Réanimation du Sepsis Traitements symptomatique et adjuvants

Didier Payen, MD, Ph D Département d’Anesthésie-Réanimation-SMUR Hôpital Lariboisière AP-HParis Université Paris 7 Denis Diderot; INSERM 1160

dpayen1234@orange.fr

Stratégie gobale • Traitement curatif

– AB « the faster the better »; contrôle de la source

• Traitement symptomatique – Volume; presseurs; ± I+;

– Assistance respiratoire si besoin

– Assistance rénale si besoin

– Coagulation si besoin…

• Traitement adjuvent: – Anti- / pro- / temps dépendant?

– RCT négatifs… revoir les concepts

Mr B., 55 ans

• Histoire de la maladie:

– Le 24/12/06, Orthopnée + toux, pas de fièvre ni expectoration

– Le 26/12/06, CS aux urgences devant majoration de la dyspnée

– Aux urgences, PA=90/60, FC=108/min, T°=36°1, SpO2=82%AA, FR=30/min

• Radio: images alvéolo-interstitielles bilatérales

Mr B., 55 ans

• Biologie:

• pH=7,39, PaCO2=21,PaO2=44, HCO3=12, BE=-9

SaO2=79%

• Na=128( Nau 30),K=3,2;Cl=98; protides=108; AG 18

• urée=13mmol/l;créatininémie=130 µmol/L

• GB=16000;Hb=13;PQ=196000, CRP=222

• ASAT/ALAT=58/37;PAL/gGT=43/75;BILI T/C =21/10

• TP=43%,TCA=1,52, fV=59%,fII=75%

• BNP=493 (nl = 500)

Au total: 1. Hypoxie, hypocapnie 2. Acidose metab a TA normal elevé Minérale car

• Prot elevé; et Cl- elevé (Na 128) 3. Insuffisance rénale… 4. Fonction hepatoque OK 5. Coag anormale: FII 75 pas antithrombique

• Fv 49% 6. Synd inflamm: CRP, GB, Tachyc, hypoTA

4 OF mais cause n’est pas claire!!

Mr B., 55 ans • Attitude initiale? Sur quel critères guidés vous votre

réanimation? • Remplissage vasculaire (comment)? Hydratation? Dépletion? 750

cc Salé rapide teste le système CV

• Bilan étiologique: – infectieux;

– Echo2D (VCI 27; VD dilate)

• Antibiothérapie par AB Large spectre (SAU)

• Solumedrol 120 mg ? (SAU)

• Ventilation: – PaO2 44; PaCO2 28; pH 7.36; BE – 8; Bicar 15

– VNI a FiO2 100% ?

• Quel est votre monitorage? • KTA/KTC cave inf (?)/ DC; VES? mais en VS…

Mr B., 55 ans (H43 hrs)

en réanimation :

• Évolution non favorable sous VNI : hypoxie malgré VNI (spO2=80%),

• collapsus non amélioré par le remplissage

• Intubation: dip/fent/celo Hypotension

– Échographie cardiaque

– Pose KT Sganz? jug Dte cote? macrocirculation

– StO2 microcirculation, ?

Mr B., 55 ans

ETT:

–VG de taille normale ; hyperkinétique, FEVG >65%

– OG et OD non dilatées, VD dilaté, Fct normale (!),

pas de foramen ovale perméable; VCI 27 !!!

DC non fait!!!

Rivers 2001, Gattinoni 1995, and Hayes 1994 (NEJM)

EGDT (Rivers) Gattinoni Hayes

Setting ED ICU ICU

Time (hrs) <1 Up to 72hrs 24hrs

Lactate (mM/L)

6.9 - 7.7 -- 2.2 – 3.5

SvO2 (%) 48.6 - 49.2 67.3 - 69.7 --

CVP (mmHg) 5.3 - 6.1 10.6 Optimized

C I (l/min/m2) 1.7 – 1.9 3.7 – 3.8 3.2 – 3.4

SVRI 1181 – 1192 708 - 735 --

Mr B., 55 ans

PA syst/dias 96/50/65

PAPs/PAPd 61/29 mmHg

POD 6 mmHg

PAPo 7 mmHg

DC 9 l/min

SvO2 82 %

Après remplissage faible. HypoTA majorée par AG NE

Crit Care Med 2006

Patients with global tissue hypoxia at early stage of disease

Nobel Prize 2011 in Medicine to innate immunity!!!

R Steinman B Beutler J Hoffmann

Nobel Price 2011

da

Impact of sepsis on innate and adaptive immune cells

pathogène Molécules du non soi

Pathogen Associated Molecular Patterns

PAMPs

Molécules du soi libérées

lors d’une destruction cellulaire

Damage Associated Molecular Patterns

DAMPs

RECEPTEURS COMMUNS Pathogen

Recognition Receptors

PRRs

• Toll-like receptors (TLRs)

• NOD-like receptors (NLRs)

• RIG-1 like receptors (RLRs)

• DNA sensors

1994 Matzinger: Danger model Réponse à la mort cellulaire non physiologique

Tolérance ＃ Autoimmunité

0 5 10 15 20 25 30

0.0

0

.1

0.2

0

.3

0.4

0

.5

0.6

Low IL10/Low comorbidities

High IL10/Low comorbidities

Low IL10/High comorbidities

High IL10/High comorbidities

Days

Surv

ival

rat

e

221 severe sepsis: 87% septic shock

Impact of systemic inflammatory response and co-morbidity on mortality

IL-10 IL-6

Traitement adjuvent

hydrocortisone

“Tight control of Glycemia”

LA PROTEINE C ACTIVEE

PROWESS-SHOCK

Percent in study hospital @ 28d: DrotAA 305 (49%) Placebo 279 (43%)

Ranieri et al NEJM 2012

Removal of mediatorsCVVH

Payen et al, Crit Care Med 2009 Vol. 37, No. 3

Comparison: conventional therapy vs conventional therapy + CVVH (25ml/kg/h)

Inclusion within 24 hours after meeting the inclusion criteria • Conventional treatment: treatment decided by the physician in charge

• HF treatment: CVVH started within 24 hrs for at least 96 hrs

Primary end point: reduction of number and duration of sepsis-induced organ failure at day 14

Secondary end point:

mortality at day 14;

withdrawal of catecholamines infusion and

length of mechanical ventilation

Primary end point

Evolution of SOFA score in the 2 groups:

SOFA was compared to Day 0. A positive value indicates a maintenance

or a deterioration

Log Rank test: Chi2 : 8.73; p<0.003 HF group

CT group

Time,days

HF group CT group

Log Rank test: Chi2 :p=0.104 p<0.04

Time,days

CVVH was associated to longer need for cathecolamines and trend toward higher mortality

Payen et al, Crit Care Med 2009 Vol. 37, No. 3

Clinical evidence of immunodepression

25 000

19 000

13 000

7 000

19-6 21-6 23-6 25-6 27-6 29-6 1-7 3-7 5-7 7-7

Mr Al… Immuno-inflammatory monitoring for innate and adaptative

immunity L

y c

ou

nt (1

Un

it = 1

00

0 /m

l H

LA

-DR

ex

pre

ss

ion

on

CD

16

+ m

on

o Ly A Count

mHLA-DR expr

27-29 June

solumedrol

20 June

solumedrol

21 June

solumedrol

1

2

interferon g

0

5000

10000

15000

20000

25000

30000

35000

Day3 Day6 Day7

Day9 Day11

Day12 Day13

Day15 Day17

discharge

BAL pseudomonas aeru 109 +++ +++ + 0 0

2603 570

mH

LA-D

R (A

B/C

)

Days after ICU admission (post cardiac arrest)

Lukaszewicz et al.Crit Care Med 2009; 37: 2746–2752

Nl

Patients with a slope of log(mHLA-DR) <0.06 (poor recovery of HLA-DR expression) had a

higher risk of secondary infection than the group with slope >0.06.

Cumulative incidences of secondary infections after 7 days:

Crit Care Med 2009; 37: 2746–2752

(Crit Care Med 2009; 37: 2746–2752)

The Lymphopenia of sepsis (apoptosis and

extravascular distribution)

Monneret et al. Mol Med 2008;14(1-2):64

Sepsis - induced effector cell apoptosis in spleen tissue

Boomer, J. S. et al. JAMA 2011;306:2594-2605

It concerns both innate and adaptive immunity

- Innate: PMNs, Mono-Macro; B Ly; (APC)

- Adaptive: all subsets of Ly pop, except Treg CD25 Foxp3

It concerns both blood and tissue cells

Biomarker guided therapy

To conclude

• Protocolized treatment for acute care positive for outcome avoiding mistakes

• Supportive therapy guidelines are reasonable

– Customized treatment based on comorbidity

• Adjunct therapies: almost all disappeared!!!

• Work on and add some BM for inflammation status

• Immunodepression seems to be a solid concept to be taken potential treatment

Pour conclure:

• Harmoniser les pratiques OUI

• Homogénéiser les prises en charges OUI

• Edicter des Règles plus que des stratégies NON

• Confisquer la connaissance entre quelques mains NON

• Les risques:

– bloquer tout innovation; NON

– bloquer toute publication dans laquelle on ne dira pas avoir suivi la SSC!!! NON