Cytokin-Adsorption in der Sepsis -...

1

Cytokin-Adsorption in der Sepsis

Detlef Kindgen-MillesKlinik für Anästhesiologie

Universitätsklinikum Düsseldorf


• Epidemiologie und Pathophysiologie

• Rationale für Cytokin-Elimination

• Konventionelle Techniken

• Unspezifische adsorptive Verfahren






Erstbeschreibung des sept. Schocks

2


Letalität 65 %


Sepsis-incidence

Kumar et al. 2011 Chest 140:1223

Sepsis following elective surgery

3

Sepsis following elective surgery Incidence of septic shock 1997-2010

12/100.000

78/100.000

ICU: Incidence of infection & sepsis

• sepsis occurs in ~ 50 % of all critically ill pts • most frequent infection:

– (1)pneumonia (2)abdominal

� AKI + Sepsis: mortality exceeds 50 %

ICU: Site of infection

4

ICU: Incidence of gram-negative bugs Denmark 2015

AKI: Increasing incidence

Siew et al. 2015 Kid Int 87:46

AKI-EPI study 2015

• 97 ICUs world wide

• point prevalence study for 1 week

• incidence and outcome AKI

5

AKI-EPI study 2015 AKI-EPI study 2015

Etiology of AKI [%]

Sepsis 41 %

Hypovolemia 34 %

Drug related 14 %

Cardiogenic shock 13 %

Hepatorenalsyndrome

3 %

Sepsis and development and mortality of AKI

Dai et al. (2015) Crit Care 19:223






6

Sepsis & AKIPathophysiology

Pathophysiology of sepsisNEJM (2013) 369:840

Immunologie bei Sepsis

Modell 1: Tod im Cytokin-Sturm

Immunologie bei Sepsis

Modell 2: Phasenhafter Verlauf mit „open-end“

Polytrauma

7

Pro-Inflammatorisch Anti-inflammatorisch

Organversagen

TOD

17

Cytokin-Sturm verursacht Multiorgan-Versagen

Pro-Inflammatorisch

Organversagen

TOD

17

Cytokin-Sturm verursacht Multiorgan-Versagen

In addition: AKI causes inflammation AKI: Loss of renal cytokine clearance

8

Plasma cytokine levels increase with AKI severityFull circles = AKIN 3

Effects independent from vasoconstrictor dependency

Pathogenic pathways involved in sepsis

Zarjou et al. (2011) JASN 22:99

Peak-Concentration HypothesisRonco et al. Int J Artif Organs 2002






9

KDIGO Guidelines 2012 Sepsis Guidelines 2012

Defining a “normal” dose for CRRT

25 ml/kg/h = 2 l/h in 80 kg

Dose dependent

„High-dose“ RRT

CRRT Dose [ml/kg/h]

Standard 25

Intensivied 25 - 45

High-volume > 45 - 50

Intermittent HD(F)

Online HDF i.e. 200 ml/kg/h

10

Own data: „Intractable“ septic shockSalvage therapy with high-volume-dialysis (SLEDD QD 300 ml/min), n = 20

No difference in Mortality

(64 %)

High volume CRRT in sepsis

Higher dialysis dose in sepsis ?

• n = 280 with severe sepsis or septic shock

• septic shock (50 %) – mechanic. ventilated 82 %

• prospective-randomized

• 2004 - 2009

• 50 ml/kg/h versus 85 ml/kg/h

• pre-/postdilution 2:1

• Dose delivered for at least 3 d (Median 8 d)

No effect on mortality

11

High-volume CRRT in sepsis: IVOIRE Study

• IVOIRE Study (hIgh VOlume in Intensive ca RE)

• CVVH: 70 ml/kg/h versus 35 ml/kg/h• Stopped after 140 Patienten

High-volume CRRT in sepsis: No effect on mortality

Meta-Analysis: HVHF inSepsis Meta-Analysis: HVHF in Sepsis

12

Meta-Analysis: HVHF in Sepsis

No effect on mortality

Hochvolumige Therapien

• hochvolumige Kaskadenfiltration• 120 ml/kg/h• n = 60

Hochvolumige Therapien Hochvolumige Therapien

13

Hochvolumige TherapienNew membranes with large

pores/high cut-off

Wall structure

• prospective – randomised• n = 30 in severe sepsis plus AKF• Hemofiltration with 31 ml / kgKG / h• High-cutoff (60 kDa) vs Standard-Filter

Sieving coefficients of cytokines

14

Effects on norepinephrine dose Effects on cytokine-levels

Prospective RCT investigating high-cut-off membranes in humans sepsis (60 kDa)

Primary objective:

Reduction of catecholamine requirements by High Cut off-CVVHD on day 5

(35 ml/kg/h plus filter change every 24 h)

Secondary objectives:

disease severity scores (SOFA) and clinical improve ments

Vorzeitiger Studienabbruch

• Studienziel: n = 120

• Abbruch nach n = 81

• Endpunkte nicht erreichbar

15






Unspezifische Zytokin - Adsorption

Blutfluss

Unspezifische Zytokin - Adsorption

• CE certified

• Polymer beads

• biocompatible

• adsorbs molecules up to 55 kDa

Größenselektivität der Adsorption

60

0

kDa

10 20 30 40 50 60 70

IL-1β

TNF-α monomer

IFN-γ monomer

IL-1ra

IL-10

TNF-α trimer

IFN-γ dimer

HMGB1

TGF-β

IL-6

sFas ligandMCP-1

IL-13

MCP-1 glycosylated AlbuminIL-8

MIP-1α

IL-18

sTNFR

IL-4

G-CSF

Hämodialyse

16

Beads adsorb Cytokines

Valenti et al 2008

Adsorption of Cytokins in vitro

Cytokine adsorption in rats

Peng & Kellum Crit Care Med 2008; 36:1573

Less hemodynamic alteration


17

Lower mortality


Erste Anwendungen am Menschen

Erste Anwendungen am Menschen

Cytokinspiegel vor und nach dem Adsorber

24

CE-Zulassungs-Studie

• Nachweis von Patientensicherheit und Effektivität (IL6-Senkung) als primäre Endpunkte

• Klinische Parameter als sekundäre Endpunkte

• Patienten mit schwerer Sepsis/septischem Schock mit ALI/ARDS

• Pilotstudie (n=22) und kontrollierte randomisierte Studie (manuelle R n=31; elektron. R n=47)

18

Publikation als Abstrakt

28

Patienten (elektron. Randomisierung)

First clinical study in Europe

• 43 ventilated pts with ALI & septic shock• randomized open-label• hemoperfusion 6 h / day for 7 days

• 18 treatments – 25 controls

• safety• reduction of cytokines

Significant reduction of cytokin - levels

Slide courtesy of Cytosorbents

19

Trend zu reduzierter Sterblichkeit bei extrem hohen Cytokin-Spiegeln ??

Slide courtesy of Cytosorbents

Einsatz während EKZ

2 x 20 Patienten mit/ohne CS-Adsorber

Einsatz während EKZ Einsatz während EKZ

20

Einsatz während EKZ Einsatz während EKZ

Case Reports Case Report

• male, 71 y• collapse: dens-fracture• osteosynthesis

• normal ward• aspiration• septic shock caused by pneumonia

�Staphylokokkus aureus (MSSA)

21

Case ReportStaphylokokkus aureus (MSSA)

• Therapy according to sepsis-guidelines– Correct antibotics treatment– Mechanical ventilation in line with ARDS-Network– NO-Inhalation / hydrocortison– Pulmonary artery catheter– KDIGO-III AKI with anuria - CVVHD

• Refractory septic shock– ARDS (FiO2 0,8 – PEEP 15= PaO2/FiO2: 178

• Noradrenaline 91 µg/min• Vasopressin 2 I.E. / h

Technically easy to use

Case Report – August 2013 Case Report – August 2013

�24 hours later:– Noradrenalin 0– Vasopressin 0– FiO2 = 0,35 with PEEP = 10– Return of diuresis

�Blood cultures: Staph. aureus

22

Case Report – August 2013

�24 hours later:– Noradrenalin 0– Vasopressin 0– FiO2 = 0,35 with PEEP = 10– Return of diuresis

�Blood cultures: Staph. aureus

CAUTION

Just a caseOptimal timing ?

High toxin load ?

…… ?






Cytokin-Adsorption in der Sepsis -...

Documents

Transcript of Cytokin-Adsorption in der Sepsis -...