Brain injury and its related increased intracranial pressure (ICP) may lead to increased vagus nerve activity and the subsequent suppression of innate immunity via the cholinergic anti-inflammatory pathway. This may explain the observed increased susceptibility to infection in these patients. In the present study, we investigated the association between brain injury, vagus nerve activity, and innate immunity. We determined heart rate variability (HRV) as a measure of vagus nerve activity, plasma cytokines, and cytokine production of ex vivo lipopolysaccharide-stimulated whole blood in the first 4 days of admission to the neurological intensive care unit (ICU) in 34 patients with various forms of brain damage. HRV, immune parameters, and the correlations between these measures were analyzed in the entire group of patients and in subgroups of patients with conditions associated with high (intracranial hemorrhage [ICH]) and normal ICP (subarachnoid hemorrhage [SAH] with an extraventricular drain alleviating ICP). Healthy volunteers were used for comparison. HRV total spectral power and ex vivo-stimulated cytokine production were severely depressed in patients compared with healthy volunteers (p<0.05). Furthermore, HRV analysis showed that normalized units of high-frequency power (HFnu, corresponding with vagus nerve activity) was higher, and the low-frequency:high-frequency ratio (LF:HF, corresponding with sympathovagal balance) was lower in patients compared to healthy volunteers (p<0.05). HFnu correlated inversely with ex vivo-stimulated tumor necrosis factor-α (TNF-α) production (r=−0.22, p=0.025). The most pronounced suppression of ex vivo-stimulated cytokine production was observed in the ICH group. Furthermore, in ICH patients, HFnu correlated strongly with lower plasma TNF-α levels (r=−0.73, p=0.002). Our data suggest that brain injury, and especially conditions associated with increased ICP, is associated with vagus nerve-mediated immune suppression.
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References
1.
AntelmiI., de PaulaR.S., ShinzatoA.R., PeresC.A., MansurA.J., GrupiC.J.2004. Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease. Am. J. Cardiol., 93:381–385.
2.
BaguleyI.J., HeriseanuR.E., FelminghamK.L., CameronI.D.2006. Dysautonomia and heart rate variability following severe traumatic brain injury. Brain Inj., 20:437–444.
3.
BergerR.D., SaulJ.P., CohenR.J.1989. Transfer function analysis of autonomic regulation. I. Canine atrial rate response. Am. J. Physiol, 256:H142–H152.
4.
BiggerJ.T.Jr., FleissJ.L., SteinmanR.C., RolnitzkyL.M., SchneiderW.J., SteinP.K.1995. RR variability in healthy, middle-aged persons compared with patients with chronic coronary heart disease or recent acute myocardial infarction. Circulation, 91:1936–1943.
5.
BiswasA.K., ScottW.A., SommerauerJ.F., LuckettP.M.2000. Heart rate variability after acute traumatic brain injury in children. Crit. Care Med., 28:3907–3912.
6.
BoddieD.E., CurrieD.G., EreminO., HeysS.D.2003. Immune suppression and isolated severe head injury: a significant clinical problem. Br. J. Neurosurg., 17:405–417.
De HerdtV, BogaertS., BrackeK.R., RaedtR., DeV.M., VonckK., BoonP.2009. Effects of vagus nerve stimulation on pro- and anti-inflammatory cytokine induction in patients with refractory epilepsy. J. Neuroimmunol., 214:104–108.
11.
DinarelloC.A.1991. Interleukin-1 and interleukin-1 antagonism. Blood, 77:1627–1652.
12.
EstafanousF.G., BrumJ.M., RibeiroM.P., EstafanousM., StarrN., FerrarioC.1992. Analysis of heart rate variability to assess hemodynamic alterations following induction of anesthesia. J. Cardiothorac. Vasc. Anesth., 6:651–657.
13.
Frasure-SmithN., LesperanceF., IrwinM.R., TalajicM., PollockB.G.2009. The relationships among heart rate variability, inflammatory markers and depression in coronary heart disease patients. Brain Behav. Immun., 23:1140–1147.
14.
GodinP.J., BuchmanT.G.1996. Uncoupling of biological oscillators: a complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit. Care Med., 24:1107–1116.
15.
GodinP.J., FleisherL.A., EidsathA., VandivierR.W., PreasH.L., BanksS.M., BuchmanT.G., SuffrediniA.F.1996. Experimental human endotoxemia increases cardiac regularity: results from a prospective, randomized, crossover trial. Crit. Care Med., 24:1117–1124.
16.
Haji-MichaelP.G., VincentJ.L., DegauteJ.P., van de BorneB.P.2000. Power spectral analysis of cardiovascular variability in critically ill neurosurgical patients. Crit. Care Med., 28:2578–2583.
17.
HirschfeldM., MaY., WeisJ.H., VogelS.N., WeisJ.J.2000. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J. Immunol., 165:618–622.
18.
HustonJ.M., TraceyK.J.2011. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J. Intern. Med., 269:45–53.
19.
HustonJ.M., OchaniM., Rosas-BallinaM., LiaoH., OchaniK., PavlovV.A., Gallowitsch-PuertaM., AshokM., CzuraC.J., FoxwellB., TraceyK.J., UlloaL.2006. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med., 203:1623–1628.
20.
HustonJ.M., Rosas-BallinaM., XueX., DowlingO., OchaniK., OchaniM., YeboahM.M., ChatterjeeP.K., TraceyK.J., MetzC.N.2009. Cholinergic neural signals to the spleen down-regulate leukocyte trafficking via CD11b. J. Immunol., 183:552–559.
21.
JanB.U., CoyleS.M., MacorM.A., ReddellM., CalvanoS.E., LowryS.F.2010. Relationship of basal heart rate variability to in vivo cytokine responses after endotoxin exposure. Shock, 33:363–368.
22.
KanayaN., HirataN., KurosawaS., NakayamaM., NamikiA.2003. Differential effects of propofol and sevoflurane on heart rate variability. Anesthesiology, 98:34–40.
23.
KawaharaE., IkedaS., MiyaharaY., KohnoS.2003. Role of autonomic nervous dysfunction in electrocardio-graphic abnormalities and cardiac injury in patients with acute subarachnoid hemorrhage. Circ. J., 67:753–756.
24.
KerenO., YupatovS., RadaiM.M., Elad-YarumR., FaraggiD., AbboudS., RingH., GroswasserZ.2005. Heart rate variability (HRV) of patients with traumatic brain injury (TBI) during the post-insult sub-acute period. Brain Inj., 19:605–611.
KoxM., de KleijnS., PompeJ.C., RamakersB.P., NeteaM.G., van der HoevenJ.G., HoedemaekersC.W., PickkersP.2011a. Differential ex vivo and in vivo endotoxin tolerance kinetics following human endotoxemia. Crit. Care Med., 39:1866–1870.
27.
KoxM., PompeJ.C., PickkersP., HoedemaekersC.W., van VugtA.B., van der HoevenJ.G.2008. Increased vagal tone accounts for the observed immune paralysis in patients with traumatic brain injury. Neurology, 70:480–485.
28.
KoxM., RamakersB.P., PompeJ.C., van der HoevenJ.G., HoedemaekersC.W., PickkersP.2011b. Interplay between the acute inflammatory response and heart rate variability in healthy human volunteers. Shock, 36:115–120.
29.
MallianiA.2005. Heart rate variability: from bench to bedside. Eur. J. Intern. Med., 16:12–20.
30.
MallianiA., PaganiM., LombardiF., CeruttiS.1991. Cardiovascular neural regulation explored in the frequency domain. Circulation, 84:482–492.
31.
MarslandA.L., GianarosP.J., PratherA.A., JenningsJ.R., NeumannS.A., ManuckS.B.2007. Stimulated production of proinflammatory cytokines covaries inversely with heart rate variability. Psychosom. Med., 69:709–716.
32.
MatsuuraS., SakamotoH., HayashidaY., KunoM.1984. Efferent discharges of sympathetic and parasympathetic nerve fibers during increased intracranial pressure in anesthetized cats in the absence and presence of pressor response. Brain Res., 305:291–301.
33.
MillerC.H., QuattrocchiK.B., FrankE.H., IsselB.W., WagnerF.C.Jr.1991. Humoral and cellular immunity following severe head injury: review and current investigations. Neurol. Res., 13:117–124.
34.
MoweryN.T., NorrisP.R., RiordanW., JenkinsJ.M., WilliamsA.E., MorrisJ.A.Jr.2008. Cardiac uncoupling and heart rate variability are associated with intracranial hypertension and mortality: a study of 145 trauma patients with continuous monitoring. J. Trauma, 65:621–627.
35.
NiijimaA., HoriT., AouS., OomuraY.1991. The effects of interleukin-1 beta on the activity of adrenal, splenic and renal sympathetic nerves in the rat. J. Auton. Nerv. Syst., 36:183–192.
36.
O'ConnorE., VenkateshB., MashongonyikaC., LipmanJ., HallJ., ThomasP.2004. Serum procalcitonin and C-reactive protein as markers of sepsis and outcome in patients with neurotrauma and subarachnoid haemorrhage. Anaesth. Intensive Care, 32:465–470.
37.
PapaioannouV., GiannakouM., MaglaverasN., SofianosE., GialaM.2008. Investigation of heart rate and blood pressure variability, baroreflex sensitivity, and approximate entropy in acute brain injury patients. J. Crit. Care, 23:380–386.
38.
PelosiG., EmdinM., CarpeggianiC., MoralesM.A., PiacentiM., DattoloP., CerraiT., MacerataA., L'AbbateA., MaggioreQ.1999. Impaired sympathetic response before intradialytic hypotension: a study based on spectral analysis of heart rate and pressure variability. Clin. Sci. (Lond.), 96:23–31.
39.
PiekJ., ChesnutR.M., MarshallL.F., van Berkum-ClarkM., KlauberM.R., BluntB.A., EisenbergH.M., JaneJ.A., MarmarouA., FoulkesM.A.1992. Extracranial complications of severe head injury. J. Neurosurg., 77:901–907.
40.
QuattrocchiK.B., FrankE.H., MillerC.H., AminA., IsselB.W., WagnerF.C.Jr.1991. Impairment of helper T-cell function and lymphokine-activated killer cytotoxicity following severe head injury. J. Neurosurg., 75:766–773.
41.
QuattrocchiK.B., FrankE.H., MillerC.H., MacDermottJ.P., HeinL., FreyL., WagnerF.C.Jr.1990. Suppression of cellular immune activity following severe head injury. J. Neurotrauma, 7:77–87.
42.
QuattrocchiK.B., IsselB.W., MillerC.H., FrankE.H., WagnerF.C.Jr.1992. Impairment of helper T-cell function following severe head injury. J. Neurotrauma, 9:1–9.
RogauschH., del RayA., KabierschA., ReschkeW., OrtelJ., BesedovskyH.1997. Endotoxin impedes vasoconstriction in the spleen: role of endogenous interleukin-1 and sympathetic innervation. Am. J. Physiol., 272:R2048–R2054.
45.
RondinaC., VidettaW., PetroniG., LujanS., SchoonP., MoriL.B., MatkovichJ., CarneyN., ChesnutR.2005. Mortality and morbidity from moderate to severe traumatic brain injury in Argentina. J. Head Trauma Rehabil., 20:368–376.
46.
SaykF., VietheerA., SchaafB., WellhoenerP., WeitzG., LehnertH., DodtC.2008. Endotoxemia causes central downregulation of sympathetic vasomotor tone in healthy humans. Am. J. Physiol. Regul. Integr. Comp. Physiol., 295:R891–R898.
47.
SloanR.P., McCreathH., TraceyK.J., SidneyS., LiuK., SeemanT.2007. RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol. Med., 13:178–184.
48.
SvigeljV., GradA., KiautaT.1996. Heart rate variability, norepinephrine and ECG changes in subarachnoid hemorrhage patients. Acta Neurol. Scand., 94:120–126.
49.
Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. 1996. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation, 93:1043–1065.
50.
TraceyK.J.2002. The inflammatory reflex. Nature, 420:853–859.
51.
VoldbyB.1988. Pathophysiology of subarachnoid haemorrhage. Experimental and clinical data. Acta Neurochir. Suppl. (Wien.), 45:1–6.
52.
WangH., YuM., OchaniM., AmellaC.A., TanovicM., SusarlaS., LiJ.H., WangH., YangH., UlloaL., Al-AbedY., CzuraC.J., TraceyK.J.2003. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature, 421:384–388.
53.
WinchellR.J., HoytD.B.1997. Analysis of heart-rate variability: a noninvasive predictor of death and poor outcome in patients with severe head injury. J. Trauma, 43:927–933.
54.
YangC.C., ChaoT.C., KuoT.B., YinC.S., ChenH.I.2000. Preeclamptic pregnancy is associated with increased sympathetic and decreased parasympathetic control of HR. Am. J. Physiol. Heart Circ. Physiol., 278:H1269–H1273.
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