Renal Replacement Therapies in Critical Care

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Renal Replacement Therapies in Critical Care

• Dr. Andrew Ferguson
• Consultant in Intensive Care Medicine
  Anaesthesia
• Craigavon Area Hospital, United Kingdom

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Where are we - too many questions?

• What therapy should we use?
• When should we start it?
• What are we trying to achieve?
• How much therapy is enough?
• When do we stop/switch?
• Can we improve outcomes?

Does the literature help us?
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Overview

• Impact of Acute Kidney Injury in the ICU
• Dose-outcome relationships IRRT v CRRT
• Mechanisms of solute clearance
• Therapies in brief
• IRRT, CRRT Hybrid therapies e.g. SLEDD
• Solute clearance with IRRT v CRRT v SLEDD
• Extracorporeal blood purification in sepsis
• Putting it together making a rational choice

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AKI classification systems 1 RIFLE
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AKI classification systems 2 AKIN
Stage Creatinine criteria Urine output criteria
1 1.5 - 2 x baseline (or rise gt 26.4 mmol/L) lt 0.5 ml/kg/hour for gt 6 hours
2 gt2 - 3 x baseline lt 0.5 ml/kg/hour for gt 12 hours
3 gt 3 x baseline (or gt 354 mmol/L with acute rise gt 44 mmol/L) lt 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
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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 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
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Mortality by AKI Severity (1)
Clermont, G et al. Kidney International 2002 62
986-996
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Mortality by AKI Severity (2)
Bagshaw, S et al. Am J Kidney Dis 2006 48
402-409
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RRT for Acute Renal Failure

• There 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 no definitive evidence for superiority
  of one therapy over another, and wide practice
  variation exists
• Accepted indications for RTT vary
• No 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
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Therapy Dose in IRRT
p 0.01
p 0.001
Schiffl, H et al. NEJM 2002 346 305-310
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Therapy Dose in CVVH
45 ml/kg/hr
35 ml/kg/hr
25 ml/kg/hr
Ronco, C et al. Lancet 2000 355 26-30
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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

there is insufficient evidence to establish
whether CRRT is associated with improved survival
in critically ill patients with ARF when compared
with IRRT
Kellum, J et al. Intensive Care Med 2002 28
29-37
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Outcome with IRRT vs CRRT (2)

• No mortality difference between therapies
• No renal recovery difference between therapies
• Unselected patient populations
• Majority of studies were unpublished

Tonelli, M et al. Am J Kidney Dis 2002 40
875-885
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Outcome with IRRT vs CRRT (3)
Vinsonneau, S et al. Lancet 2006 368 379-385
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Proposed Indications for RRT

• Oliguria lt 200ml/12 hours
• Anuria lt 50 ml/12 hours
• Hyperkalaemia gt 6.5 mmol/L
• Severe acidaemia pH lt 7.0
• Uraemia gt 30 mmol/L
• Uraemic complications
• Dysnatraemias gt 155 or lt 120 mmol/L
• Hyper/(hypo)thermia
• Drug overdose with dialysable drug

Lameire, N et al. Lancet 2005 365 417-430
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Implications of the available data
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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 (?)

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Solute Clearance - Diffusion

• Small (lt 500d) molecules cleared efficiently
• Concentration gradient critical
• Gradient achieved by countercurrent flow
• Principal clearance mode of dialysis techniques

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Solute Clearance Ultrafiltration Convection
(Haemofiltration)

• Water movement drags solute across membrane
• At high UF rates (gt 1L/hour) enough solute is
  dragged to produce significant clearance
• Convective clearance dehydrates the blood passing
  through the filter
• If filtration fraction gt 30 there is high risk
  of filter clotting
• Also clears larger molecular weight substances
  (e.g. B12, TNF, inulin)

In post-dilution haemofiltration
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Major Renal Replacement Techniques
Intermittent
Continuous
Hybrid
IHD Intermittent haemodialysis
SLEDD Sustained (or slow) low efficiency daily
dialysis
CVVH Continuous veno-venous haemofiltration
IUF Isolated Ultrafiltration
CVVHD Continuous veno-venous haemodialysis
SLEDD-F Sustained (or slow) low efficiency daily
dialysis with filtration
CVVHDF Continuous veno-venous haemodiafiltration
SCUF Slow continuous ultrafiltration
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Intermittent Therapies - PRO
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Intermittent Therapies - CON
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Intradialytic Hypotension Risk Factors

• LVH with diastolic dysfunction or 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 lt100 mm Hg
• Age 65 years
• Pressor requirement

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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)

2005 National Kidney Foundation K/DOQI GUIDELINES
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Continuous Therapies - PRO
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Continuous Therapies - CON
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SCUF

• High flux membranes
• Up to 24 hrs per day
• Objective VOLUME control
• Not suitable for solute clearance
• Blood flow 50-200 ml/min
• UF rate 2-8 ml/min

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CA/VVH

• Extended duration up to weeks
• High flux membranes
• Mainly convective clearance
• UF gt volume control amount
• Excess UF replaced
• Replacement pre- or post-filter
• Blood flow 50-200 ml/min
• UF rate 10-60 ml/min

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CA/VVHD

• Mid/high flux membranes
• Extended period up to weeks
• Diffusive 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

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CVVHDF

• High flux membranes
• Extended period up to weeks
• Diffusive convective solute
• clearance
• Countercurrent dialysate
• UF exceeds volume control
• Replacement 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

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SLED(D) SLED(D)-F Hybrid therapy

• Conventional dialysis equipment
• Online dialysis fluid preparation
• Excellent 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 required

Fliser, T Kielstein JT. Nature Clin Practice
Neph 2006 2 32-39
Berbece, AN Richardson, RMA. Kidney
International 2006 70 963-968
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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
b2 microglobulin TAC (mg/L) 9.4 24.2 40.3
b2 microglobulin EKR (ml/min) 18.2 7.0 4.2
TAC time-averaged concentration (from area
under concentration-time curve) EKR equivalent
renal clearance Inulin represents middle molecule
and b2 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
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Uraemia Control
Liao, Z et al. Artificial Organs 2003 27 802-807
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Large molecule clearance
Liao, Z et al. Artificial Organs 2003 27 802-807
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Comparison of IHD and CVVH
John, S Eckardt K-U. Seminars in Dialysis 2006
19 455-464
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Beyond renal replacementRRT as blood
purification therapy
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Extracorporeal Blood Purification Therapy (EBT)
Intermittent
Continuous
TPE Therapeutic plasma exchange
HVHF High volume haemofiltration
UHVHF Ultra-high volume haemofiltration
PHVHF Pulsed high volume haemofiltration
CPFA Coupled plasma filtration and adsorption
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Peak Concentration Hypothesis

• Removes cytokines from blood compartment during
  pro-inflammatory phase of sepsis
• Assumes 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 unknown

Ronco, C Bellomo, R. Artificial Organs 2003
27 792-801
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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 fall
• ? pro-inflammatory processes halted when
  cytokines fall to threshold level
• We dont know when such a point is reached

Honore, PM Matson, JR. Critical Care Medicine
2004 32 896-897
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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

Di Carlo, JV Alexander, SR. Int J Artif Organs
2005 28 777-786
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High Volume Hemofiltration

• May reduce unbound fraction of cytokines
• Removes
• endothelin-I (causes early pulm hypertension in
  sepsis)
• endogenous cannabinoids (vasoplegic in sepsis)
• myodepressant factor
• PAI-I so may eventually reduce DIC
• Reduces post-sepsis immunoparalysis (CARS)
• Reduces inflammatory cell apoptosis
• Human trials probably using too low a dose (40
  ml/kg/hour vs 100 ml/kg/hour in animals)

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CRRT, Haemodynamics Outcome

• 114 unstable (pressors or MAP lt 60) patients
• 55 stable (no pressors or MAP gt 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 lt 0.001)
• In unstable patients responder mortality 30 vs
  non-responder mortality 87 (p lt 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
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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
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Towards Targeted Therapy?
Non-septic ARF
Septic ARF
Cathecholamine resistant septic shock
Daily IHD
Daily IHD?
HVHF 60-120 ml/kg/hour for 96 hours
Daily SLEDD
Daily SLEDD?
CVVHD/F ? dose
EBT
PHVHF 60-120 ml/kg/hour for 6-8 hours then CVVH gt
35 ml/kg/hour
CVVH gt 35ml/kg/hour ? 50-70 ml/kg/hour
CVVH _at_ 35ml/kg/hour
Cerebral oedema
Honore, PM et al. Int J Artif Organs 2006 29
649-659
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You should listen to your heart, and not the
voices in your head
Marge Simpson