higher dose with progress in technical equipment. Continuous Dialysis: Dose and Antikoagulation. prescribed and delivered

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1 1 2 Continuous Dialysis: Dose and Antikoagulation higher dose with progress in technical equipment Comparison of pump-driven and spontaneous continuous haemofiltration in postoperative acute renal failure. Torsten Slowinski University Hospital Charité, Berlin Dept. of Nephrology Germany 116 pts. with acute renal failure 48 CAVH 68 CVVH p<.5 CAVH CVVH 2 Storck et al., Lancet (1991) 3 4 prescribed and delivered dose in CVVH prescribed and delivered 24.5±6.7 High Kt/V = >1, 16.6± ±3.5 Low Kt/V = <1, 68% of prescribed dose 67% of total hours in day Prescribed Dose (ml/kg/hr) Delivered Dose (ml/kg/hr) Time/Day (hours) 4 Paganini et al., AJKD (1996) Venkataraman et al., J Crit Care (22) 5 6 different weight adapted doses in post CVVH different weight adapted doses in post CVVH 492 patients considered 67 excluded 425 patients randomized Group 1 2 ml/kg/h Group 2 35 ml/kg/h 146 assigned ultrafiltration at 2 ml h -1 kg -1 ~1,5 l l/h 139 assigned ultrafiltration at 35 ml h -1 kg -1 ~2,8 l/h 14 assigned ultrafiltration at 45 ml h -1 kg - ~3,6 l/h Group 3 45 ml/kg/h 146 Patients completed study with ultrafiltration of >85% of prescribed 139 Patients completed study with ultrafiltration of >85% of prescribed 14 Patients completed study with ultrafiltration of >85% of prescribed Ronco et al., Lancet (2) Ronco et al., Lancet (2) 1

2 7 8 different weight adapted doses in post CVVH Acute Renal Failure Trial Network (ATN) trial p=.13 8 p=.7 p=.87 Survival Total No sepsis Sepsis 2 ml/kg/h 35 ml/kg/h 45 ml/kg/h Trial group Group 1 No sepsis (%) 55/126 (44%) Sepsis (%) p 5/2 (25%) 9 for CRRT 36.2 ml/kg/h 21.5 ml/kg/h Group 2 76/122 (62%) 3/17 (18%) 1 Group 3 74/125 (59%) 7/15 (47%) 256 Ronco et al., Lancet (2) Palevsky et al., NEJM (28) 9 1 Acute Renal Failure Trial Network (ATN) trial Acute Renal Failure Trial Network (ATN) trial Predilution CVVHDF Intensive strategy equals post CVVHDF Less intensive strategy equals post CVVHDF 35,8 L/kg/h 24 ml/kg/ 22 ml/kg/h 15 ml/kg/h plus 1% of all patients had extra UF sessions for volume control (interm. HD) Palevsky et al., NEJM (28) RENAL study RENAL study postcvvhdf 4 ml/kg/h 25 ml/kg/h delivered 84% 88% Bellomo et al., NEJM (29) Bellomo et al., NEJM (29) 2

3 13 14 side effects of CRRT side effects of CRRT: antibiotics clearance ATN study: intensive less-intensive RENAL study: 4x 4.5 g piperacillin/tazobactam 15 Adding a dialysis dose to filtration 16 continuous hemofiltration versus continuous hemodialysis Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure 42 ml/kg/h Adding a dialysis dose 25 ml/kg/h predultion CVVHDF! equals post CVVHDF 18 vs 3 ml/kg/h Randomized controlled study CVVH Group: 25 ml/h/kg, 12 patients CVVHDF Group: ml/h/kg, 14 patients OMAKI: Optimal Mode of clearance in Acute Kidney Injury => Prospective, randomised comparison of CVVH and CVVHD Saudan P et al., Kidney Int 26 Wald R et al Crit Care16:R25, OMAKI study: results 9% 8% 76% 82% 7% 6% CVVH CVVHD 5% 4% 3% 2% 44% CVVH 45% CVVHD 1% % survival at day 6 survivors without RRT at day 6 Largest prospective RCT comparing CVVH and CVVHD in critically ill patients with AKI (78 patients) => no significant difference in outcome 3

4 19 filtration versus dialysis: mortality 2 sepsis and the peak concentration hypothesis Ronco et al, Artif Organs (23) 21 Extended daily on-line high-volume haemodiafiltration in septic multiple organ failure: a well-tolerated and feasible procedure 22 Extended daily on-line high-volume haemodiafiltration in septic multiple organ failure: a well-tolerated and feasible procedure Treatment characteristics High volume online HDF Duration (h:min) 1:15 (6 23) convective exchange per treatment (l) ± 65.2 convective exchange per hour (l/h) 17.8 ± 3.7 Survival (%) On-line high volume HDF BEST-Kidney 2 1 Kron et al, NDT (212) Time (days) Kron et al, NDT (212) 23 optimal dose > 2 ml/kg/h? one size fits all? 24 Anticoagulation in CRRT 4

5 25 26 Systemic anticoagulation for CRRT clotting bleeding Heparin dose coagulation cascade and calcium Why citrate? To minimize bleeding risk. Multivariable Poisson regression model of relative risk of definite or occult hemorrhage during CRRT Ca Ca Ca Ca Thrombus formation Kutsogiannis DJ et al., Kidney Int (25) 29 Different protocols for RCA in continuous therapy. 3 Development of a protocol: e-dose for Anticoagulation e CVVH most studies in predilution (=expensive) e CVVHD e CVVHDF Zero calcium fluids Calcium containing fluids High or low concentration of citrate (i.e. 4 % up to 3 %) Nuthall et al. Crit Care Med 3:9-93, 22 5

6 31 development of a protocol: citrate-dose for anticoagulation 32 e anticoagulated CVVH filter survival vs. nadroparine Calatzis et al., Nephron (21) James et al., JCVA (24) post-filter ica: mmol/l 4 mmol citrate per L blood 97 pts with citrate, 13 with nadroparine post-dilutional CVVH, effluent 4 l/h - e 3 mmol pro L blood, no post-filter ica measurment, no dose adjustments - Fraxiparin ~3 bolus, ~4 IE /h Oudemans-van Straaten et al., Crit Care Med (Feb 29) 33 infused calcium-citrate complexes in CiCa-CVVHD 34 basics: citrate metabolism 4% Trisodiumcitrate (Na 3 C 6 H 5 O 7 ) citrate is metabolized into bicarbonate Molecular weight: ~ 3 Dalton 1 mol citrate forms 3 mol bicarbonate 5% Ca-citrate into systemic circulation bicarbonate is a buffer 5% Ca-citrate eliminated into dialysate control of acidosis in renal failure is a goal in RRT substitution of buffer principally makes sense 35 dialysate for citrate anticoagulation in CVVHD 36 Why do we need calcium-substitution? [mmol/l] Standard e Not for restoring coagulation! Potassium 2 2 Sodium Chloride Magnesium.5.75 Calcium 1.5 Bicarbonate 35 2 Glucose [g/l] 1 1 Calcium e 5% Ca-e eliminated CiCa Dialysate K2 Fresenius Calcium substitution rate: 1.7 mmol / Liter dialysate flow 6

7 37 protocol with variable treatment efficacy - our actual protocol 38 regional citrate anticoagulation in CVVHD group 1 < 6 kg group kg group 3 > 9 kg Blood flow [ml/min] Predefined starting values Dialysate flow [ml/h] e solution flow [ml/h] = 4 mmol/l blood Calcium solution flow [ml/h] = 1.7 mmol/l dialysate regional citrate anticoagulation in CRRT 4 Ci-Ca CVVHD citrate and calcium dose adjustments safety with integrated citrate and calcium pumps 25 Ci-Ca pumps control via the user interface -Pumps start/stop automatically CiCa modul: citrate and calcium pump -e flow linked to blood flow -Calcium flow linked to dialysate flow 7

8 43 44 safety: integrated lines for citrate and calcium metabolic control e and calcium lines connected with the blood lines => Mixing-up of citrate and calcium lines at the catheter impossible! 45 adjustments of parameters in citrate anticoagulation 46 Ci-Ca CVVHD: Effect of blood and dialysate flow on the acid-base status expected blood bicarbonate concentration [mmol/l] Alkalosis 2 calcium flow per L dialysate Blood flow [ml/min] Acidosis 18 Possibilities to adjust the effect on the acid-base status: Change of blood flow with automatic and proportional change of citrate infusion Change of dialysate flow with automatic and proportional change of Calcium infusion 6 Multifiltrate Fresenius Ci-Ca Dialysate K2 [ml/h] 47 Protocol with variable treatment efficacy Base excess 48 Risk for metabolic alkalosis in citrate anticoagulation? Dialysate to blood flow [%] 5% 48% 46% 44% 42% 4% 38% 36% 34% 32% 3% 28% 26% baseline Duration of citrate-cvvhd [days] Base excess [mmol/l] group 1 group 2 group 3 S. Morgera et al., Crit Care Med, 29 standard HF and HD solutions for CRRT contain 35 mmol/l bicarbonate Oudemans-van Straaten et al., Crit Care Med (29) 8

9 49 5 The three pillars of citrate anticoagulation Anticoagulation Start with e Dose of 4. mmol/l Mesaure post-filter ion. Ca Calcium Balance Start with Calcium Dose of 1.7 mmol/l Measure systemic ion. Ca Acid-Base-State Start with Standard Ratio of Blood/Dialysate e.g.: 1 ml/min : 2 l/h Masure Acid-Base-State filter run-time In target range mmol/l? Yes In target range? Yes In target range? Yes No No No Adjustment of e Dose Adjustment of Calcium Dose Adjustment of Ratio of Blood/Dialysate 51 CiCa-CVVHD Filter run-time 52 filter run-time 211 Still running filters [%] 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% Filter clotting is no problem! all observed hemofilters without censoring only hemofilters discontinued for CRRT reasons 181 filters analyzed - 5 filters clotted overall = 3% - 4 filters clotted before 72h = 2% 98% at 72 h % Filter lifetime [h] S. Morgera et al., Crit Care Med, 29 Slowinski et al., submitted e-cvvhdf in postdilution citrate postcvvhdf CaCl 2 MultiBic Dosis I < 6 kg II 6 9 kg III > 9 kg 4% Na- CiCa Dialysat K2 Content Ci-Ca Dialysate MutiBic [mmol/l] K2 Sodium Potassium 2 2/4 Filtrat Chloride Magnesium.75.5 Calcium 1.5 BIC 2 35 Glucose (g/l) 1 1 Blutfluß ml/min Na- ml/h CaCl 2 ml/h Ci-Ca Dialysat K2 MultiBic Substitution L/h L/h

10 55 56 CiCa-CVVHDF citrate post CVVHDF Slowinski et al., submitted Meta-Analysis: Bleeding complications Meta-Analysis: transfusion requirements 4 1, Monchi Kutsogiannis Betjes van Straten Hetzel 1,5 Monchi Kutsogiannis Betjes van Straten Hetzel Heparin Oudemans-van Starten (211) Critical Care 15:22 Heparin 59 transfusions not only because of bleeding! 6 transfundierte Erythozytenkonezentrate pro CVVH Tag 1,2 1,8,6,4,2 Heparin transfundierte Patienten [%] after clotting of hemofilter other causes Heparin e outcome studies Monchi et al. Intensive Care Med 3:26 265, 24 1

11 61 Survival 1 62 Survival 1 Oudemans-van Straaten et al., Crit Care Med (29) Oudemans-van Straaten et al., Crit Care Med (29) Survival 2 Multicenter-trial, 174 pts, all on mechanical ventilation e-cvvh versus Heparin-CVVH meta analysis 1 meta analysis 2 11

12 67 68 RCTs bleeding risk 1 6 RCT RCA vs. systemic anticoagulation in total 488 patients 6 RCTs: lower bleeding incidence with RCA, p<.1 Intensive Care Med 69 bleeding risk 2 7 Kidney Disease: Improving Global Outcomes (KDIGO) March 212 signifikant weniger Blutungen mit 6 RCTs: lower bleeding incidence with RCA, p=.1, Odds.33 AJKD year incidence of citrate accumulation (28-21) 3-year incidence of citrate accumulation (28-21) Parameter Patients with determined citrate accumulation All Patients treated with CiCa-CVVHD N= 32 N= 193 Age, years 63.9 ± ± 12.5 Gender, male (%) 65.6% 64.8% Bodyweight, kg 79.7 ± ± 22.6 APACHE Score 34.2 ± ± 8.9 SAPS II Score 64.4 ± ± 16.7 SOFA Score (range) 11. ± ± 3.6 Initial creatinine before RRT, mg/dl 2.4 ± ± 1.7 Duration of CVVHD with RCA, hours median (min max) (19 932) (1 266) ICU stay, days median (min max) (1-52) (1-296) Reasons for ICU admission, %: Postsurgical 62.5% 52.8% Medical 37.5% 47.2% 193 patients 32 patients with citrate accumulation mean treatment time: 25 h incidence: 2.9% mg/dl 31 of 32 Patienten with citrate accumulation died on ICU Khadzhynov et al., Crit Care (in press) Khadzhynov et al., Crit Care (in press) 12

13 73 74 lactate and citrate metabolism citrate metabolism Isocitrat dehydrogenase Dependent on NAD + Supressed by NADH+H + wikipedia.org citrate metabolism is oxygen-dependent! electron transport chain wikipedia.org Biochemical J,