1. Advances in Continuous Renal Replacement Therapy CSM 2011 Dr Anne Leung 17 th May 2011

2. Overview DOSE Fluid and anticoagulation Timing of initiation Membrane

3. To begin the “Dosing” story of CRRT…. 20mL/Kg/hr 35 mL/Kg/hr 45 mL/Kg/hr 15-days Survival 41%57%58% Lancet 2000

4. Higher the dose the better EIHF vs Conventional 45mL/Kg/hr for 6 hours then 20mL/Kg/hr vs 20mL/Kg/hr 28-day Survival: 55% vs 27.5% Piccinni ICM 2006

5. CVVHDF: more may not be better PRCT Single Center N=200 Pre-dilution CVVHDF: 20mL/Kg/Hr CVVDHF: 35mL/Kg/Hr Tolwani et al JASN 2008

6. IntenseConventional Hemodynamic stable IHD /SLED 6x/week with Kt/V of 1.2-1.4 IHD /SLED 3x/week with Kt/V of 1.2-1.4 Hemodynamic unstable CVVHDF 35mL/Kg/Hr CVVHDF 20mL/Kg/Hr

7. Intensive RRT = Equal ATN trial PRCT N=1124 60 days mortality Intensive: 53.6% Less Intensive: 51.5%

8. What Dose ? Before the ATN trial CRRT: 35mL/Kg/Hr Daily iHD After the ATN trial SOFA 0-2: 3x/week iHD (Kt/V 1.2) SOFA 3-4: CRRT 20 mL/Kg/hr or SLED 3x/week But beware for the need for extra treatment!

9. Randomized (Post-dilution CVVH) 1508 Low dose (25ml/Kg/hr) 761 High dose (40ml/Kg/hr) 747 Lost to follow up = 1 Consent withdrawn = 2 Consent not obtained = 23 Analyzed 722 Lost to follow-up = 0 Consent withdrawn = 2 Consent not obtained = 16 Analyzed 743

10. RENAL Study High Intensity Low Intensity 90-days mortality44.7% 28-days mortality38.5%36.5%

11. Conclusion Intensity of RRT DOES matter Beyond the threshold dose ( 25ml/kg/hr), increasing intensity does not provide further clinical benefit Be-aware of the difference between prescribed and delivered dose of RRT ATN study: 89% -95% RENAL study: 84-88% Minimize the interruption of the treatment time

12. IVOIRE (hIgh Volume in Intensive Care)— French Study Inclusion criteria: Septic shock <24 hrs and RIFLE criteria of injury or worse Intervention: High volume (70ml/kg/hr) vs Standard (35ml/Kg/hr) for 96 hours Patient number: total of 460 patients Primary outcome: 28-day mortality Study period: 3 years and completed by Oct 2010

13. INITIATION OF THERAPY

14. RIFLE Criteria Currr Opin Crit Care 8: 509-514 (2002) Level of injury Outcome measures

15. From RIFLE to AKIN Serum Creatinine Increase SCr ≥24.6mmol/L 2-3 folds Stage 1 Stage 2 Stage 3

16. The Acute Kidney Injury Network Classification ( AKIN) Crti Care 11:R31 (2007)

17. Biomarkers of AKI uNGAL Serum Cystatin C

18. MEMBRANE OF FILTER

19. Super High-Flux or High Cut-ff Membranes Achieve greater clearance of inflammatory cytokines - Superior elimination of IL-6 - Decrease need of Nor- adrenaline over time

20. P. 20 SepteX—High Cut Off Membrane

21. Pilot Randomized Controlled Study Comparing the Effect of High Cut-off Point Hemofiltration with Standard Hemofiltration in Patient with Acute Renal Failure Study Population: Critically ill patient with AKI and shock that require Nor-adrenaline Intervention: Standard polyamide high flux membrane vs High cut-off polyamide membrane (P2SH) CVVH: Qb: 200ml/min, UF of 25ml/Kg/hr Size of the study: 72 patients Primary measures NA-free time in first week after randomization Status: start in Jun 2009 and still recruiting

22. P. 22 Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock-- The EUPHAS Randomized controlled Trial JAMA 2009 Polymyxin B immobilized fiber Direct Hemo-Perfusion Early Use of Polymyxin B Hemoperfusion in Abdominal sepsis Decrease vasopressor requirement Better BP and low SOFA score Mortality of 32 % vs 53%

23. FLUID & ANTICOAGULANT

24. Continuous renal replacement therapy: B.E.S.T. Kidney (The Beginning and Ending Supportive Therapy for the kidney). a worldwide practice survey. 23 Countries, 54 ICUs, 1006 patients with ARF on CRRT Intensive Care Med. 2007;33(9):1563-70

25. Less clotting in Hollow Fibers membrane Kid Int 1999

26. Commercial preparation of citrate solution—Morgera S. et al. CCM 2009 Gp 1 (60Kg) Gp 2 (60- 90Kg) Gp 3 (>90Kg) Patient No 199745 Blood flow (mL/min) 80100120 Dialysate flow (mL/hr) 150020002500 Citrate flow( mL/hr) 140170205

27. A safe citrate anticoagulation protocol with variable treatment efficacy and excellent control of the acid- base status— CCM 2009 Result Median filter time of 61.5 hrs 5% had filter clot Excellent control of acid- base and electrolyte

28. Use of citrate CVVH was safer and reduced mortality Oudemans MH et al CCM 37:545-552 ( 2009)

29. Hospital mortality 41 vs 57% (p=0.03) 3-month Mortality 45 vs 62% (p=0.02) CCM 37: 545 - 552 ( 2009) Surgical Sepsis Higher SOFA Younger than 73

30. Negative Fluid Balance Predicts Survival in Patients with Septic Shock -- Alsous F. et al Chest 2000 3567 241 Net negative fluid balance within first 3 days in ICU 100% 20%

31. The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock— Murphy CB et al Chest 2009 3567 241 20ml/Kg with CVP≥8 within 4 hrs after vasopressors Neutral or negative fluid for 2 consecutive days during first 7 days Hospital mortality of 18.3%

32. The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock— Murphy CB et al Chest 2009 3567 241 20ml/Kg with CVP≥8 within 4 hrs after vasopressors Neutral or negative fluid for 2 consecutive days during first 7 days Hospital mortality of 77.1%

33. 3567 241 Survivor: Fluid balance non-positive by D4

34. Sepsis in European Intensive Care Units: Results of the SOFA study— JL Vincent et al 2006;344-353 3567 241 Cumulative fluid balance within 72 hrs after onset of sepsis was independent predictor of mortality 10% increase in mortality with each 1L increase in cumulative fluid balance

35. Comparison of Two Fluid-Management Strategies in Acute Lung Injury— NEJM 2006 3567 241 Conservative fluid mx -higher ventilator-free and ICU free days -Less cardiovascular failure -Less on dialysis Conservative group: zero balance by D4

36. Fluid Accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury— (PICARD study)Bouchard J et al KI 2009 id removal Fluid overload patient tended to be sicker patient No Fluid overload Fluid overload APACHE III score 7990 SOFA score 6.78.7 No of organ failure 2.63.2 Resp failure 55%86% On ventilator 32%65% Sepsis/Septic shock 22%39% For each weight change class, fluid overload is independent predictor of mortality

37. ? “Fluid” as the AKI biomarker

38. USE OF RCA IN QEH ICU If I find 10,000 ways something won't work, I haven't failed. I am not discouraged, because every wrong attempt discarded is often a step forward....Thomas Edison

39. Citrate dose Citric Acid mmol/L Sodium Citrate mmol/L Complementary solutionTherapyBFR mL/min Citrate dose (mmol/L blood) Country Apsner510-CVVH1003.7Austria Dorval / Leblanc515Dia: 0.9% Saline (if needed)CVVH(DF)1253.7Canada Niles-13.3-CVVH1802.0USA Gabutti-13.3Dialysate same as citrateCVVH(DF)1252.66Switzerland Tolwani-2%0.9% SalineCVVHD1502.0USA Sramek-2.2%Na=120, Bicar=22CVVHDF1003.6 - 6.3Czech Republic BunchmanACD-ADia: NormocarbCVVHD(F)1502.8USA ChadhaACD-APre: Na=140, Bicar=20CVVH50 - 1501.9 - 4.2USA Mitchell / HeemannACD-ACalcium in dialysateCVVHD755.7 - 8.5Germany GuptaACD-ACalcium in dialysateCVVHDF1501.9USA CointaultACD-ACalcium in dialysate & preCVVHDF1253.9France Kustogiannis / Gibney-3.9%Dia: Na=110, Bicar=variableCVVHDF1253.6Canada Mehta-4%Dia: Na=117, Bicar=0CVVHD(F)1003.7 - 5.9USA Hoffmann-4%Pre: 0.9% SalineCVVH1253.1USA Monchi-1000Post: Na=120, Bicar=0CVVH1504.3France Evenepoel-1035Calcium in dialysateIHD3004.3Belgium

40. Who can do that ?

41. PYNEH ICU (1995-2003)

42. AK 10 machine Non-integrated approach

43. Ci-Ca Dialysate solution

44. Solution for RCA--Gambro

45. PYNEH ICU ( 2004 …..

46. RCA CRRT—QEH Regime

48. CaCl 2 infusion

49. Summary of the regime Machine: Prismaflex Pre-dilution with Primocitrate 10/2 at rate of 2500mL/hr Blood flow at 150ml/min Both UF and blood flow rate fixed Separate infusion of NaHCO3 ( initial 50ml/hr for 2 hr then 30ml/hr ) and Calcium chloride infusion via CVC at 6 ml/hr For fluid removal= desired fluid removal + flowrate of NaHCO3 Measure Na, K, BE, ABG and ionized calcium Q4-6 hr Target ionized calcium 0.9 – 1.3 mmol/L

50. Implementation Theory Session For both nurses and doctors Practical Session By Gambro in early March Guideline as the reference Case selection Avoid those with liver dysfunction, after massive transfusion and severe metabolic acidosis with pH<7.1 Start with post-op case with mild to moderate acidosis and fluid problems Start during the daytime Gambro technical support stand-by during the initial phase Trouble shooting Contact Dr Anne Leung

51. Mechanism of action Exclusion criteria Set up of the citrate circuit Monitoring during RCA Titration of electrolyte and acid-base Citrate toxicity

52. 7 th Jul 2010

53. Demographic data

54. Reasons for admission for CRRT

55. How long the circuit last? Mean duration ( hr)31.4±14.4 Maximum duration( hr)62.3 Minimum duration ( hr)5.2 Circuit time Number of episode Percentage 24 hrs2341% >24%3359% >48%916%

56. Reasons for termination CRRT Last from 22 to 49.5 hrs -5 due to procedures -3 due to nursing manpower restrain

57. Electrolyte disturbance during Citrate CVVH Only 2 patients had citrate accumulation Only 2 patients with Total Ca/iCa >2.5 had citrate accumulation

58. Rate of correction of metabolic acidosis Median BE o f-4.5 and it took 20 hrs to reach the median BE of 0

59. Cases of citrate accumulation Circuit time(hr) Base Excess changes over time Anion Gap Total Ca/iCa Bil(start) Baseline BE 4hrs8 hrs12 hrs16 hrs20 hrs24 hrs Case 1 9.6-12-6-8-10 294.1 27 Case 2 24-3-5-3 -5-4-1.2272.87 61 Case 3 9.8-17-15-16 322.4 54 Case 4 25-14-11 -13-15 362.46 5 Onset:10 to 25 hours after commencement of therapy Lab data suggesting citrate accumulation: slow correction of metabolic acidosis or worsening of control of metabolic acidosis Confirmation: Increased anion gap; High Total Ca/iCa >2.5 and Spontaneous correction of metabolic acidosis after stopping the therapy

60. ICU and Hospital outcome ICU mortality of 23% Hospital mortality of 54.5%

61. "Genius is one per cent inspiration and ninety-nine per cent perspiration. Accordingly, a 'genius' is often merely a talented person who has done all of his or her homework." --Thomas Edison