Role of CRRT in Sepsis

1. Role of CRRT in Sepsis Dr Apoorva Jain Agra

2. SEPSIS: BACKGROUND • Severe Sepsis and Septic Shock are the primary causes of Multiple Organ Dysfunction Syndrome (MODS) [of which Acute Renal Failure-is part of] • One of the most common cause of mortality in the ICU setting

3. SEPSIS: BACKGROUND • Variety of Water soluble mediators with Pro & Anti- Inflammatory Activities play a strategic role in Septic Syndrome including (but not limited to): TNF, IL-6,IL-8 and IL-10, Kinins, Thrombins, heat shock proteins

4. SEPSIS: BACKGROUND • Stimulus –Receptor coupling sets off the signal transduction cascade resulting in exacerbated generation of; Platelet activating factor, cytokines, leukotrienes, Arachidonic acid derivatives etc.) and activation of the complement cascade and coagulation pathways.

5. SEPSIS: Pathophysiology • Dysfunctional homeostatic balance results in increased biological activity of sepsis associated mediators and loss of control over these by specific inhibitors-cell hypo-responsiveness • This excessive anti-inflammatory counterpart to SIRS has been coined “CARS- Compensated Anti-inflammatory Response Syndrome” • Bone et al. Chest 112:235-43, 1997

6. Goals of Treatment are hemodynamic and relate to outcome • Early Goal-Directed Therapy in the treatment of Severe Sepsis and Septic Shock. Rivers E, N Engl J Med 2001;345:1368-1377. • RCT 130 adults randomized to aggressive care In First few hours • Results: In Hospital Mortality 30.5% vs 46.5% in Controls • Early goal directed therapy improves shock outcome(Han Y. 2000 Pediat Res 47:108a. Ceneviva G. Pediatrics 1998;102:e19.)

7. OUTLINE • 1 CRRT for Sepsis - associated AKI • 2. CRRT as Immunomodulatory therapy

8. CRRT for Sepsis-associated AKI

9. CRRT for Sepsis-associated AKI • Role & Indications • Dosing • Alternative therapies

10. CRRT for Sepsis-associated AKI • Dialysis allows: – Correction of acid-base status – Correction of electrolyte abnormalities – Clearance of toxins – Control of fluid balance

11. CRRT for Sepsis-associated AKI • Advantages of using CRRT • Suitable for use in hemodynamically unstable patients • Precise, adaptable, volume control • Very effective control of uremia, PO4, K • Rapid control of metabolic acidosis • Improved nutritional support (full protein diet) • Available 24 hours a day • May have an effect as an adjuvant therapy in sepsis

12. CRRT for Sepsis-associated AKI • Disadvantages of using CRRT • Expense – more than IHD, due to fluids • Continuous anticoagulation may be required • Risk of line disconnection • Hypothermia • Severe depletion of electrolytes (K and PO4), nutrients

13. CRRT for Sepsis-associated AKI • Dosing of dialysis in AKI • 425 patients randomized • Post-dilution CVVH mode • only 12% had sepsis Ronco et al, Lancet 2000; 355: 26

14. CRRT for Sepsis-associated AKI • Modes of CRRT

15. CRRT for Sepsis-associated AKI • Modes of CRRT

16. CRRT for Sepsis-associated AKI • Modes of CRRT

17. CRRT for Sepsis-associated AKI • Dosing of dialysis in AKI • 206 patients randomized • 60% sepsis • CVVH versus CVVH + added D Saudan et al, Kidney Int 2006; 70:1312

18. CRRT for Sepsis-associated AKI • Negative dosing studies • 200 patients • CVVHDF 20 v 35 ml/kg/hr • No difference Tolwani et al J Am Soc Nephrol 2008; 19:1233 • 1124 patients, multicentred (NIH ATN study) • Intensified (35ml/kg, 6x/wk IHD) versus • Standard (20ml/kg, 3x/wk IHD) • No difference Palevsky et al N Engl J Med 2008; 359:7.

19. CRRT for Sepsis-associated AKI • Reasons for differences • Delayed initiation of RRT in Tolwani and ATN studies: 6 to 8 days • No clear separation of dose delivered when combining CRRT and IHD dosing (ATN study) • Majority (65%) enrolled after initial dialysis • Dosing was not actually achieved in the ATN study

20. CRRT for Sepsis-associated AKI • RENAL study • 1508 patients, approx 50% sepsis • 48-54 hr in ICU before randomisation • Prescribed dose achieved: 84 – 88% • CVVHDF, postdilution (1:1 dialysate:filtration) • Low intensity: 25 ml/kg/hr • High intensity: 40 ml/kg/hr • No difference in mortality N Engl J Med Oct 22nd, 2009.

21. CRRT for Sepsis-associated AKI • Alternative therapies • IHD • mortality higher in many CRRT studies • 5 RCT’s: no difference in mortality • 7 meta-analyses: no differences

22. CRRT for Sepsis-associated AKI • Alternative therapies Kellum et al. Intensive Care Med 2002; 28:29

23. CRRT for Sepsis-associated AKI • Alternative therapies Bagshaw et al, Crit Care Med 2008; 36:610

24. CRRT for Sepsis-associated AKI • Alternative therapies • IHD • mortality higher in many CRRT studies • 5 RCT’s: no difference in mortality • 7 meta-analyses: no differences • SLED: sustained low efficiency dialysis • safe, effective, cheaper than CRRT • limited comparative data Berbece & Richardson, Kidney Int 2006; 70:963

25. Epidemiology of AKI • BEST Kidney study: • 23 countries, over 30,000 patients, 2001 • 1738 developed acute renal failure • Dialysis • CRRT 80% --- • IHD 17% • SLED/PD 3% • Hospital mortality 60% CVVH 53% CVVHD 13% CVVHDF 34% Uchino et al, JAMA 2005; 294:813 Uchino et al, Intensive Care Med, 2007 33:1563

26. CRRT as Immunomodulatory therapy

27. CRRT as Immunomodulatory therapy • Background & rationale • Studies supporting this hypothesis • Clinical studies • Variations on standard CRRT

28. CRRT as Immunomodulatory therapy • Rationale – Removal of “Bad Humours”

29. CRRT as Immunomodulatory therapy • Rationale – Removal of “Bad Humours”

30. CRRT as Immunomodulatory therapy

31. CRRT as Immunomodulatory therapy Ronco et al. Artiforgans 2003; 27:792

32. CRRT as Immunomodulatory therapy Ronco et al. Artiforgans 2003; 27:792

33. CRRT as Immunomodulatory therapy • Mechanism of cytokine removal • Convective • High flux membranes cut-off 30 – 40 kD • Should remove many cytokines (17 – 30 kD) • Is removal rate significant given high production? • Adsorption • Filter dependent: higher with polyacrylonitrile (AN69) than with polysulfone membranes

34. CRRT as Immunomodulatory therapy • Convective therapy can: • Remove cytokines • In some, but not all studies • Adsorption important • Frequent filter changes • Plasma levels unchanged • Improve hemodynamics • In animal studies • In open clinical studies Heering et al Intensive Care Med. 1997;23:288

35. CRRT as Immunomodulatory therapy • 15 pts, sepsis, AKI • first 24 hr hemofiltration • AN69 filter De Vriese et al. J Am Soc Nephrol 1999;10:846-853

36. CRRT as Immunomodulatory therapy Morgera et al. Crit Care Med 2006; 34:2099

37. CRRT as Immunomodulatory therapy Morgera et al. Crit Care Med 2006; 34:2099

38. CRRT as Immunomodulatory therapy • Outcome studies

39. CRRT as Immunomodulatory therapy • Ronco study Ronco et al, Lancet 2000; 355: 26

40. CRRT as Immunomodulatory therapy • RENAL study

41. CRRT as Immunomodulatory therapy • CRRT without AKI • Sepsis, no renal failure • CVVH, 2L/hr, AN69 filter • No significant reduction in cytokines • No clinical benefit Cole et al, Crit Care Med 2002; 30:100

42. CRRT as Immunomodulatory therapy • Outcome studies • 80 patients, early CVVH 25ml/kg/hr or control • High flux polysulfone filter Payen et al Crit Care Med 2009; 37:803

43. CRRT as Immunomodulatory therapy • Outcome studies • 80 patients, early CVVH 25ml/kg/hr or control • High flux polysulfone filter • No benefit, deleterious? Payen et al Crit Care Med 2009; 37:803

44. CRRT as Immunomodulatory therapy • Outcome studies • 80 patients, early CVVH 25ml/kg/hr or control • High flux polysulfone filter • No benefit, deleterious? Payen et al Crit Care Med 2009; 37:803

45. CRRT as Immunomodulatory therapy • Outcome studies • 80 patients, early CVVH 25ml/kg/hr or control • High flux polysulfone filter • No benefit, deleterious? • Can’t expect a mortality benefit with the wrong intervention in the wrong dose Payen et al Crit Care Med 2009; 37:803

46. Variations on standard CRRT • High volume hemofiltration • High cutoffhemofiltration • Plasmafiltration • Cascade filtration • Coupled plasma filtration adsorption

48. Thank You!