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Blood Purification in Sepsis

Blood Purification in Sepsis. Dr. Peter Skippen, PICU. BC Children’s Hospital, Vancouver. CANADA. Outline. Basic concepts of SIRS and therapies Rationale for blood purification Types of blood purification Evidence for efficacy The future?. What are we doing?.

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Blood Purification in Sepsis

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  1. Blood Purification in Sepsis Dr. Peter Skippen, PICU. BC Children’s Hospital, Vancouver. CANADA.

  2. Outline • Basic concepts of SIRS and therapies • Rationale for blood purification • Types of blood purification • Evidence for efficacy • The future?

  3. What are we doing? Remove the “evil humors” OR Restore the balance OR Both OR Neither

  4. Synopsis of SIRS immune Status infecting Organism HOST genetic map systemic insult Stereotypical host response humoral response cellular response ENDOTHELIUM Mediators spills over into circulation pro-inflammatory systemic inflammation local inflammation anti-inflammatory complement • Bound • Nonspecific protein bound • Soluble receptor bound Unbound phospholipase A2 dependent products coagulation fibrinolysis / anticoagulation • CLEARANCE • non-specific • cpecific • cell bonud • circulating • REMOTE INJURY • ARDS • renal dysfunction • liver dysfunction Death or Recovery

  5. SIRS Evolution TNF- IL-1ß IL-6 IL-8 PAF iNOS COX2 Clinical presentation Biologic sequelae IL-1 ra IL-10 sTNFr-1/11 TGF- IL-4 Sepsis SIRS Monocyte activation PROINFLAMMATORY ANTI-INFLAMMATORY IL-1 ra IL-10 sTNFr-1/11 TGF- IL-4 TNF- IL-1ß IL-6 IL-8 PAF iNOS COX2 Monocyte deactivation SEPTIC SHOCK PROINFLAMMATORY ANTI-INFLAMMATORY + CELL HYPORESPONSIVENESS / IMMUNOPARALYSIS

  6. Stereotypical Response sepsis trauma panceatitis Similar cellular inflammatory response Similar clinical response TNF TLR CELL MEMBRANE Fever Hypotension Respiratory distress Oliguria Elevated liver enzymes CD14 CD11b upregulation kinases oxidative stress Mitochondrial oxidative stress HSF NF-kB TNF mRNA/HSP mRNA NUCLEUS

  7. Sepsis Therapy Bacterial sepsis exotoxin LPS mediators antibiotics / surgical drainage general ICU support IMMUNOMODULATION monoclonal antibodies other anti-inflammatories steroids - high dose - low dose mediator adsorption / removal

  8. most known mediators are water soluble possible contenders 500-60,000D (“middle molecules”) cytokines anti/pro-coagulants other molecules complement phospholipase A-2 dependent products likely many unknown contenders What are the targets?

  9. Convective Removal of Mediators ß2 microglobulin myoglobin creatinine IL-6 sucrose inulin urea albumin IL-8 ionic compounds Vit B12 TNF IL-1 10 102 103 104 105 MW (Daltons) Filter cutoff

  10. Convective Removal of Mediators MEDIATOR MW (Daltons) SIEVING COEFFICIENT AA metabolites +/- 600 0.5-0.9 Bradykinin +/- 1100 Endothelin +/- 2,500 0.19 C3a/C5a +/- 11,000 0.11-0.77 MDS +/- 600-30,000 Endotoxin > 106 LPS +/- 67,000 TNF monomer +/- 17,000 0-0.2 TNF trimer +/- 54,000 IL-1 +/- 17,500 0.07-0.42 IL-6 +/- 22,000 IL-8 +/- 8,000 0.48 IL-10 +/- 18,000 0 INF +/- 20,000

  11. Types of Blood Purification • hemofilters • regular pore size (MW < 40,000D) • Low flux • High flux • large pore filtration (MW < 100,000D) • open pore plasma filters • plasma exchange • plasmapheresis • adsorption • coupled plasma filtration / adsorption • combinations

  12. Mechanisms of Clearance of Mediators • diffusion • convection • adsorption • decreased production • ? “feedback” effect

  13. Potential Adverse Effects of Blood Purification • interaction of immune system with foreign surface of circuit • cellulosic vs. biocompatible • complement activation • bradykinin generation • leukocyte activation / adhesins? • clearance of anti-inflammatory mediators • clearance of unknown “good” mediators

  14. Problems with the Concept • what do the plasma levels of mediators really mean? • animal studies not clinically applicable to human sepsis

  15. What is the Evidence for Blood Purification?

  16. Systematic Review: Levels of Evidence Level 1: randomized clinical trials with substantial treatment effects Level 2: randomized clinical trials with smaller treatment effects Level 3: prospective, controlled, non-randomized, cohort studies Level 4: historic, non-randomized, cohort studies Level 5: case series, no control group Level 6: animal studies Level 7: extrapolations from existing data Level 8: rational conjecture, common practices

  17. indirect evidence cytokines in ultrafiltrate adverse effects of reinfused ultrafiltrate direct evidence animal studies human improved ventricular function human improved lung compliance human survival advantage Types of Studies on Blood Purification in Sepsis

  18. Level of Evidence • mediator clearance • in-vitro • in-vivo • all level 5 or 6 • animal studies (level 6) • many • clinical studies • 2 level 1 studies (Ronco et al & Reeves et al) • 5 level 2 studies • remainder level 3 or 4

  19. Experimental Studies in-Vivo • Detection of mediators in ultrafiltrate • Detection of changes in serum levels of mediators • Detection of changes of hemodynamics / resp. function septic animals • Detection of effects of UF on hemodynamics of normal animals • Detection of effects of UF on lymphocyte activation in-vitro

  20. Experimental Studies In Vivo REGULAR PORE SIZE: INDIRECT MEDIATOR REMOVAL Author Model Results Reference Stein 90 pig endotoxemia  hemodynamics Int Care Med 16:494-9 Gomez 90 dog sepsis  LV contractility Anesthesiol 73:671-85 Stein 91 pig endotoxemia  lung compliance Int Care Med 17:293-8 Grootendorst 92 pig endotoxemia  CO, RVEF Int Care Med 18:235-40 Grootendorst 93 pig endotoxemia effluent causes shock J Crit Care 8:161-9 Lee 93 pig, sepsis  survival Crit Care Med 21:914 Heideman 94 rat endotoxemia  survival Circ Shock 44:183-7 Bellomo 95 dog endotoxemia  CO, hemodynamics AJRCCM 151:A318 Mink 95 dog sepsis  hemodynamics Anesthesiol 83:178-90 Flynn 94 pig endotoxemia  LV contractility Anesth Analg 80:S129 Freeman 95 dog sepsis no effect J Am Coll Surg 180:286-92 Bottoms 96 pig endotoxemia no effect Shock 5:149-54 Murpy 97 pig endotoxemia no effect J Vet Res 58:408-13 Mink 99 dog sepsis no effect Int Care Med 25:733-43

  21. Experimental Studies In Vivo REGULAR PORE SIZE: DIRECT MEDIATOR REMOVAL Author Model Results Reference Bellomo 93 human sepsis IL-1, TNF Crit Care Med 21:522-6 Tonnesen 93 human sepsis IL-1, IL-6, TNF Anaes Int Care 21:752-8 Andreasson 93 human CPB cytokines Ann Thor Surg 56:1499-1502 Journois 94 human CPB IL-6, TNF Anesthesiol 81:1181-9 Hoffman 94 human sepsis C3, C5a Int Care Med 20:A73 Heideman 94 rat endotoxemia PGF, TxB2 Circ Shock 44:183-7 Hoffman 95 human sepsis Kidney Int 48:1563-1570 Bellomo 95 human sepsis IL-6, IL-8 Ren Fail 17:457-466 Van Bommel 95 human sepsis TNF, IL_1, IL-6 Contrib Nephrol 116:62-75 Hoffman 96 human sepsis Int Care Med 26:1360-1367 Kellum 96 dog endotoxemia endothelin, PGF AJRCCM 153:A838 Heering 97 human sepsis cytokines Int Care Med 23:288-96 Kellum 98 human sepsis TNF, IL-6 Crit Care Med 26:1995-2000 Bellomo 98 human sepsis C3a Kidney Int 53:S182-5 Ishihara 99 pig endotoxemia TNF, PGF, TxB J of Trauma 46:894-99 Hoffman 99 human sepsis UF cardiotoxins Shock 12:174-80 Lonnemann 99 human sepsis TNF Kidney Int 56:S84-87

  22. Experimental Studies In Vivo HIGH VOLUME HF Author Model Results Reference Grootendorst 92 pig endotoxemia  hemodynamics Int Care Med 18:235-40 Grootendorst 94 pig gut ischemia  hemodynamics Shock 2:72-8 Rogiers 99 dog endotoxemia  hemodynamics Crit Care Med 27:1848-55 Bellomo 2000 dog endotoxemia  MAP; no ∆ CO AJRCCM 161:1429-36 LARGE PORE FILTRATION Lee 98 pig septicemia  hemodynamics, survival Crit Care Med 26:730-37 Kline 99 dog endotoxemia  hemodynamics, survival Crit Care Med 27:588-96

  23. Plasma exchange (PE) centrifugation membrane Plasmapheresis (PP) Plasmapheresis Plasma PLASMA FILTER PLASMA FILTER Plasma ADSORBANT COLUMN FFP/colloid/IgG Patient Patient

  24. Plasmapheresis: Clinical Studies ANIMAL STUDIES Author Results Reference Busund 91 no survival advantage Arch Surg 126:591-7 Natanson 93 no survival advantage Transfusion 33:243-48 HUMAN STUDIES Author Type of Study Results Reference Van Deuren 92 observational no benefit Clin Infect Dis 15:424-30 Reeves 95 retrospective no benefit Int Care Med 21:500-4 Berlot 97 observational no benefit Blood Purif 15:45-53 Kumar 98 observational no benefit Nephrol Dial Trans 13:484-7 Reeves 99 RCT no benefit Crit Care Med 27:2096-104 Schmidt 2000 observational no benefit Int Care Med 26:532-7

  25. Human Clinical Studies of High Volume CVVH Level 1 Studies Author Design Results Reference Ronco 2000 PRCT improved outcome Lancet 355:26-30 Level 2 Studies Cosentino 91 RCT (ARDS) no difference Contrib Nephrol 93:94-97 Braun 95 RCT (SIRS)  Apache III score Contrib Nephrol 116:89-98 Reigel 95 RCT (trauma) attenuates CO Contrib Nephrol 116:56-61 Sander 97 RCT (SIRS) no difference CVS Int Care Med 23:878-884 Riera 97 RCT (trauma)  CVS/oxygenation Surgery 122:902-908 Level 3 Studies Wakabayashi 96 cross over Br J Surg 83:393-4 Jacob 96 Review no difference Nephrol Dial Transp 11:1250-55 Honore 97 cohort improved CVS Int Care Med 23:S77 Bellomo 98 cohort reduced inotropes Kidney Int 53:S182-5 Oudmans 99 cohort improved mortality Int Care Med 25:814-21

  26. Problems? • Can accuracy of machines handle high flows for pediatric patients? • Will there be prospective randomized controlled studies? • Will one filter fit all comers? • What about unique genetic makeup? • Cost?

  27. The way of the future? • Adsorption • Continuous Plasma Filtration Adsorption (CPFA)

  28. Coupled Plasma Filtration Adsorption (CPFA) PLASMA FILTER HEMODIAFILTER BLOOD IN BLOOD OUT DIALYSATE SORBENT

  29. Adsorbents • non selective • charcoal • coated • uncoated • uncharged resins • liposomes (+ Vit C & Vit E) • selective • hydrophobic resins • powdered adsorbent • microsphere based detoxification system • engineered matrices • polymyxin B • polyethyleneimine • specific • antibody-coated microspheres detoxification system • anti-TNF MDS • anti-IL-1 MDS

  30. PMX-F Hemoperfusion Animal Models Author Model Survival % Reference Rx vs control Hanasawa 84 dog e-toxemia 83 vs 12.5 Therapeutic Apheresis, P 167-70 Hanasawa 89 live e-coli 60 vs 0 ASAIO Trans 35:341-43 Hanasawa 89 dog e-toxemia 83 vs. 0 Surg Gyn Obstet 168:323-331 Kodama 90 dog e-toxemia 75 vs. 0 Jpn J Artif Org 17:277-79 Shoji 93 dog e-toxemia 60 vs. 20 Jpn J Artif Org 22:204-11 Sato 93 dog e-toxemia 80 vs.0 ASAIO Trans 39:M790-M793 Human Studies (all uncontrolled) Aoki 94 observational ET clearance / inotropes Am J Surg 167:412-17 Kodama 97 phase II/III survival/ET clearance Shock 7 supp:6 (abstract) • Adsorbs endotoxin

  31. CPFA: Experimental Studies • In-Vitro studies • much more efficient clearance of cytokines • Animal Studies • rabbit model of LPS septic shock (Tetta C, Coupled plasma filtration-adsorption in a rabbit model of endotoxic shock. Crit Care Med 28:1526-33, 2000) • 85% survival in rabbits supported with CPFA • 80% mortality in control rabbits • Human Clinical Study (Brendolan A, Coupled plasma filtration-adsorption technique in sepsis-associated acute renal failure: hemodynamic effects. J Am Soc Nephrol 9:A0655, 1998) • improved hemodynamics SVR • reduced inotrope requirements • improved monocyte responsiveness

  32. The Past and the Future CRRT • mid 1960’s Henderson first demonstrated pumped ultrafiltration • 1977 Kramer first performed CAVH • early 1990’s pumped continuous hemofiltration (CVVH) • 2002: • wide range of customized machinery • synthetic biocompatible membrane Blood Purification • 1990: • initial studies demonstrating mediator clearance • ?2020 • specific therapy for sepsis / SIRS

  33. Conclusions • “tip of the iceburg”? • potentially important adjunctive therapy • do no harm vs. improving outcome ?

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