Blood Purification in the ICU: State of the Art A/Prof. Rinaldo Bellomo Austin & Repatriation Medical Centre Melbourne Australia Similarities between sepsis and renal failure 感染与肾功能衰竭之间的相似之处               !  "  #             !$  "$ The Mediators of Sepsis (the Humoral Theory of Sepsis)  %&'()*+, /  01*'()2*+, /3014'()25, /3016 '()277, /  8&9'()27-, /, :,-'()2**, /  ;8<7,=>;7'() /  =?&8()26  8@0=, ,,  '()2-, /,= The CRRT Membranes  %=A87.:.B9  "!   !   !          CRRT and complement 0 100 200 300 400 500 600 700 t 0 t 4 t 12 C3a C5a ng/ml for C3a (/ 10 for C5a) Time on CVVH at 2L / h UF rate p < 0.001 p < 0.01 C3a SC = 0.2 C5a SC = 0.02   TNF levels: CVVH vs. CVVHD -50 0 50 100 150 200 1 2 3 4 5 6 7 8 9 10 CVVHD CVVH p < 0.02 PATIENTS % Change   High Volume Hemofiltration • The term was first used by Grootendorst in 1992 • Animal experiments in pigs (weight 36-39 kg) • Blood flow 300 ml/min • UF flow 6000 ml/hr • Replacement fluid given pre-filter • Polysulfone filters (Amicon, USA) • IV endotoxin over 30 minutes HVHF and RVEF 0 10 20 30 40 50 60 0 30 60 90 120 150 180 210 240 Time in minutes RVEF (%) Control HVHF p<0.001 Grootendorst et al, Intensive Care Med 1992 HVHF and MAP 0 20 40 60 80 100 120 140 0 30 60 90 120 150 180 210 240 Time in minutes MAP in mmHg Control HVHF p<0.001 Grootendorst et al, Intensive Care Med 1992 Effect of septic UF on MAP 0 5 10 15 20 25 30 35 40 0 15 30 45 60 75 90 105 120 135 150 2L Normal UF 2L LPS UF Change in MAP (mmHg) Grootendorst et al, J Crit Care 1993 p < 0.05 [...]... available in limited amounts • If done continuously, after a while one is removing the FFP given • FFP contains many of the proteins we want to remove Intermittent therapy is unlikely to be enough • No effect in Phase Ib trial (Reeves et al Crit Care Med 1999; 27: 2096-2104) Why Coupled Plasma Filtration Adsorption (CPFA)? • All plasma becomes available for purification • Therapy can be continuous • No interaction...Effect of HVHF on ischemic gut injury p < 0.05 4 Gut injury score Perforatio n 3 Ulcer s 2 Sloughin g 1 0 Mucosal injury HVHF No CVVH Grootendorst et al Shock 1994 HVHF • HVHF may be beneficial in human septic shock • If Hct of 30% and blood flow of 300 ml/min and pre-dilution small solute clearance = approx 6070 ml/min (110ml/kg/hr) • In 70 kg patient in pre-dilution need about 11 L/hr of UF rate... between cells and adsorptive cartridges CPFA: Ex-vivo testing - cytokine adsorption 100 90 80 70 60 50 40 30 20 10 0 Resin: XAD 1600 Adsorption as % IL-1 beta IL-8 TNF Tetta et al Nephrol Dial Transplant 1998; 13: 1458-64 CPFA in animal models • Test whether biochemical findings translate into clinical effects • • • • Assess magnitude of clinical effects Assess nature of clinical effects Exclude major... CPFA in the rabbit - TNF adsorption 30000 25000 20000 U/mil TNF bioactivity preresin TNF-bioactivity postresin 15000 10000 5000 0 60 min 90 min 120 min 180 min Tetta et al Crit Care Med 2000; 28: 1526-1533 CPFA in the rabbit % survival p =0.004 90 80 70 60 50 LPS only LPS + CPFA 40 30 20 10 0 2 4 Days 6 8 Tetta et al Crit Care Med 2000; 28: 15261533 Phase I trial of CPFA • 10 patients • Single ICU •... randomization No predefined criteria of response However Provocative study Findings consistent with expectations Conclusions • We have no consensus definition for the term “HVHF” but we have several phase I studies suggesting that “more” UF might be better • We have limited understanding of mechanisms, dose and duration, however, and no markers like urea • This is a promising and exciting area of research We... L/hr of UF rate less if post-dilution but need big blood flows (>400 ml/min) HVHF • 11L/hr of UF is technically demanding/very difficult in human beings • Can we achieve similar results at lower UF rates? • Dog experiment in 20 kg dogs and UF rate of 2000ml/min (blood flow 200 ml and pre-dilution) • Small solute clearance = approx 80 ml/kg/hr Change in MAP after IV LPS 0 MAP -10 (mmHg) -20 -30 p < 0.05... heparin/protamine regional approach • Buffer: lactate • Estimate small solute clearance: approx 85 ml/min (70 ml/kg/hr) Cole, Bellomo et al Intensive Care Med 2001; 27: 978-986 Norepinephrine Requirements: HVHF vs CVVH p < 0.02 10 Change (µg/min) over 8 h 5 0 -5 1 2 3 4 5 6 7 8 9 -10 -15 -20 -25 -30 Cole, Bellomo et al Intensive Care Med 2001 ; 27: 978-986 10 HVHF CVVH % Change in Norepinephrine Dose:... hours of HVHF (blood flow 450 ml/min, 1.6 m2 Fresenius polysulfone filter, bicarbonate buffer, post-dilution, UF rate 8750 ml/hr) • Approx small solute clearance: 116ml/kg/hr Results • 11 responders (rapid increase in CI, MVSO2, pH>7.3 and 50% reduction in adrenaline dose) • 9 of 11 responders survived • Responders weighed less : 66 vs 83 kg • Responders got more UF: 132 ml/kg/min vs 107 ml/kg/min •... Bellomo et al Intensive Care Med 2001 Conclusions • HVHF has beneficial short term effects in human septic shock similar to those in animals • With AN69 and molecules >8-9 kD it results in adsorptive removal, not filtration of inflammatory mediators • There is now a rationale for phase II studies Short Term-Very HVHF • Patrick Honore et al (Crit Care Med 2000; 28: 3581-3587) • 20 patients in severe refractory... after IV LPS (minutes) Bellomo et al AJRCCM 2000; 161: 1429-1436 HVHF vs CVVH • 10 patients with septic shock and ARF • Noradrenaline dependent • Randomized to 8 hrs of HVHF (6L/hr) or CVVH (1L/hr) in random order • Physiological outcome: hemodynamic response • Biological outcome: Complement and cytokines Technique for HVHF • Filtral 16 (1.6 m2)- AN 69 membrane • Blood flow: 300 ml/min • Catheter: 13.5 . Blood Purification in the ICU: State of the Art A/Prof. Rinaldo Bellomo Austin & Repatriation Medical Centre Melbourne Australia Similarities. be beneficial in human septic shock • If Hct of 30% and blood flow of 300 ml/min and pre-dilution small solute clearance = approx. 60- 70 ml/min (110ml/kg/hr) • In 70 kg patient in pre-dilution. need about 11 L/hr of UF rate less if post-dilution but need big blood flows (>400 ml/min) HVHF • 11L/hr of UF is technically demanding/very difficult in human beings • Can we achieve