human brain. Crit Care. 2010;14:R81. [ Links ]

57. Grandi C, Tomasi CD, Fernandes K, Stertz L, Kapczinski F, Quevedo J, et al. Brain-derived neurotrophic factor and neuron-specific enolase, but not S100β, levels are associated to the occurrence of delirium in intensive care unit patients. J Crit Care. 2011;26:133-7. [ Links ]

58. Comim CM, Pereira JG, Steckert A, Petronilho F, Barichello T, Quevedo J, et al. Rivastigmine reverses habituation memory impairment observed in sepsis survivors rats. Shock. 2009;32:270-1. [ Links ]

59. Willard LB, Hauss-Wegrzyniak B, Wenk GL. Pathological and biochemical consequences of acute and chronic neuroinflammation within the basal forebrain cholinergic system of rats. Neuroscience. 1999;88:193-200. [ Links ]

60. Ofek K, Krabbe KS, Evron T, Debecco M, Nielsen AR, Brunnsgaad H, et al. Cholinergic status modulations in human volunteers under acute inflammation. J Mol Med (Berl). 2007;85:1239-51. [ Links ]

61. Belluardo N, Mudò G, Blum M, Fuxe K. Central nicotinic receptors, neurotrophic factors and neuroprotection. Behav Brain Res. 2000;113:21-34. [ Links ]

62. Cormier A, Morin C, Zini R, Tillement JP, Lagrue G. Nicotine protects rat brain mitochondria against experimental injuries. Neuropharmacology. 2003:44:642-52. [ Links ]

63. Guan ZZ, Yu WF, Nordberg A. Dual effects of nicotine on oxidative stress and neuroprotection in PC12 cells. Neurochem Int. 2003;43:243-9. [ Links ]

64. Newman MB, Arendash GW, Shytle RD, Bickford PC, Tighe T, Sanberg PR. Nicotine's oxidative and antioxidant properties in CNS. Life Sci. 2002;1:71:2807-20. [ Links ]

65. Thomsen MS, Mikkelsen JD. The α7 nicotinic acetylcholine receptor ligands methyllycaconitine, NS6740 and GTS-21 reduce lipopolysaccharide-induced TNF-α release from microglia. J Neuroimmunol. 2012;251:65-72. [ Links ]

66. Romani L, Fallarino F, De Luca A, Montagnoli C, D'Angelo C, Zelante T, et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature. 2008;451:211-5. [ Links ]

67. Zeden JP, Fusch G, Holtfreter B, Schefold JC, Reinke P, Domanska G, et al. Excessive tryptophan catabolism along the kynurenine pathway precedesongoing sepsis in critically ill patients. Anaesth Intensive Care. 2010;38:307-16. [ Links ]

68. Klotz L, Sastre M, Kreutz A, Gavrilyuk V, Klockgether T, Feinstein DL, et al. Noradrenaline induces expression of peroxisome proliferator activated receptor gamma (PPARgamma) in murine primary astrocytes and neurons. J Neurochem. 2003;86:907-16. [ Links ]

69. Shekhar A, Truitt W, Rainnie D, Sajdyk T. Role of stress, corticotrophin releasing factor and amygdala plasticity in chronic anxiety. Stress. 2005;8:209-19. [ Links ]

70. Palomero-Gallagher N, Zilles K. Neurotransmitter receptor alterations in hepatic encephalopathy: a review. Arch Biochem Biophys 2013;536:109-21. [ Links ]

71. van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, et al. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomized trial. Lancet. 2010;27:376:1829-37. [ Links ]

72. Kox M, Pompe JC, Gordinou de Gouberville MC, van der Hoeven JG, Hoedemaekers CW, Pickkers P. Effects of the α7 nicotinic acetylcholine receptor agonist gts-21 on the innate immune response in humans. Shock. 2011;36:5-11. [ Links ]

73. Freund H, Atamian S, Holroyde J, Fischer JE. Plasma amino acids as predictors of the severity and outcome of sepsis. Ann Surg. 1979;190:571-6. [ Links ]

74. Flacker JM, Lipsitz LA. Large neutral amino acid changes and delirium in febrile elderly medical patients. J Gerontol A Biol Sci Med Sci. 2000;55:B249-52. [ Links ]

75. van den Boogaard M, Schoonhoven L, van Achterberg T, van der Hoeven JG, Pickkers P. Haloperidol prophylaxis in critically ill patients with a high risk for delirium. Crit Care. 2013;17:R9. [ Links ]

76. van den Boogaard M, Pickkers P, Slooter AJ, Kuiper MA, Spronk PE, van der Voort PH, et al. Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ. 2012;344:e420. [ Links ]

77. Gourdin M, Dubois P, Mullier F, Chatelain B, Dogné JM, Marchandise B, et al. The effect of clonidine, as alpha-2 adrenergic receptor agonist, on inflammatory response and postischemic endothelium function during early reperfusion in healthy volunteers. J Cardiovasc Pharmacol. 2012;60:553-60. [ Links ]

78. Jugé M, Grimaud N, Petit JY. Involvement of alpha-2 adrenergic mechanisms in experimental analgesic and anti-inflammatory activities of a benzamide derivative. Pharmacol Res. 1997;36:179-85. [ Links ]

79. Moss RF, Parmar NK, Tihe D, Davies DC. Adrenergic agents modify cerebral edema and microvessel ultrastructure in porcine sepsis. Crit Care Med. 2004;32:1916-21. [ Links ]

80. Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, et al. Effect of dexmdetomidine versus lorazepam on outcome outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14:R38. [ Links ]

81. Wilms H, Claasen J, Röhl C, Sievers J, Deuschl G, Lucius R. Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro. Neurobiol Dis. 2003;14:417-24. [ Links ]

82. Tanabe K, Kozawa O, Iida H. Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells. J Neuroinflammation. 2011;8:68. [ Links ]

83. Hshieh TT, Fong TG, Marcantonio ER, Inouye SK. Cholinergic deficiency hypotesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci. 2008;63:764-72. [ Links ]

84. Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka MT. Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat. 2005;30:144-57. [ Links ]

85. Belluardo N, Mudo G, Blum M, Amato G, Fuxe K. Neurotrophic effects of central nicotinic receptor activation. J Neural Transm Suppl. 2000;(60):227-45. [ Links ]

86. Terry AV Jr, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003;306:821-7. [ Links ]

87. Streit WJ, Sparks DL. Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med (Berl). 1997;75:130-8. [ Links ]

88. Mrzljak L, Goldman-Rakic PS. Acetylcholinesterase reactivity in the frontal cortex of human and monkey: contribution of AChE-rich pyramidal neurons. J Comp Neurol. 1992;324:261-81. [ Links ]

89. Hirano H, Day J, Fibiger HC. Serotonergic regulation of acetylcholine release in rat frontal cortex. J Neurochem. 1995;65:1139-45. [ Links ]

90. Platt MM, Breitbart W, Smith M, Marotta R, Weisman H, Jacobsen PB. Efficacy of neuroleptics for hypoactive delirium. J Neuropsychiatry Clin Neurosci. 1994;6:66-7. [ Links ]

91. Wilkinson LS. The nature of interactions involving prefrontal and striatal dopamine systems. J Psychopharmacol. 1997;11:143-50. [ Links ]

92. van der Mast RC, van den Broek WW, Fekkes D, Pepplinkhuizen L, Habbema JD. Is delirium after cardiac surgery related to plasma amino acids and physical condition? J Neuropsychiatry Clin Neurosci. 2000;12:57-63. [ Links ]

93. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:1112-20. [ Links ]

94. Pandharipande PP, Morandi A, Adams JR, Girard TD, Thompson JL, Shintani AK, et al. Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients. Intensive Care Med. 2009;35:1886-92. [ Links ]

95. Berg RM, Taudorf S, Bailey DM, Lundby C, Larsen FS, Pedersen BK, et al. Cerebral net exchange of large neutral amino acids afterlipopolysaccharide infusion in healthy humans. Crit Care. 2010;14:R16. [ Links ]

96. Freund HR, Ryan JA Jr, Fischer JE. Amino acid derangements in patients with sepsis: treatment with branched chain amino acid rich infusions. Ann Surg. 1978;188:423-30. [ Links ]

97. Adams Wilson JR, Morandi A, Girard TD, Thompson JL, Boomershine CS, Shintani AK, et al. The association of the kynurenine pathway of tryptophan metabolism with acute brain dysfunction during critical illness. Crit Care Med. 2012;40:835-41. [ Links ]

98. Girard TD, Pandharipande PP, Carson SS, Schmidt GA, Wright PE, Canonico AE, et al. Feasibility, efficacy, and safety of antipsychotics for intensive care unit delirium: the MIND randomized, placebo-controlled trial. Crit Care Med. 2010;38:428-37. [ Links ]

99. O'Sullivan JB, Ryan KM, Curtin NM, Harkin A, Connor TJ. Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: implications for depression and neurodegeneration. Int J Neuropsychopharmacol. 2009;12:687-99. [ Links ]

100. Brede M, Braeuninger S, Langhauser F, Hein L, Roewer N, Stoll G, et al. alpha2-adrenoceptors do not mediate neuroprotection in acute ischemic stroke in mice. J Cereb Blood Flow Metab. 2011;31:e1-7. [ Links ]

101. Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, et al. β-adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci. 2011;31:6277-88. [ Links ]

102. Markus T, Hansson SR, Cronberg T, Cilio C, Wieloch T, Ley D. β-adrenoceptor activation depresses brain inflammation and is neuroprotective in lipopolysaccharide-induced sensitization to oxygen-glucose deprivation in organotypic hippocampal slices. J Neuroinflammation. 2010;7:94. [ Links ]

103. Gleeson LC, Ryan KJ, Griffin EW, Connor TJ, Harkin A. The β2-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity. Brain Behav Immun. 2010;24:1354-61. [ Links ]

104. Price LH, Goddard AW, Barr LC, Godman WK. Anxiety disorders: pharmacological challenges in anxiety disorders. In: Bloom FE, Kupfer DJ. Psychopharmacology: the fourth generation of progress. An official publication of the American College of Neuropsychopharmacology. New York: Raven Press; 1995. p. 1287-359. [ Links ]

105. Mora F, Segovia G, Del Arco A, de Blas M, Garrido P. Stress, neurotransmitters, corticosterone and body-brain integration. Brain Res. 2012;1476:71-85. [ Links ]

106. Wang DS, Zurek AA, Lecker I, Yu J, Abramian AM, Avramescu S, et al. Memory deficits induced by inflammation are regulated by α5-subunit-containing GABAA receptors. Cell Rep. 2012;2:488-96. [ Links ]

107. Kadoi Y, Saito S. An alteration in the gamma-aminobutyric acid receptor system in experimentally induced septic shock in rats. Crit Care Med. 1996;24:298-305. [ Links ]

108. Komatsubara T, Kadoi Y, Saito S. Augmented sensitivity to benzodiazepine in septic shock rats. Can J Anaesth. 1995;42:937-43. [ Links ]

109. Boegel K, Gyulai FE, Moore KK, Gold MS. Deleterious impact of a γ-aminobutyric acid type A receptor preferring general anesthetic when used in the presence of persistent inflammation. Anesthesiology. 2011;115:782-90. [ Links ]

110. Matsumoto T, Ogata M, Koga K, Shigematsu A. Effect of peripheral benzodiazepine receptor ligands on lipopolysaccharide-induced tumor necrosis factor activity in thioglycolate-treated mice. Antimicrob Agents Chemother. 1994;38:812-6. [ Links ]

111. Lei B, Popp S, Cottrell JE, Kass IS. Effects of midazolam on brain injury after transient focal cerebral ischemia in rats. J Neurosurg Anesthesiol. 2009;21:131-9. [ Links ]

Received: August 16, 2013; Accepted: November 11, 2013

Correspondence: Felipe Dal-Pizzol, Universidade do Extremo Sul Catarinense (UNESC), Av. Universitária, 1105, Universitário, CEP 88806-000, Criciúma, SC, Brazil. E-mail: piz@unesc.net

Disclosure The authors report no conflicts of interest.