Renal Replacement
Therapies in Critical Care
Dr. Andrew Ferguson
Consultant in Intensive Care Medicine & Anaesthesia
Craigavon Area Hospital, United Kingdom
Where are we - too many questions?
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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?
Overview
AKI classification systems 1: RIFLE
AKI classification systems 2: AKIN
Stage
Creatinine criteria
Urine output criteria
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1.5 - 2 x baseline (or rise > 26.4
mmol/L)
< 0.5 ml/kg/hour for > 6 hours
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>2 - 3 x baseline
< 0.5 ml/kg/hour for > 12 hours
3
> 3 x baseline (or > 354 mmol/L
with acute rise > 44 mmol/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
Acute Kidney Injury in the ICU
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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
Mortality by AKI Severity (1)
Clermont, G et al. Kidney International 2002; 62: 986-996
Mortality by AKI Severity (2)
Bagshaw, S et al. Am J Kidney Dis 2006; 48: 402-409
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
Therapy Dose in IRRT
p = 0.01
p = 0.001
Schiffl, H et al. NEJM 2002; 346: 305-310
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
Outcome with IRRT vs CRRT (1)
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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
Outcome with IRRT vs CRRT (2)
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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
Outcome with IRRT vs CRRT (3)
Vinsonneau, S et al. Lancet 2006; 368: 379-385
Proposed Indications for RRT
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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
Implications of the available data
AKI is not an innocent bystander in ICU
We must strive to avert acute kidney injury
We must ensure adequate dosing of RRT
Choice of RRT mode may not be critical
Septic AKI may be a different beast
The Ideal Renal Replacement Therapy
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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 (?)
Solute Clearance - Diffusion
• Small (< 500d) molecules
cleared efficiently
• Concentration gradient
critical
• Gradient achieved by
countercurrent flow
• Principal clearance mode
of dialysis techniques
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
Major Renal Replacement Techniques
Intermittent
Hybrid
Continuous
IHD
SLEDD
CVVH
Intermittent
haemodialysis
Sustained (or slow)
low efficiency daily
dialysis
Continuous veno-venous
haemofiltration
IUF
Isolated
Ultrafiltration
SLEDD-F
Sustained (or slow)
low efficiency daily
dialysis with
filtration
CVVHD
Continuous veno-venous
haemodialysis
CVVHDF
Continuous veno-venous
haemodiafiltration
SCUF
Slow continuous
ultrafiltration
Intermittent Therapies - PRO
(Relatively) Inexpensive
Flexible timing allows for mobility/transport
Rapid correction of fluid overload
Rapid removal of dialyzable drugs
Rapid correction of acidosis & electrolyte abnormality
Minimises anticoagulant exposure
Intermittent Therapies - CON
Hypotension 30-60%
Cerebral oedema
Limited therapy duration
Renal injury & ischaemia
Gut/coronary ischaemia
Intradialytic Hypotension: Risk Factors
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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 <100 mm Hg
Age 65 years +
Pressor requirement
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
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Midodrine if not on pressors
UF profiling
Colloid/crystalloid boluses
Sertraline (longer term HD)
2005 National Kidney Foundation K/DOQI GUIDELINES
Continuous Therapies - PRO
Haemodynamic stability => ??? better renal recovery
Stable and predictable volume control
Stable and predictable control of chemistry
Stable intracranial pressure
Disease modification by cytokine removal (CVVH)?
Continuous Therapies - CON
Anticoagulation requirements
Higher potential for filter clotting
Expense – fluids etc.
Immobility & Transport issues
Increased bleeding risk
High heparin exposure
SCUF
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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
CA/VVH
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Extended duration up to weeks
High flux membranes
Mainly convective clearance
UF > volume control amount
Excess UF replaced
Replacement pre- or post-filter
• Blood flow 50-200 ml/min
• UF rate 10-60 ml/min
CA/VVHD
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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
CVVHDF
• High flux membranes
• Extended period up to weeks
• Diffusive & convective solute
clearance
• Countercurrent dialysate
• UF exceeds volume control
• Replacement fluid as required
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Blood flow 50-200 ml/min
UF rate 10-60 ml/min
Dialysate flow 15-30 ml/min
Replacement 10-30 ml/min
SLED(D) & SLED(D)-F : Hybrid therapy
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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
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
Uraemia Control
Liao, Z et al. Artificial Organs 2003; 27: 802-807
Large molecule clearance
Liao, Z et al. Artificial Organs 2003; 27: 802-807
Comparison of IHD and CVVH
John, S & Eckardt K-U. Seminars in Dialysis 2006; 19: 455-464
Beyond renal replacement…
RRT as blood purification
therapy
Extracorporeal Blood Purification
Therapy (EBT)
Intermittent
TPE
Therapeutic plasma
exchange
Continuous
HVHF
UHVHF
High volume
haemofiltration
Ultra-high volume
haemofiltration
PHVHF
Pulsed high volume
haemofiltration
CPFA
Coupled plasma
filtration and
adsorption
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
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 don’t know when such a point is reached
Honore, PM & Matson, JR. Critical Care Medicine 2004; 32: 896-897
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
High Volume Hemofiltration
• May reduce unbound fraction of cytokines
• Removes
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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)
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
Herrera-Gutierrez, ME et al. ASAIO Journal 2006; 52: 670-676
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
Towards Targeted Therapy?
Non-septic ARF
Septic ARF
Daily IHD
Daily IHD?
Daily SLEDD
Daily SLEDD?
Cathecholamine
resistant septic
shock
HVHF 60-120
ml/kg/hour
for 96 hours
CVVHD/F ? dose
CVVH @
35ml/kg/hour
CVVH >
35ml/kg/hour
? 50-70
ml/kg/hour
EBT
PHVHF 60-120
ml/kg/hour
for 6-8 hours
then CVVH > 35
ml/kg/hour
Cerebral oedema
Honore, PM et al. Int J Artif Organs 2006; 29: 649-659
“You should listen to your heart, and
not the voices in your head”
Marge Simpson