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Primary goal: to assess oXiris™ adsorption capacities (endotoxins, cytokines) in septic patients Secondary goal: to assess oXiris™ effects on hemodynamics and survival in septic patient[r]
(1)Thomas RIMMELE – MD PhD
Anesthesiology and Intensive Care Medicine Edouard Herriot Hospital
LYON, FRANCE
thomas.rimmele@chu-lyon.fr
Use of Oxiris during CVVH
in patients with septic shock and AKI
(2)Conflicts of Interest
Scientific partnership with the following companies: - Baxter
- Fresenius Medical Care - Bbraun
- Nikkiso
(3)OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
(4)OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
(5)Hotchkiss et al Nat Med 2009 TNF, IL-6, IL-8 (early deaths)
IL-4, IL-10, IL-1ra (late deaths)
- No clinical signs of this immunosuppression - Increased risk of HAI - 70-80% of total mortality
(6)Singer et al JAMA 2016
(7)Singer et al JAMA 2016
(8)Immunology
(9)(10)Initiation of a RRT session: possible goals for the intensivist doctor
AKI Sepsis-induced AKI Sepsis
RRT: Renal support Renal support Blood purification + Blood purification
1- Renal support for AKI
(11)(12)+ + + + + +
-Ionic (or electrostatic) interactions Van der Waals
(13)OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
(14)(15)Endotoxin
(16)(17)(18)- Interaction sorbent-leucocyte leading to a modification of expression of leucocyte surface markers (ex: HLA-DR increase)
- Removal by adsorption of activated leucocytes
Rimmelé et al Crit Care 2013
(19)Electronic microscopy and immunofluorescence pictures showing leucocytes adsorption on adsorptive polymer
(20)(21)OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
(22)• High-volume hemofiltration • Cascade hemofiltration
• Plasma exchanges
• Coupled Plasma Filtration Adsorption • Hemoperfusion
• New membranes (high adsorptive hemofiltration and high cut-off membranes)
(23)• High-volume hemofiltration • Cascade hemofiltration
• Plasma exchanges
• Coupled Plasma Filtration Adsorption • Hemoperfusion
• New membranes (high adsorptive hemofiltration and high cut-off membranes)
(24)Hemoperfusion devices
Device Company Composition Substance eliminated
PMX Toray, Japan PMX covalently bound to
polypropylene-polystyrene fiber Endotoxin
HA330 Jafron, China Neutral resin Cytokines
MG350 Biosun, China Neutral resin Cytokines
Cytosorb Cytosorbents, USA Polystyrenedivinyl benzene copolymer beads with biocompatible
polyvinylpyrrolidone coating
Cytokines LPS adsorber Alteco, Sweden Synthetic polypeptide bound to porous
(25)(26)(27)EUPHAS study
Cruz et al JAMA 2009
- Multicenter RCT performed in 10 Italian ICUs from 2004 to 2007 - 64 patients in septic shock, randomized in groups:
- Conventional treatment
(28)Effects of
Hemoperfusion with a Polymyxin B Membrane in Peritonitis with
Septic shock
Dieppe
La Roche sur Yon
LensLille Limoges Clemont-Ferrand Roanne Paris Rennes Saint-Malo Strasbourg Tours Orleans Bordeau Poitiers Rouen Saint-Louis Perpignan
PMX Trial in France
ABDO-MIX Study
Dr.Shoji
(29)(30)Primary outcome: day 28 mortality -PMX HP (n=119) = 27%
-Conventional treatment (n=113) = 19%
(31)(32)• High-volume hemofiltration • Cascade hemofiltration
• Plasma exchanges
• Coupled Plasma Filtration Adsorption • Hemoperfusion
• New membranes (high adsorptive hemofiltration and « high cut-off » membranes)
(33)Oxiris® : pathophysiology
(34)(35)Oxiris® CH2 CH C -CH2 CH2 CH3 CN
SO3 Na
(36)- Oxiris®: Adsorption of negatively charged endotoxins on mb surface
(37)Oxiris®: animal data
- P Aeruginosa porcine model of septic shock
- × 10 pigs : h of HF with oxiris versus h of HF with a standard mb - Arterial and Swan-Ganz catheters to assess hemodynamics
(38)(39)(40)(41)N=10 rats per group
Rimmelé, Peng, Kellum unpublished data
oxiris ®
Hemoperfusion
(42)Shum et al Hong Kong Med J 2013
- Prospective case series study with historical controls
- From October 2011 to June 2012, patients with sepsis-induced AKI due to gram negative bacteria
- CVVH with Oxiris
(43)(44)The main advantages of Oxiris
- Hybrid therapy: RRT for AKI + blood purification for sepsis
- Targets endotoxins + cytokines
(45)OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2017
(46)(47)How to answer this question?
Please, come on…There have been in the past some promising experimental, animal and clinical observational studies about blood purification for sepsis That’s right BUT, all recent human RCTs are
negative !!!!
(48)How to answer this question?
Big NO !!!
(49)(50)(51)EUPHAS study
Cruz et al JAMA 2009
- Multicenter RCT performed in 10 Italian ICUs from 2004 to 2007 - 64 patients in septic shock, randomized in groups:
- Conventional treatment
(52)Livigni et al BMJ Open 2014
(53)(54)(55)(56)Any limits in these works?
IVOIRE
ABDOMIX
(57)(58)(59)(60)(61)• High-volume hemofiltration • Cascade hemofiltration
• Plasma exchanges
• Coupled Plasma Filtration Adsorption • Hemoperfusion outside PMX
• New membranes
- high adsorptive hemofilters - High cut-off membranes
HAVE YOU NOTICED IN THE LITERATURE LARGE RCTs ASSESSING THESE TECHNIQUES?
(62)Promotor: Hospices Civils de Lyon PI: Thomas Rimmelé
Multicenter (7 centers in France), interventional, Randomized Controlled Trial
Primary goal: to assess oXiris™ adsorption capacities (endotoxins, cytokines) in septic patients Secondary goal: to assess oXiris™ effects on hemodynamics and survival in septic patients Main criteria: Endotoxin and cytokine plasma levels
Secondary criteria: Cytokine levels in ultrafiltrate, Hemodynamic parameters, Patient survival Patients: Septic shock patients with confirmed peritonitis
CVVH with citrate regional anticoagulation
Intervention group: oXiris™ filter
(63)(64)Negative large RCTs: importance of the studied population
Tested intervention
(Too?) large population
(65)(66)(67)Past Future
Technological progress Medical knowledge
MANY UNANSWERED QUESTIONS : Which patients exactly?
Which Timing?
How these therapies exactly work? What to ultimately remove?
(68)Futuristic technology?
(69)(70)The Aethlon Hemopurifier®: Ongoing research from San Diego University, USA
(71)(72)IN THE FUTURE, we should find out what is best to remove in
order to modulate the host immuno-inflammatory response!
(73)1) Sepsis = frequent, poor prognosis, expensive
2) 2017: Immunology is now part of the sepsis definition!
3) Patients die of septic shock because of immununosuppression
4) Extracorporeal blood purification as an adjuvant treatment for sepsis? several promising techniques such as OXIRIS under investigation
5) Multicenter RCTs = negative studies… but were they well-designed?
6) Many unanswered questions that should be addressed in the near future: Which patients exactly? Which Timing? Which technique is best?
How these therapies exactly work? Hybrid technique? Futuristic technique? What to ultimately remove (cytokines, endotoxins, leukocytes, bacteria or viruses)? 7) Research in this field should definitely continue