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Continuous Renal Replacement Therapy

Continuous Renal Replacement Therapy. Annual Refresher Course in CRITICAL CARE McGill Course Director: Peter Goldberg, MD Didier Payen CC Division & Dept of Anesthesiology 13/4/2000. Content. Physical principles Definitions Techniques Clinical issues

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Continuous Renal Replacement Therapy

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  1. Continuous Renal Replacement Therapy Annual Refresher Course in CRITICAL CARE McGill Course Director: Peter Goldberg, MD Didier Payen CC Division & Dept of Anesthesiology 13/4/2000

  2. Content • Physical principles • Definitions • Techniques • Clinical issues • Supportive therapy or active therapy? • Sepsis an example • Why? • How? • For what goal?

  3. PHYSICAL PRINCIPLES& DEFINITIONS

  4. Clearance =(C uf/C I) * Quf Quf = C H2O x S x Ptm All molecules lower than Pore diam cross the Mbne PTM <30 000 Da >30 000 Da<65 000 Da >65000 Da CONVECTION

  5. Clearance =(C uf/C I) * Quf Quf = C H2O x S x Ptm All molecules lower than Pore diam cross the Mbne PTM <30 000 Da >30 000 Da<65 000 Da >65000 Da CONVECTION

  6. Clearance =(C uf/C I) * Quf Quf = C H2O x S x Ptm All molecules lower than Pore diam cross the Mbne PTM <30 000 Da >30 000 Da<65 000 Da >65000 Da CONVECTION

  7. Clearance =(C uf/C I) * Quf Quf = C H2O x S x Ptm All molecules lower than Pore diam cross the Mbne PTM <30 000 Da >30 000 Da<65 000 Da >65000 Da CONVECTION

  8. Pdialysat = P blood Cd <<< Csang <30 000 Da Progressive equilibrium of the [plasma] and [dial] ONLY SMALL MOLECULES CROSS THE MBNE >30 000 Da<65 000 Da >65000 Da DIFFUSION

  9. Progressive equilibrium of the [plasma] and [dial] ONLY SMALL MOLECULES CROSS THE MBNE Pdialysat = P blood Cd <<< Csang <30 000 Da >30 000 Da<65 000 Da >65000 Da DIFFUSION

  10. Progressive equilibrium of the [plasma] and [dial] ONLY SMALL MOLECULES CROSS THE MBNE Pdialysat = P blood Cd << Csang <30 000 Da >30 000 Da<65 000 Da >65000 Da DIFFUSION

  11. Progressive equilibrium of the [plasma] and [dial] ONLY SMALL MOLECULES CROSS THE MBNE Pdialysat = P blood Cd < Csang <30 000 Da >30 000 Da<65 000 Da >65000 Da DIFFUSION

  12. substitution FILTRATION RATE 0 TO 2 L/Hr Filtration <30 000 Da >30 000 Da<65 000 Da >65000 Da SCUF& CVVH Blood

  13. DEFINITIONSBELLOMO et al. Am J Kidney Dis, 28, (Suppl 3) 1996 SCUF: Use only for fluid control in overhydrated status CVVH:The ultrafiltrate produced during membrane transit is replaced in part or completely to achieve blood purification and volume control. UF is in excess if weight loss is mandatory: clearance of solutes equals UF CVVHD: continuous hemodialysis. + countercurrent flow of dialysis solution. Both diffusion & convection Efficiency is limited to small molecules (low Perm filter) CVVHDF: same. Both diffusion & convection but higher dialysate flow (High Perm filter)

  14. Access Return P R I S M A S Effluent Therapy options SCUFSlow Continuous Ultrafiltration Maximum Pt. Fluid removal rate = 2000 ml/h

  15. Access Return P R I S M A Replacement S Effluent Therapy options CVVHContinuous Veno-Venous Hemofiltration Maximum Pt. Fluid removal rate = 1000 ml/h

  16. Access Dialysate Return P R I S M A S Effluent Therapy Options CVVHDContinuous Veno-Venous Hemodialysis • Maximum Pt. fluid removal rate = 1000 ml/h

  17. Access Dialysate Return P R I S M A S Effluent Therapyoptions CVVHDFContinuous Veno-Venous Hemodiafiltration • Replacement Maximum Pt. Fluid removal rate = 1000 ml/h

  18. EFFICIENCY

  19. CLINICAL ISSUES

  20. CLINICAL INDICATIONS • IHD vs CRRT: no randomized trials but inferiority of IHD manisfests itself at many levels. • Hemodynamic stability Hypotension, volume control • Uremic control > with CRRT than IHD (Clark et al JASNephrol, 1994) • Metabolic control: metabolic acidosis; phosphate levels • In ICU patients • CRRT prevents the surge in ICP • Cardiac disease restore dry body weight, improve V flow • Cardiac surgical patients optimization between function and preload • Sepsis and inflammatory patients

  21. CRRT AND INFLAMMATIONSepsis an example

  22. HYPOTHESIS FOR MODS PREVENTION • Control of tissue edema • EDTX adsorption • Immunomodulation

  23. CAVH after Staph Aureus in swine(Lee PA et al; Crit Care Med 1993; 21: 914-924) • Goals: 1) CAVH impact on morbidity and mortality 2) If UF contains mediators • Design: prospective, randomized, controlled (n=65) • Staph aureus (8 x 10 9 CFU) over 1 hr • Part 1: Group 1: 5.5% plasma filtration fraction Group 2: 16.6% " " " " " Group 3: 33.4% Control clean UF • Part 2: UFiltrate concentrate from each group infused into healthy pigs

  24. CAVH after Staph Aureus in swine(Lee PA et al; Crit Care Med 1993; 21: 914-924) Measurements and results: • In G 1, 2, 3, the survival rate increased in relation to FF in comparison with control • UF concentrate injection led to animal death similarly to Staph aureus in control group. • Conclusion: CAVH-improved survival rate might be related to mediators removal

  25. EDTX & HEMOFILTRATION :In vivo experimental studies (1) • Stein et al, Intens. Care Med., 1991 • pig model, LPS injection • membrane : polysulfone, zero balanced HF • decrease in PVR, EVLW ==> other mechanisms than water balance

  26. EDTX & HEMOFILTRATION :In vivo experimental studies (2) • Gomez et al, Anesthesiology, 1990 • dog model, alive E coli ; in vitro study • cuprophane membrane • CHF reversed myocardial depression • septic sera depressed ex vivo myocardial contraction, an effect which is prevented by CHF ==> removal of cardio-depressive substances

  27. EDTX & HEMOFILTRATION :In vivo experimental studies Grootendorst et al, J. Crit. Care, 1993 - Endotoxin shock in pigs - Polysulfone membrane - Ultrafiltrate contains filtrable factors that increase Pap and depress cardiac performance in healthy animals Mateo et al, Am. Resp. J. Crit. Care Med., 1993, 1994 - Rabbit endotoxinic shock model - AN 69 adapted circuit; Hemo-adsorption only; pre-EDTX injection - No resuscitation; Ao BF, Pas, HR, - EDTX clearance; TNF; ex vivo vascular reactivity.

  28. Mean Arterial Pressure (%) Aortic Blood Flow Velocity (%) * 110 110 * * * * * 100 100 90 90 80 80 70 70 HAD + LPS HAD + LPS LPS 60 60 LPS 50 50 0 30 60 90 120 150 180 0 30 60 90 120 150 180 TIME (min) TIME (min) From Mateo et al AJR&CCM 1996 (Abst)

  29. 6000 5000 4000 LPS LPS + HAD 3000 2000 1000 0 0 10 60 120 180 0 30 60 120 180 From Mateo et al AJR&CCM 1996 (Abst) (E.U / ML) EDTX levels 10000 TNF-levels ( U.I / ML) 8000 LPS 6000 * LPS + HAD * p < 0,05 4000 3000 2000 * * 1000 * * * 0 TIME (min) TIME (min)

  30. 1 8 0 % of KCl 1 6 0 * 1 4 0 1 2 0 1 0 0 C o n t r o l 8 0 E D T X * 6 0 E D T X + H A D 4 0 * 2 0 0 1 10-9M 10-8M 10-7M 10-6M 10-5M From Mateo et al AJ R&CCM 1996 (Abst) NE

  31. CAVH ATTENUATES PMN PHAGOCYTOSIS IN PORCINE MODEL OF PRITONITIS A. DiScipio et al, Am J Surg. 173; 1997 • CLP model of acute peritonitis in pig • 24 hrs of CAVH vs no CAVH • ex vivo test of PMN phagocytosis for Candida (T0, T24, 48, 72H) • hemodynamic, gazometric & biologic data

  32. CAVH ATTENUATES PMN PHAGOCYTOSIS IN PORCINE MODEL OF PERITONITIS (A. DiScipio et al, Am J Surg. 173; 1997) • RESULTS • No difference in hemodynamic & gasometric parameters between CAVH & control • CAVH decreases intensity of PMN phagocytosis (opsonisation) and PMN hyperactivity until the early phase of sepsis

  33. Extensive activation of inflammatory responses • vasoactive • cardiodepressant mediators organ dysfunction Supportive Therapies Symptomatic Symptomatic + Mediator Regulation (HF) PEEP ventilation Hemodialysis - Removal of inflammatory mediators - Fluid balance control - Metabolic status control persistant SIRS MODS CHANGE IN MORTALITY ?

  34. CONVECTIVE ELIMINATION OF CYTOKINES • The concept of “the tip of the iceberg” (JM Cavaillon) : • Plasma elevation of cytokines ==> saturation of : • Origin cells • Target cells • Extracellular compartment • Plasma removal may have then small effect in • term of tissue/cell levels of cytokines

  35. CONVECTIVE ELIMINATION OF CYTOKINES • No drop in serum levels of IL except IL-1 • More rapid production than elimination • Shift of IL from the tissues to the serum • High volume hemofiltration ? • Coupled HVHF + HADsorption ?

  36. Elimination of inflammatory mediators by hemofiltration mediator elimination change study ref. Bacterial toxins: Endotoxin Adsorption  Ex-vivo, An. Vanholder, Matéo Lipid A Adsorption ? Ex-vivo Dinarello Anaphylatoxins : C3a Filtration  Human Hoffmann C5a Adsorption  Human Hoffmann Arachidonic acid derivatives: TxB2 Filtration  Animal Heidemann 6-keto PGF2 Filtration  An. Hum Heideman,Staubach Cytokines : TNF no = Human IL-1b Filtration = Human Bellomo, Hoffmann IL-6 no = Human Hoffmann,Millar IL-8 Filtration ? Human Hoffmann,Millar Myocardial depressing factor: Filtration ? An. Hum. Coraim,Gomez,Hallström

  37. High volume HF in severe sepsis(P Honoré et al . Hop St Pierre) (in press CCM) • 20 Ptsin refractory shock (PA<55mmHG, + Adre/Nor + Met • acidosis <7.15; SIRS 3 to 4; +/- renal failure) • Technique: HVHF, PAN; 4 hrs at 35 l/hr; Post-dilution • technique followed by LVHF (2 l/hr). • Goals: Responders ==> + 2 hrs increase about 50% for • CO + 25% SvO2; + 4 hrs pHa > 7.3; Reduction 50% • vasoactive drugs. • Results: 11 responders; 9 survivors; 1 died from MOSF and 1 • from Nosoc Infect; the non responders died at 80%

  38. How to limit adverse effects ? • Adequate biocompatibility • blood - membrane interaction • induction of chronic inflammatory reaction • Substrate losses (glucose, amino-acids, ...) • Hormones losses • Heat loss • Catheter-associated complications/infections • Costs • Need for prolonged anticoagulation coating systems

  39. CONTROL STUDIES • Substances involved ? • Mechanisms of the inflammatory reaction ? • Before or after renal failure appearance? • End-points : mortality ? Organ failure ? Cost/benefit ? design?????

  40. PERSPECTIVES Materials • Enhanced adsorption • Definitions of cut-offs for specific molecules • Selective or non-selective removal • Anticoagulation coating systems

  41. in vivo un état de choc ou des effets comparables à l'endotoxinémie. in vitro ou ex vivo une dépression de la contraction des fibres myocardiques isolées Au cours de l'insuffisance cardiaque ; Coraim et al, 1995 Au cours du choc septique ; Parillo et al , 1985; Gomez et al, 1990; Grootendorst et a l, 1993; Lee et al, 1993 Amélioration de la survie proportinnelle à la fraction filtrée, Lee et al, 1993 "Facteur Dépresseur Myocardique"L'ultrafiltrat des animaux septiques provoque :

  42. Systemic reaction SIRS (pro-inflammatory) CARS (anti-inflammatory) MARS (mixed) Initial insult (bacterial, viral, traumatic, thermal) from Bone Local anti-inflammatory response Local pro-inflammatory response Systemic spillover of pro-inflammatory mediators Systemic spillover of anti-inflammatory mediators CRRT???? • S • Suppression • of the • immune • system • CARS • predominates • O • Organ • dysfunction • SIRS • predominates H Homeo- stasis CARS and SIRS balanced • A • Apoptosis • (cell death) • Death with • minimal • inflammation C Cardiovascular compromise (shock) SIRS predominates

  43. Hemodiafiltration The use of hemodialysis, hemofiltration and ultrafiltration

  44. Dialysis The use of diffusion (dialysis fluid) to achieve clerance

  45. Slow Continuous Ultrafiltration The removal of plasma water (ultrafiltrate) using pressures

  46. Hemofiltration Use of convection (solute drag) to remove small and middle molecules

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