AKI in the ICU Principles of RRT Modes of RRT Indications for RRT Optimal timing: When to start Optimal modality: What Modality and Where ?? Optimal dosing- How Much? Summary and Conclusions

1. Renal ReplacementRenal Replacement
Therapies in Critical CareTherapies in Critical Care
By Syed Hussain – Clinical
Application Specialist

2. Where are we - too many questions?
• What therapy should we use?What therapy should we use?
• When should we start it?When should we start it?
• What are we trying to achieve?What are we trying to achieve?
• How much therapy is enough?How much therapy is enough?
• When do we stop/switch?When do we stop/switch?
• Can we improve outcomes?Can we improve outcomes?
Does the literature help us?Does the literature help us?

3. Overview

4. AKI classification systems 1: RIFLE

5. AKI classification systems 2: AKINStage Creatinine criteria Urine output criteria
1
1.5 - 2 x baseline (or rise > 26.4
µmol/L)
< 0.5 ml/kg/hour for > 6 hours
2 >2 - 3 x baseline < 0.5 ml/kg/hour for > 12 hours
3
> 3 x baseline (or > 354 µmol/L
with acute rise > 44 µmol/L)
< 0.3 ml/kg/hour for 24 hours or
anuria for 12 hours
Patients receiving RRT are Stage 3 regardless of creatinine or urine output

6. Acute Kidney Injury in the ICU
• AKIis common: 3-35%* of admissions
• AKI is associated with increased mortality
• “Minor” rises in Cr associated with worse outcome
• AKI developing after ICU admission (late) is
associated with worse outcome than AKI at
admission (APACHE underestimates RODAPACHE underestimates ROD)
• AKI requiring RRT occurs in about 4-5% of ICU
admissions and is associated with worst mortality
risk **
* Brivet, FG et al. Crit Care Med 1996; 24: 192-198
** Metnitz, PG et al. Crit Care Med 2002; 30: 2051-2058

7. Mortality by AKI Severity (1)
Clermont, G et al. Kidney International 2002; 62: 986-996

8. Mortality by AKI Severity (2)
Bagshaw, S et al. Am J Kidney Dis 2006; 48: 402-409

9. RRT for Acute Renal Failure
• There is some evidenceThere is some evidence for a relationship
between higher therapy dose and better
outcome, at least up to a point
• This is true for IHD* and for CVVH**
• There is nono definitive evidencedefinitive evidence for superiority
of one therapy over another, and wide
practice variation exists***
• Accepted indications for RTT vary
• No definitive evidenceNo definitive evidence on timing of RRT
*Schiffl, H et al. NEJM 2002; 346: 305-310 ** Ronco, C et al. Lancet 2000; 355: 26-30
*** Uchino, S. Curr Opin Crit Care 2006; 12: 538-543

10. Therapy Dose in IRRTp = 0.01
p = 0.001
Schiffl, H et al. NEJM 2002; 346: 305-310

11. Therapy Dose in CVVH
25 ml/kg/hr
35 ml/kg/hr
45 ml/kg/hr
Ronco, C et al. Lancet 2000; 355: 26-30

12. Outcome with IRRT vs CRRT (1)
• Trial quality low: many
non-randomized
• Therapy dosing variable
• Illness severity variable or
details missing
• Small numbers
• Uncontrolled technique,
membrane
• Definitive trial would
require 660 patients in each
arm!
• Unvalidated instrument
for sensitivity analysis
Kellum, J et al. Intensive Care Med 2002; 28: 29-37
“there is insufficient evidence to establish whether CRRT is associated with
improved survival in critically ill patients with ARF when compared with IRRT”

13. Outcome with IRRT vs CRRT (2)
Tonelli, M et al. Am J Kidney Dis 2002; 40: 875-885
• No mortality difference between therapies
• No renal recovery difference between therapies
• Unselected patient populations
• Majority of studies were unpublished

14. Outcome with IRRT vs CRRT (3)
Vinsonneau, S et al. Lancet 2006; 368: 379-385

15. Proposed Indications for RRT
• Oliguria < 200ml/12 hours
• Anuria < 50 ml/12 hours
• Hyperkalaemia > 6.5 mmol/L
• Severe acidaemia pH < 7.0
• Uraemia > 30 mmol/L
• Uraemic complications
• Dysnatraemias > 155 or < 120 mmol/L
• Hyper/(hypo)thermia
• Drug overdose with dialysable drug
Lameire, N et al. Lancet 2005; 365: 417-430

16. Implications of the available data

17. The Ideal Renal Replacement
Therapy
• Allows control of intra/extravascular volume
• Corrects acid-base disturbances
• Corrects uraemia & effectively clears “toxins”
• Promotes renal recovery
• Improves survival
• Is free of complications
• Clears drugs effectively (?)
• Allows control of intra/extravascular volume
• Corrects acid-base disturbances
• Corrects uraemia & effectively clears “toxins”
• Promotes renal recovery
• Improves survival
• Is free of complications
• Clears drugs effectively (?)

18. Solute Clearance - Diffusion
• Small (< 500d) molecules
cleared efficiently
• Concentration gradient critical
• Gradient achieved by
countercurrent flow
• Principal clearance mode of
dialysis techniques
• Small (< 500d) molecules
cleared efficiently
• Concentration gradient critical
• Gradient achieved by
countercurrent flow
• Principal clearance mode of
dialysis techniques

19. Solute Clearance – Ultrafiltration &
Convection (Haemofiltration)
• Water movement “drags” solute
across membrane
• At high UF rates (> 1L/hour) enough
solute is dragged to produce
significant clearance
• Convective clearance dehydrates the
blood passing through the filter
• If filtration fraction > 30% there is
high risk of filter clotting*
• Also clears larger molecular weight
substances (e.g. B12, TNF, inulin)
* In post-dilution haemofiltration

20. Major Renal Replacement Techniques
Intermittent ContinuousHybrid
IHDIHD
Intermittent
haemodialysis
IUFIUF
Isolated
Ultrafiltration
SLEDDSLEDD
Sustained (or slow)
low efficiency daily
dialysis
SLEDD-SLEDD-
FF
Sustained (or slow)
low efficiency daily
dialysis with
filtration
CVVHCVVH
Continuous veno-venous
haemofiltration
CVVHDCVVHD
Continuous veno-venous
haemodialysis
CVVHDFCVVHDF
Continuous veno-venous
haemodiafiltration
SCUFSCUF
Slow continuous
ultrafiltration

21. Intermittent Therapies - PRO

22. Intermittent Therapies - CON

23. Intradialytic Hypotension: Risk Factors
• LVH with diastolic dysfunction oror LV systolic dysfunction / CHF
• Valvular heart disease
• Pericardial disease
• Poor nutritional status / hypoalbuminaemia
• Uraemic neuropathy or autonomic dysfunction
• Severe anaemia
• High volume ultrafiltration requirements
• Predialysis SBP of <100 mm Hg
• Age 65 years +
• Pressor requirement
• LVH with diastolic dysfunction oror LV systolic dysfunction / CHF
• Valvular heart disease
• Pericardial disease
• Poor nutritional status / hypoalbuminaemia
• Uraemic neuropathy or autonomic dysfunction
• Severe anaemia
• High volume ultrafiltration requirements
• Predialysis SBP of <100 mm Hg
• Age 65 years +
• Pressor requirement

24. Managing Intra-dialytic Hypotension
• Dialysate temperature modelling
• Low temperature dialysate
• Dialysate sodium profiling
• Hypertonic Na at start decreasing to 135 by end
• Prevents plasma volume decrease
• Midodrine if not on pressors
• UF profiling
• Colloid/crystalloid boluses
• Sertraline (longer term HD)
• Dialysate temperature modelling
• Low temperature dialysate
• Dialysate sodium profiling
• Hypertonic Na at start decreasing to 135 by end
• Prevents plasma volume decrease
• Midodrine if not on pressors
• UF profiling
• Colloid/crystalloid boluses
• Sertraline (longer term HD)
2005 National Kidney Foundation K/DOQI GUIDELINES

25. Continuous Therapies - PRO

26. Continuous Therapies - CON

27. SCUF
• High flux membranes
• Up to 24 hrs per day
• Objective VOLUME control
• NotNot suitable for solute clearance
• Blood flow 50-200 ml/min
• UF rate 2-8 ml/min
• High flux membranes
• Up to 24 hrs per day
• Objective VOLUME control
• NotNot suitable for solute clearance
• Blood flow 50-200 ml/min
• UF rate 2-8 ml/min

28. CA/VVH
• Extended duration up to weeks
• High flux membranes
• Mainly convectiveconvective clearance
• UF > volume control amount
• Excess UF replacedreplaced
• Replacement pre- or post-filter
• Blood flow 50-200 ml/min
• UF rate 10-60 ml/min
• Extended duration up to weeks
• High flux membranes
• Mainly convectiveconvective clearance
• UF > volume control amount
• Excess UF replacedreplaced
• Replacement pre- or post-filter
• Blood flow 50-200 ml/min
• UF rate 10-60 ml/min

29. CA/VVHD
• Mid/high flux membranes
• Extended period up to weeks
• DiffusiveDiffusive solute clearance
• Countercurrent dialysate
• UF for volume control
• Blood flow 50-200 ml/min
• UF rate 1-8 ml/min
• Dialysate flow 15-60 ml/min
• Mid/high flux membranes
• Extended period up to weeks
• DiffusiveDiffusive solute clearance
• Countercurrent dialysate
• UF for volume control
• Blood flow 50-200 ml/min
• UF rate 1-8 ml/min
• Dialysate flow 15-60 ml/min

30. CVVHDF• High flux membranes
• Extended period up to weeks
• DiffusiveDiffusive & convective& convective solute
clearance
• Countercurrent dialysate
• UF exceeds volume control
• ReplacementReplacement fluid as required
• Blood flow 50-200 ml/min
• UF rate 10-60 ml/min
• Dialysate flow 15-30 ml/min
• Replacement 10-30 ml/min
• High flux membranes
• Extended period up to weeks
• DiffusiveDiffusive & convective& convective solute
clearance
• Countercurrent dialysate
• UF exceeds volume control
• ReplacementReplacement fluid as required
• Blood flow 50-200 ml/min
• UF rate 10-60 ml/min
• Dialysate flow 15-30 ml/min
• Replacement 10-30 ml/min

31. SLED(D) & SLED(D)-F : Hybrid therapy
• Conventional dialysis equipment
• Online dialysis fluid preparation
• ExcellentExcellent small molecule detoxification
• Cardiovascular stability as good as CRRT
• Reduced anticoagulation requirement
• 11 hrs SLED comparable to 23 hrs CVVH
• Decreased costs compared to CRRT
• Phosphate supplementation requiredFliser, T & Kielstein JT. Nature Clin Practice Neph 2006; 2: 32-39
Berbece, AN & Richardson, RMA. Kidney International 2006; 70: 963-968

32. Kinetic Modelling of Solute Clearance
CVVH (predilution) Daily IHD SLED
Urea TAC (mg/ml) 40.3 64.6 43.4
Urea EKR (ml/min) 33.8 21.1 31.3
Inulin TAC (mg/L) 25.4 55.5 99.4
Inulin EKR (ml/min) 11.8 5.4 3.0
β2 microglobulin TAC (mg/L) 9.4 24.2 40.3
β2 microglobulin EKR (ml/min) 18.2 7.0 4.2
TAC = time-averaged concentration (from area under concentration-time curve)
EKR = equivalent renal clearanceEKR = equivalent renal clearance
Inulin represents middle molecule and β2 microglobulin large molecule.
CVVH has marked effects on middle and large molecule clearance not seen with IHD/SLED
SLED and CVVH have equivalent small molecule clearance
Daily IHD has acceptable small molecule clearance
Liao, Z et al. Artificial Organs 2003; 27: 802-807

33. Uraemia Control
Liao, Z et al. Artificial Organs 2003; 27: 802-807

34. Large molecule clearance
Liao, Z et al. Artificial Organs 2003; 27: 802-807

35. Comparison of IHD and CVVH
John, S & Eckardt K-U. Seminars in Dialysis 2006; 19: 455-464

36. Beyond renalrenal replacement…
RRT as blood purificationblood purification
therapytherapy
Beyond renalrenal replacement…
RRT as blood purificationblood purification
therapytherapy

37. Extracorporeal Blood Purification Therapy
(EBT)
Intermittent Continuous
TPETPE
Therapeutic plasma
exchange
HVHF
High volume
haemofiltration
UHVHFUHVHF
Ultra-high volume
haemofiltration
PHVHFPHVHF
Pulsed high volume
haemofiltration
CPFACPFA
Coupled plasma
filtration and adsorption

38. Peak Concentration Hypothesis• Removes cytokines from blood compartment during
pro-inflammatory phase of sepsis
• Assumes blood cytokine level needs to fallAssumes blood cytokine level needs to fall
• Assumes reduced “free” cytokine levels leads to
decreased tissue effects and organ failure
• Favours therapy such as HVHF, UHVHF, CPFA
• But tissue/interstitial cytokine levels unknownunknown
• Removes cytokines from blood compartment during
pro-inflammatory phase of sepsis
• Assumes blood cytokine level needs to fallAssumes blood cytokine level needs to fall
• Assumes reduced “free” cytokine levels leads to
decreased tissue effects and organ failure
• Favours therapy such as HVHF, UHVHF, CPFA
• But tissue/interstitial cytokine levels unknownunknown
Ronco, C & Bellomo, R. Artificial Organs 2003; 27: 792-801

39. Threshold Immunomodulation
Hypothesis• More dynamic view of cytokine system
• Mediators and pro-mediators removed from blood to alter tissue
cytokine levels but blood level does not need to fallbut blood level does not need to fall
• ? pro-inflammatory processes halted when cytokines fall to
“threshold” level
• We don’t know when such a point is reached
• More dynamic view of cytokine system
• Mediators and pro-mediators removed from blood to alter tissue
cytokine levels but blood level does not need to fallbut blood level does not need to fall
• ? pro-inflammatory processes halted when cytokines fall to
“threshold” level
• We don’t know when such a point is reached
Honore, PM & Matson, JR. Critical Care Medicine 2004; 32: 896-897

40. Mediator Delivery Hypothesis• HVHF with high incoming fluid volumes (3-6 L/hour) increases
lymph flow 20-40 times
• “Drag” of mediators and cytokines with lymph
• Pulls cytokines from tissues to blood for removal and tissue
levels fall
• High fluid exchange is key
• HVHF with high incoming fluid volumes (3-6 L/hour) increases
lymph flow 20-40 times
• “Drag” of mediators and cytokines with lymph
• Pulls cytokines from tissues to blood for removal and tissue
levels fall
• High fluid exchange is key
Di Carlo, JV & Alexander, SR. Int J Artif Organs 2005; 28: 777-786

41. High Volume Hemofiltration
• May reduce unboundunbound fraction of cytokines
• Removes
– endothelinendothelin-II (causes early pulm hypertension in sepsis)
– endogenous cannabinoidsendogenous cannabinoids (vasoplegic in sepsis)
– myodepressant factormyodepressant factor
– PAI-IPAI-I so may eventually reduce DIC
• Reduces post-sepsis immunoparalysis (CARS)
• Reduces inflammatory cell apoptosis
• Human trials probably using too low a dosetoo low a dose (40
ml/kg/hour vs 100+ ml/kg/hour in animals)
• May reduce unboundunbound fraction of cytokines
• Removes
– endothelinendothelin-II (causes early pulm hypertension in sepsis)
– endogenous cannabinoidsendogenous cannabinoids (vasoplegic in sepsis)
– myodepressant factormyodepressant factor
– PAI-IPAI-I so may eventually reduce DIC
• Reduces post-sepsis immunoparalysis (CARS)
• Reduces inflammatory cell apoptosis
• Human trials probably using too low a dosetoo low a dose (40
ml/kg/hour vs 100+ ml/kg/hour in animals)

42. CRRT, Haemodynamics & Outcome
• 114 unstable (pressors or MAP < 60) patients
• 55 stable (no pressors or MAP > 60) patients
• Responders = 20% fall in NA requirement or 20%
rise in MAP (without change in NA)
• Overall responder mortality 30%, non-responder
mortality 74.7% (p < 0.001)
• In unstable patients responder mortality 30% vs
non-responder mortality 87% (p < 0.001)
• Haemodynamic improvement after 24 hours CRRT
is a strong predictor of outcome
• 114 unstable (pressors or MAP < 60) patients
• 55 stable (no pressors or MAP > 60) patients
• Responders = 20% fall in NA requirement or 20%
rise in MAP (without change in NA)
• Overall responder mortality 30%, non-responder
mortality 74.7% (p < 0.001)
• In unstable patients responder mortality 30% vs
non-responder mortality 87% (p < 0.001)
• Haemodynamic improvement after 24 hours CRRT
is a strong predictor of outcome
Herrera-Gutierrez, ME et al. ASAIO Journal 2006; 52: 670-676

43. Common Antibiotics and CRRT
These effects will be even more dramatic with HVHF
Honore, PM et al. Int J Artif Organs 2006; 29: 649-659

44. Towards Targeted Therapy?
Non-septic ARFNon-septic ARF Septic ARFSeptic ARF
Cathecholamine
resistant septic
shock
Cathecholamine
resistant septic
shock
Daily IHDDaily IHD
Daily SLEDDDaily SLEDD
CVVHD/F ? doseCVVHD/F ? dose
CVVH >>
35ml/kg/hour
? 50-70
ml/kg/hour
CVVH >>
35ml/kg/hour
? 50-70
ml/kg/hour
CVVH @
35ml/kg/hour
CVVH @
35ml/kg/hour
Daily IHD?Daily IHD?
Daily SLEDD?Daily SLEDD?
HVHF 60-120
ml/kg/hour
for 96 hours
HVHF 60-120
ml/kg/hour
for 96 hours
PHVHF 60-120
ml/kg/hour
for 6-8 hours
then CVVH >> 35
ml/kg/hour
PHVHF 60-120
ml/kg/hour
for 6-8 hours
then CVVH >> 35
ml/kg/hour
EBEB
TT
EBEB
TT
Honore, PM et al. Int J Artif Organs 2006; 29: 649-659
Cerebral oedemaCerebral oedema

45. “You should listen to your heart, and
not the voices in your head”