Stress and autonomic dysfunction

Transcription

1 Stress and autonomic dysfunction Autonomic dysfunction during critical illness Djillali ANNANE, Hôpital Raymond Poincaré (AP-HP) Université de Versailles SQY, Garches

2 Host response to stress Cannon (1930) Selye (1950) Autonomic Nervous System Response to Stress HPA Axis

3 Fever GABA Hippocampus Amy Hypothalamus CRF Regulators LC (NE) Wakefullness Behaviour ACTH VP NR (5-HT) BAN PO Glucocorticoïds Baroreflex Effectors Σ ParaΣ Catecholamines Cardio-vascular System Endothelium Maintenance of homeostasis NO Immune System

4 Cytokines Trafficking to the Brain Blood brain barrier Hippocampus Amygdala Hypothalamus CRF AVP Brain stem nuclei Carrier s CVOs Infected tissue Th-1 cytokines Negative feedback Efferent vagal and sympathetic fibres Adrenals Cortisol C

5 CD14-LPS ME-ARC 1H-Placebo 1H-LPS 3H-LPS 6H-LPS 24H-LPS CD14 mrna Lacroix et al Brain Pathol 1998

6 Circumventricular organs: 1) Organum subfornicale; 2) Organum subcomisurale; 3) Corpus pineale 4) Area postrema; 5) Neurohypophysis; 6) Organum vasculosum laminae terminalis CD14, TLR 2, 4 and 9 cytokines receptors Vagus nerve

7 Cytokines Trafficking to the Brain Blood brain barrier Hippocampus Amygdala Hypothalamus CRF AVP Brain stem nuclei Infected tissue Th-1 cytokines Negative feedback Efferent vagal and sympathetic fibres Adrenals Cortisol C

8 IL-1b expression LPS i.p. - 2H Konsman et al Neuroscience 1999

9 Brain Expression Cytokines in a Patient with Abdominal Sepsis Hypothalamus Sharshar, Lancet 2003

10 Cytokines Trafficking to the Brain Blood brain barrier Hippocampus Amygdala Hypothalamus CRF AVP Brain stem nuclei X Breakdown (C5a) Adrenals Th-1 cytokines Negative feedback Cortisol C Infected tissue Efferent vagal and sympathetic fibres

11 Breakdown of the Blood-Brain-Barrier in a Patient with CAP Day 1 of sepsis Day 3 of sepsis Sharshar, ICM 2008

12 LPS activates Complement Pathway Nadeau, FASEB 2001

13 Sharshar et al, Lancet 2003 Neuronal Apoptosis in Autonomic Nuclei Locus Coeruleus

14 inos expression within vessels walls in the Locus Coeruleus after death from septic shock

15 NEURO-CARDIOVASCULAR CONNEXIONS EFFERENT Fibers AFFERENT Fibers. Centres vasopresseurs Noyau Vasopressor dorsal moteur centers du X Dorsal motor nucleus of X HEART P A R A S Y M P A T H I Q U E SYMPATHIQUE VESSELS Nucleus Solitarius THORACIC SPINE chemo.. IX baro. chemo. X baro. Sinus carotide HEART

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17 Autonomic Nervous Failure Contributes to Shock Goldstein et al, CCM 1995

18 Korach et al, CCM 2001

19 Experimental human endotoxemia increases cardiac regularity: Results from a prospective, randomized, crossover trial Godin et al CCM 1996 Saline/placebo ou Ibuprofe RR intervals LPS/ placebo ou Ibuprofen RR SDs

20 Decreased physiologic variability as a generalized response to human endotoxemia Rassias et al CCM 2005 ApEn

21 NOREPINEPHRINE EPINEPHRINE PLASMA RENIN ACTIVITY ALDOSTERONE NITRATES/NITRITES Annane et al, Am J Respir Crit Care Med LYING CONTROLS TILTED CONTROLS SEPSIS SYNDROM E SEPTIC SHOCK * * * *

22 Annane et al, Am J Respir Crit Care Med. 1999

23 Toweill et al, CCM 2000

24 Relationship of Basal Heart Rate Variability to in Vivo Cytokine Responses Following Endotoxin Badar U. Jan et al. Shock. 2010

25 Relationship of Basal Heart Rate Variability to in Vivo Cytokine Responses Following Endotoxin Badar U. Jan et al. Shock. 2010

26 Heart Rate Variability as Early Marker of MODS in Septic Patients Pontet J et al. Journal of Critical Care 2003

27 Autonomic dysfunction predicts mortality in patients with multiple organ dysfunction syndrome of different age groups Schmidt et al CCM 2005

28 severe sepsis septic shock refractory shock (n=44) (n=28) (n=19) Heart Rate (m ± sd) AUC-HR 506 ± ± ± 570 LF-HR 93 ± ± ± 415 HF-HR 44 ± ± ± 72 LF-HR/HF-HR $ 1.39 ± ± 0.4 Systolic Blood Pressure (m ± sd) AUC-SBP 78.9 ± ± ± 52.6 LF-SBP 13.1 ± ± ± 6.1 HF-SBP 20.3 ± ± ± 13 Diastolic Blood Pressure (m ± sd) AUC-DBP 178 ± 198 $ 51 ± ± 95 LF-DBP 1.4 ± 2.9 $ 1.1 ± ± 1.1 HF-DBP 0.17 ± ± ± 0.11 ALPHA* 5.4 ± ± ± 4.6 * = Baroreflex $ = A versus C (S) + = B versus A (S)

29 Survivors Non survivors P n= 47 n=22 LF/HF 3.2 ± ± LF-DBP 2.55 ± ±

30 Physiology and immunology of the cholinergic antiinflammatory pathway Kevin J. Tracey J. Clin. Invest. 117: (2007)

31 GTS-21 : a7nachr Selective Agonist Pavlov, CCM 2007

32 GTS-21 : a7nachr Selective Agonist Rosas Ballina, Mol Med 2009

33 GTS-21 : a7nachr Selective Agonist Pavlov, CCM 2007

34 Summary Sepsis causes brain inflammation Subsequently altering ANS response, mainly via an NO mediated pathway Then, sustained systemic inflammation compromises organ function and host survival