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:
RCT 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 Pediat Res 47:108a. Ceneviva G. Pediatrics ;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)
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, :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. Artif organs 2003; 27:792

32. CRRT as Immunomodulatory therapy
Ronco et al. Artif organs 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:

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 cutoff hemofiltration
Plasmafiltration
Cascade filtration
Coupled plasma filtration adsorption

48. Thank You!