Albumin Detoxification for Sepsis

Transcription

1 Albumin Detoxification for Sepsis 1.-Sepsis Modulation? 4.- The First «Small Proof» of Concept 2.- The New Hypothesis 5.- Can we Apply to the Recent PRT s The Experimentations Explaining this Hypothesis Conclusions and Perspectives Prof Patrick Honoré, MD, PhD,FCCM Intensivist-Nephrologist Prof of ICU Medicine,Senior Lecturer,VUB University,Bxl(Bel) 21 Annual Meeting on CRRT and AKI Manchester Grand Hyatt San Diego February

2 Did We «Immunomodulate» Correctly the Sepsis Cascade? Honore PM et al., Annals of Intensive Care 2011;1:24

3 The Concept of «Albumin Detoxification» in CRRT.. Immunomodulation : Removal of Free Mediators but also to Remove some bounded Mediators. Albumin Detoxification Knudsen-Sand KM et al.front Immunol

4 Filtration Fraction :Marker of «Circuit Patency» Filtration Fraction (FF) = (Post + Pre + Net UF) / (Qb (-Het) + Pre) Example Qb : 250 ml/min = ml/h Quf : 3000 ml/h (Post (2000)+ Pre (1000)) FF = (3000 / 16000) FF = 0,18 (18%) Copyright 2015 NIKKISO Co., LTD. All rights reserved. Journois D-Hemofiltration Techniques Masson Editions 1996

5 Filtration Ratio : Marker of «Convection Impact» Filtration Ratio (FR) = (Post + Net UF) / Qb (-Het) Example Qb : 250 ml/min = ml/h Quf : 3000 ml/h (Post only) FR = 0,2 (20%) Copyright 2015 NIKKISO Co., LTD. All rights reserved. Journois D-Hemofiltration Techniques Masson Editions- 1996

6 In Practice : it turn out to be more simple using some Examples QS (ml/min) QS (ml/h) Post (ml/h) Pre (ml/h) FLR (ml/h) FF FR % 25% % 25% % 8% % 0% % 42% % 33% Honore PM,Constantin JM, Guilbaud J-Ch et al -Manuscript in preparation

7 Middle size molecules Clearance Post versus Pre

8 How Does Work FR in Practice? WHAT WE NOTICED IS HIGH CHLORIDE CONCENTRATION IN UF WHEN HFR IS PERFORMED COMPARED TO STANDARD FR Hemo-Concentration and Gibbs-Donnan: Anions x Cations in UF = Anions x Cations in Blood path Increase in albumin [] -> Breakdown of Albumin Bindings -> Albumin is becoming electro-negative -> Increase in UF Chloride will induce a decrease in blood ph - > Further Breakdown of Albumin bindings Guilbaud J-Ch.Unpublished Data.2014 (Courtesy of Dr Guilbaud )

9 High FR effect? FR 22%, UF 3000 FR 32%, UF 3000 GIBBS-DONNAN Equilibrium! (SID, Albuminates, Chloride ) Constantin JM.Unpublished Data.2014-(Courtesy of Prof JM Constantin )

10 ph Variation in the blood circuit Constantin JM.Unpublished Data.2014 (Courtesy of Prof JM Constantin )

11 Acidosis is Decreasing Albumin Fixation Capabilities

12 Increase of Albumin Concentration is Decreasing its Binding Capabilities Rocal C, Caligaris S, Wennberg RP et al.pediat Res 2006;60:

13 Hemoconcentration Effects on Blood ph Variations By increasing FR increase of Chloride ions is noticed into the ultrafiltrate What about Albumin and its fixation capability? Example with Bilirubin and Ammonium with FR at 32% (4 hours) Constantin JM.Unpublished Data.2014 (Courtesy of Prof Constantin )

14 Survival (%) P < 0, * ml/kg/hr 35 ml/kg/hr 45 ml/kg/hr Ultrafiltration rate

15 Effect of different doses of CVVH on Survival CVVH with post-dilution only; Qb ~207 ml/min (45 ml group) Group 3 = 45 ml/kg/h Group 2 = 35 ml/kg/h Group 1 = 20 ml/kg/h ml/kg/h FR 20 0, , ,27 Ronco C. et al. Lancet 2000, 356:26-30

16 Summarising the Hypothesis and the Possible Underlying Mechanisms Ronco Study : 45 ml/kg/h(3,150 ml/h) /Post-dilution only/fr = 27 % (Only Positive PRT so far ) Possible Link between Survival & More Removal of Cytokines Dose has to be at least 45 ml/kg/ml & will perhaps remove more Free Mediators FR of 27 %= Hemoconcentration Effect shall increase perhaps the Albumin Detoxification Honore PM,Constantin JM, Guilbaud J-Ch et al -Manuscript in preparation

17 FR :20.5 %(70) 11 % (35) Joannes-Boyau O, Honore PM et al.icm 2013;39:

18 FR 14 % (85) All patients in both groups were treated with continuous venous hemofiltration(cvvh). Replacement fluid was delivered into the extracorporeal circuit at a pre-dilution/post-dilution ratio of 2/1. The replacement fluid was based on patient body weight at the time of randomization and was 50mL/kg/h (HVHF group) or 85 ml/kg/h (EHVHF group). FR 8 % (50 ) Copyright 2015 NIKKISO Co., LTD. All rights reserved. Zhang P et al.ndt 2012 ; 27:

19 Convection Efficacy is Depending on Dose BUT also on FR & Hemoconcentration Author Honore et al (CCM 2000) Population (n) Refractory septic shock (20) HVHF Regimen 35L UF/4 hr followed by CVVH Outcome 55% Responders + 81% survived FR 32,4% (4h) Ronco et al (Lancet 2000) Sepsis subgroup 45 ml/kg/h 45 ml/kg/hr Continuous Mb change 24 h Best Survival Rate (sepsis subgroup) as compared to 20 and 35 ml 27 % Joannes-Boyau O,Honore PM et al (ICM 2013) Septic Shock + AKI 200 patients 140 rand 70 vs 35 ml/kg/hr for continued CVVH Mb change 48 h No change in Survival at 28, 60 and 90 days %(70) 14 % (35) Payen D et al (CCM 2009) Severe Sepsis/Septic Shock/No AKI 76 Rand 25 ml versus control 4 days CVVH (QB 150 ml) Worsen SOFA score in CVVH group 20,6 % Zhang P et al (NDT 2012) Severe Sepsis + AKI 280 rand 85 vs 50 ml/kg/hr Continuous CVVH No Change in Survival at 28, 60 and 90 days 15 % (85) 9 % (50 ) Honore PM,Constantin JM, Guilbaud J-Ch et al -Manuscript in preparation

20 Do we need more PRT s on HVHF or more Mechanistic Studies on HVHF? High-volume hemofiltration for septic acute kidney injury: a systematic review and meta-analysis Conclusions: Insufficient evidence exists of a therapeutic benefit for routine use of HVHF for septic AKI, other than on an experimental basis. Given the logistic challenges related to patient recruitment along with an incomplete understanding of the biologic mechanisms by which HVHF may modify outcomes, further trials should focus on alternative extracorporeal therapies as an adjuvant therapy for septic AKI rather than HVHF. Edward Clark, Amber O Molnar, Olivier Joannes-Boyau, Patrick M Honoré, Lindsey Sikora and Sean M Bagshaw Clark et al. Critical Care 2014, 18:R7

21 Mechanistic Studies to Test The Underlying Hypothesis Dose of 45ml-Full post-dilution for both groups FR of 32 % vs 22 % 20 Septic Shock Patients/Filter change every 24 H Cross over Design In this Study, Het (filter) should be Consider Cytokines Elimination (Free + through albumin detoxification ) (Primary Endpoint) Hemodynamics,pH (Filter),Bilirubin & Delta Chloride (Secondary Endpoint) Honore PM,Constantin JM, Guilbaud J-Ch et al -Manuscript in preparation

22 Optimising Anticoagulation in HFR By Albumin Detoxification, more calcium is Removed RCA maybe the Best Approach for the Following Reasons: -Citrate Could Further Decrease ph in the Hemofilter -An Higher FR will Require Less Citrate for Adequate Anticoagulation. -There is a protocol right now available for this.. 22

23 Conclusions & Perspectives Moving Quickly to an other therapy for the next Trial without take a look back is not the best way to learn from our mistakes.. We need to find out why the Initial trials were positive including one PRT (Ronco)while the recent PRT s were all negative. Numerous confounders are on «Trial» :FR (Hemoconcentration..), Type of Membrane,Timing of therapy Dose «Alone» may not mean everything-we need to look out for Post- Dilution (convection Dose) and Hemoconcentration % (FR) We went for the «Olympic Medal» with very high doses (70 and 85) but our efforts were partially waste because neglecting Hemoconcentration Immunomodulation through Albumin Detoxification need to be investigated Further Through Optimising Convection by Post-Dilution & Hemoconcentration to Remove Unbound & Bound Mediators

24 BELIEVE THOSE WHO ARE SEEKING THE TRUTH. DOUBT THOSE WHO FIND IT. Andre Gide