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Room a a04. thomasrimmele-oxiris_(en)

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Room a a04. thomasrimmele-oxiris_(en)

  1. 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. 2. Conflicts of Interest Scientific partnership with the following companies: - Baxter - Fresenius Medical Care - Bbraun - Nikkiso - Bellco-Medtronic - Biomérieux
  3. 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. 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. 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. 6. Singer et al. JAMA 2016 2016: new definition of sepsis
  7. 7. Singer et al. JAMA 2016 Reference to immunology is now part of the sepsis definition!
  8. 8. Immunology ICU
  9. 9. 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)
  10. 10. + + + + + + - - - - - - Ionic (or electrostatic) interactions Van der Waals forces ADSORPTION Hydrophobic domain Hydrophobic interactions SORBENT
  11. 11. OUTLINE - Introduction - Pathophysiology: how does blood purification work? - Techniques for blood purification in 2018 - What will be the future of blood purification for sepsis?
  12. 12. Endotoxin Blood purification therapy targets?
  13. 13. Ronco et al. Artif Organs 2003
  14. 14. Peng et al. Crit Care 2014
  15. 15. - 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?
  16. 16. Electronic microscopy and immunofluorescence pictures showing leucocytes adsorption on adsorptive polymer Rimmelé et al. Crit Care 2013
  17. 17. Aoki et al. Dig Dis Sci 2007
  18. 18. OUTLINE - Introduction - Pathophysiology: how does blood purification work? - Techniques for blood purification in 2018 - What will be the future of blood purification for sepsis?
  19. 19. • 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
  20. 20. • 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
  21. 21. 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
  22. 22. Polymyxin-B hemoperfusion
  23. 23. 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
  24. 24. 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
  25. 25. Primary outcome: day 28 mortality -PMX HP (n=119) = 27% -Conventional treatment (n=113) = 19% Payen et al. Intensive Care Med 2015
  26. 26. Is polymyxin B-immobilized fiber column ineffective for septic shock? A discussion on the press release for EUPHRATES trial -2017-May 30 th?
  27. 27. • 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
  28. 28. Oxiris® : pathophysiology Targets the endotoxin (“starter”of the host inflammatory response)
  29. 29. Oxiris® = AN69 based membrane filter CH2CH C - CH2 CH2 CH3 CN SO3-- -- AN69 (polyacrylonitrile)
  30. 30. 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)
  31. 31. - Oxiris®: Adsorption of negatively charged endotoxins on mb surface - AN69 based mb (PAN): Adsorption of cytokines in the bulk of the mb
  32. 32. 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
  33. 33. Rimmelé et al. Nephrol Dial Tranplant 2009
  34. 34. Oxiris® : animal data
  35. 35. Peng, Rimmelé et al. J Surg Res 2013
  36. 36. N=10 rats per group Rimmelé, Peng, Kellum. unpublished data oxiris ® Hemoperfusion Sham
  37. 37. 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
  38. 38. Shum et al. Hong Kong Med J 2013
  39. 39. 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
  40. 40. OUTLINE - Introduction - Pathophysiology: how does blood purification work? - Techniques for blood purification in 2017 - What will be the future of blood purification for sepsis?
  41. 41. What’s next?
  42. 42. 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 ???
  43. 43. How to answer this question? Big NO !!!... For at least 6 reasons…
  44. 44. 1
  45. 45. Zhou et al. Crit Care Med 2013
  46. 46. 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
  47. 47. Livigni et al. BMJ Open 2014 Hospital mortality decreased when patients received a high CPFA dose
  48. 48. Hazzard et al. J R Army Med Corps 2015
  49. 49. Is polymyxin B-immobilized fiber column ineffective for septic shock? A discussion on the press release for EUPHRATES trial -2017-May 30 th?
  50. 50. 2
  51. 51. Any limits in these works? IVOIRE ABDOMIX COMPACT 1
  52. 52. 3
  53. 53. 4
  54. 54. • 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!
  55. 55. 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)
  56. 56. 5
  57. 57. Negative large RCTs: importance of the studied population Tested intervention (Too?) large population + = -
  58. 58. 6
  59. 59. FUTURE = CONSTANT TECHNOLOGICAL PROGRESS
  60. 60. 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 !
  61. 61. Futuristic technology? Ongoing research from Harvard University, Boston, USA
  62. 62. Khang et al. Nat Med 2016
  63. 63. The Aethlon Hemopurifier®: Ongoing research from San Diego University, USA Futuristic technology?
  64. 64. Tullis et al. Blood Purif 2009 Marleau et al. Journal of translational medicine 2012
  65. 65. 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?
  66. 66. 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

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