hồi sức

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
April, 12 2018 – Dalat, Viet-Nam

2. Conflicts of
Interest
Scientific partnership with the following companies:
- Baxter
- Fresenius Medical Care
- Bbraun
- Nikkiso
- Bellco-Medtronic
- Biomérieux

3. OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
- What will be the future of blood purification for sepsis?

4. OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
- What will be the future of blood purification for sepsis?

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
Septic shock: Hyperinflammation followed by severe immunosuppression

6. Singer et al. JAMA 2016
2016: new definition of sepsis

7. Singer et al. JAMA 2016
Reference to immunology is now part of the sepsis definition!

8. Immunology
ICU

10. Initiation of a RRT session: 2 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
2- Blood purification for sepsis
(immunomodulation)

12. + + +
+ + +
- - -
- - -
Ionic (or electrostatic) interactions
Van der Waals
forces
ADSORPTION
Hydrophobic
domain
Hydrophobic
interactions
SORBENT

13. OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
- What will be the future of blood purification for sepsis?

15. Endotoxin
Blood purification therapy targets?

16. Ronco et al. Artif Organs 2003

17. Peng et al. Crit Care 2014

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
Indirect or direct action on the leucocyte itself?

19. Electronic microscopy and immunofluorescence pictures showing leucocytes adsorption on adsorptive polymer
Rimmelé et al. Crit Care 2013

20. Aoki et al. Dig Dis Sci 2007

21. OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2018
- What will be the future of blood purification for sepsis?

22. • High-volume hemofiltration
• Cascade hemofiltration
• Plasma exchanges
• Coupled Plasma Filtration Adsorption
• Hemoperfusion
• New membranes (high adsorptive hemofiltration and high cut-off membranes)
BLOOD PURIFICATION TECHNIQUES AVAILABLE IN 2018

23. • High-volume hemofiltration
• Cascade hemofiltration
• Plasma exchanges
• Coupled Plasma Filtration Adsorption
• Hemoperfusion
• New membranes (high adsorptive hemofiltration and high cut-off membranes)
BLOOD PURIFICATION TECHNIQUES AVAILABLE IN 2017

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
polyethylene discs
Endotoxin

25. Polymyxin-B hemoperfusion

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 2 groups:
- Conventional treatment
- Conventional treatment + 2 polymyxin B hemoadsorption sessions
- Improvement of hemodynamics, PaO2 / FiO2 and SOFA score

28. Effects of
Hemoperfusion with a
Polymyxin B Membrane
in Peritonitis with
Septic shockDieppe
La Roche
sur Yon
Lens
Lille
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
240 patients enrollment finished at 20 Centers
Principal Investigator: Prof. Didier Payen

30. Primary outcome: day 28 mortality
-PMX HP (n=119) = 27%
-Conventional treatment (n=113) = 19%
Payen et al. Intensive Care Med 2015

31. Is polymyxin B-immobilized fiber column ineffective for septic shock? A discussion on
the press release for EUPHRATES trial -2017-May 30 th?

32. • High-volume hemofiltration
• Cascade hemofiltration
• Plasma exchanges
• Coupled Plasma Filtration Adsorption
• Hemoperfusion
• New membranes (high adsorptive hemofiltration and « high cut-off »
membranes)
BLOOD PURIFICATION TECHNIQUES AVAILABLE IN 2017

33. Oxiris® : pathophysiology
Targets the endotoxin (“starter”of the host inflammatory response)

34. Oxiris® = AN69 based membrane filter
CH2CH C
-
CH2
CH2
CH3
CN
SO3-- --
AN69
(polyacrylonitrile)

35. Oxiris®
CH2CH C
-
CH2
CH2
CH3
CN
SO3 Na-- --
+
Basis structure
(polyacrylonitrile)
N
NH
N
NH
NH2
NH
NH
Polycation :
Polyethyleneimine
Endotoxin adsorption
(negatively charged)

36. - Oxiris®: Adsorption of negatively charged endotoxins on mb surface
- AN69 based mb (PAN): Adsorption of cytokines in the bulk of the mb

37. Oxiris®: animal data
- P. Aeruginosa porcine model of septic shock
- 2 × 10 pigs : 6 h of HF with oxiris versus 6 h of HF with a standard mb
- Arterial and Swan-Ganz catheters to assess hemodynamics
- MAP and PCWP maintained stable with crystalloids, colloids and epinephrine continuous infusion

38. Rimmelé et al. Nephrol Dial Tranplant 2009

39. Oxiris® : animal data

40. Peng, Rimmelé et al. J Surg Res 2013

41. N=10 rats per group
Rimmelé, Peng, Kellum. unpublished data
oxiris ®
Hemoperfusion
Sham

42. Shum et al. Hong Kong Med J 2013
- Prospective case series study with historical controls
- From October 2011 to June 2012, 6 patients with sepsis-induced AKI due
to gram negative bacteria
- CVVH with Oxiris
- 24 matched controls from 2009 to 2011 who received CVVH with
polysulfone-based hemofilter

43. Shum et al. Hong Kong Med J 2013

44. The 3 main advantages of Oxiris
- Hybrid therapy: RRT for AKI + blood purification for sepsis
- Targets endotoxins + cytokines
- Low price as compared to other techniques

45. OUTLINE
- Introduction
- Pathophysiology: how does blood purification work?
- Techniques for blood purification in 2017
- What will be the future of blood purification for sepsis?

46. What’s next?

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 !!!!
Don’t you think this is enough ???

48. How to answer this question?
Big NO !!!...
For at least 6 reasons…

49. 1

50. Zhou et al. Crit Care Med 2013

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 2 groups:
- Conventional treatment
- Conventional treatment + 2 polymyxin B hemoadsorption sessions
- Improvement of hemodynamics, PaO2 / FiO2 and SOFA score

52. Livigni et al. BMJ Open 2014
Hospital mortality decreased when patients received a high CPFA dose

53. Hazzard et al. J R Army Med Corps 2015

54. Is polymyxin B-immobilized fiber column ineffective for septic shock? A discussion on
the press release for EUPHRATES trial -2017-May 30 th?

55. 2

56. Any limits in these works?
IVOIRE
ABDOMIX
COMPACT 1

57. 3

60. 4

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?
I HAVE NOT!

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
Control group: PrismaFlex HF1400 filter
34 patients (2 groups of 17 patients)

63. 5

64. Negative large RCTs: importance of the studied population
Tested intervention
(Too?) large population
+ = -

65. 6

66. FUTURE = CONSTANT TECHNOLOGICAL PROGRESS

67. Past Future
Technological progressMedical knowledge
MANY UNANSWERED QUESTIONS :
Which patients exactly?
Which Timing?
How do these therapies exactly work?
What to ultimately remove?
BUT BE CAREFUL !

68. Futuristic technology?
Ongoing research from Harvard University, Boston, USA

69. Khang et al. Nat Med 2016

70. The Aethlon Hemopurifier®: Ongoing research from San Diego University, USA
Futuristic technology?

71. Tullis et al. Blood Purif 2009
Marleau et al. Journal of translational medicine 2012

72. IN THE FUTURE, we should find out what is best to remove in
order to modulate the host immuno-inflammatory response!
Cytokines?
Endotoxins?
Bacteria?
Activated
Leukocytes?
Viruses?

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 do 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
Conclusions – Take home messages