Renal Replacement

Therapies in Critical Care

Dr. Andrew Ferguson

Consultant in Anaesthesia & Intensive Care Medicine
Craigavon Area Hospital
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?

Overview
AKI classification systems 1: RIFLE
AKI classification systems 2: AKIN
Stage Creatinine criteria Urine output criteria

1.5 - 2 x baseline (or rise > 26.4

1 < 0.5 ml/kg/hour for > 6 hours
mmol/L)

2 >2 - 3 x baseline < 0.5 ml/kg/hour for > 12 hours

> 3 x baseline (or > 354 mmol/L < 0.3 ml/kg/hour for 24 hours or
3
with acute rise > 44 mmol/L) anuria for 12 hours

Patients receiving RRT are Stage 3 regardless of creatinine or urine output

 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)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)
• 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)

• 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
• 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
The Ideal Renal Replacement Therapy

• Allows control of intra/extravascular volume

• Corrects acid-base disturbances
• Corrects uraemia & effectively clears “toxins”
“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 Sustained (or slow) Continuous veno-venous
haemodialysis low efficiency daily haemofiltration
dialysis

IUF SLEDD-F CVVHD

Isolated Continuous veno-venous
Ultrafiltration Sustained (or slow) haemodialysis
low efficiency daily

CVVHDF
dialysis with
filtration
Continuous veno-venous
haemodiafiltration

SCUF
Slow continuous
ultrafiltration
Intermittent Therapies - PRO
Intermittent Therapies - CON
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 <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
• Midodrine if not on pressors
• UF profiling
• Colloid/crystalloid boluses
• Sertraline (longer term HD)

2005 National Kidney Foundation K/DOQI GUIDELINES

Continuous Therapies - PRO
Continuous Therapies - CON
SCUF

•• High
High flux
flux membranes
membranes
•• Up
Up to
to 24
24 hrs
hrs per
per day
day
•• Objective
Objective VOLUME
VOLUME control
control
•• Not
Not suitable
suitable for
for solute
solute clearance
clearance

•• Blood
Blood flow
flow 50-200
50-200 ml/min
ml/min
•• UF
UF rate
rate 2-8
2-8 ml/min
ml/min
CA/VVH

•• Extended
Extended duration
duration upup to
to weeks
weeks
•• High
High flux
flux membranes
membranes
•• Mainly
Mainly convective
convective clearance
clearance
•• UF
UF >> volume
volume control
control amount
amount
•• Excess
Excess UF
UF replaced
replaced
•• Replacement
Replacement pre-pre- or
or post-filter
post-filter

•• Blood
Blood flow
flow 50-200
50-200 ml/min
ml/min
•• UF
UF rate
rate 10-60
10-60 ml/min
ml/min
CA/VVHD

•• Mid/high
Mid/high flux
flux membranes
membranes
•• Extended
Extended period
period up
up to
to weeks
weeks
•• Diffusive
Diffusive solute
solute clearance
clearance
•• Countercurrent
Countercurrent dialysate
dialysate
•• UF
UF for
for volume
volume control
control

•• Blood
Blood flow
flow 50-200
50-200 ml/min
ml/min
•• UF
UF rate
rate 1-8
1-8 ml/min
ml/min
•• Dialysate
Dialysate flow
flow 15-60
15-60 ml/min
ml/min
CVVHDF
•• High
High flux
flux membranes
membranes
•• Extended
Extended period
period up
up to
to weeks
weeks
•• Diffusive
Diffusive && convective
convective solute
solute
clearance
clearance
•• Countercurrent
Countercurrent dialysate
dialysate
•• UF
UF exceeds
exceeds volume
volume control
control
•• Replacement
Replacement fluid
fluid as
as required
required

•• Blood
Blood flow
flow 50-200
50-200 ml/min
ml/min
•• UF
UF rate
rate 10-60
10-60 ml/min
ml/min
•• Dialysate
Dialysate flow
flow 15-30
15-30 ml/min
ml/min
•• Replacement
Replacement 10-30
10-30 ml/min
ml/min
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
 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 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

 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 Continuous

TPE HVHF UHVHF

Therapeutic plasma
High volume Ultra-high volume
exchange
haemofiltration haemofiltration

PHVHF CPFA
Coupled plasma
Pulsed high volume
filtration and
haemofiltration
adsorption
 Peak Concentration Hypothesis
•• Removes
Removes cytokines
cytokines from
from blood
blood compartment
compartment
during
during pro-inflammatory phase of sepsis
sepsis
•• Assumes
Assumes blood
blood cytokine
cytokine level
level needs
needs to
to fall
fall
•• Assumes
Assumes reduced
reduced “free”
“free” cytokine
cytokine levels leads to
decreased
decreased tissue
tissue effects
effects and
and organ failure
•• Favours
Favours therapy
therapy such
such asas HVHF,
HVHF, UHVHF,
UHVHF, CPFA
•• But
But tissue/interstitial
tissue/interstitial cytokine
cytokine levels
levels unknown
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
but blood
blood
level
level does
does not
not need
need to
to fall
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
May reduce
reduce unbound
unbound fraction
fraction of
of cytokines
cytokines
•• Removes
Removes
–– endothelin-
endothelin-
endothelin II (causes
endothelin (causes early
early pulm
pulm hypertension
hypertension in in sepsis)
sepsis)
–– endogenous
endogenous cannabinoids
cannabinoids (vasoplegic
(vasoplegic in
in sepsis)
sepsis)
–– myodepressant
myodepressant factor
factor
–– PAI-I
PAI-I so
so may
may eventually
eventually reduce
reduce DIC
DIC
•• Reduces
Reduces post-sepsis
post-sepsis immunoparalysis
immunoparalysis (CARS)
(CARS)
•• Reduces
Reduces inflammatory
inflammatory cell
cell apoptosis
apoptosis
•• Human
Human trials
trials probably
probably using
using too
too low
low aa dose
dose (40
(40
ml/kg/hour
ml/kg/hour vs
vs 100+
100+ ml/kg/hour
ml/kg/hour inin animals)
animals)
CRRT, Haemodynamics & Outcome
•• 114
114 unstable
unstable (pressors
(pressors oror MAP
MAP << 60)
60) patients
•• 55
55 stable
stable (no
(no pressors
pressors oror MAP
MAP >> 60)
60) patients
patients
•• Responders
Responders == 20% 20% fall in NA requirement
requirement or 20%
rise
rise inin MAP (without
(without change
change in
in NA)
NA)
•• Overall
Overall responder
responder mortality
mortality 30%,
30%, non-responder
non-responder
mortality
mortality 74.7%
74.7% (p
(p << 0.001)
0.001)
•• In
In unstable
unstable patients
patients responder mortality 30% vs
non-responder
non-responder mortality 87% (p < 0.001) 0.001)
•• Haemodynamic
Haemodynamic improvement
improvement after
after 24 hours
hours CRRT
is
is aa strong
strong predictor
predictor ofof outcome
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
Cathecholamine
Cathecholamine
Non-septic ARF
Non-septic ARF Septic ARF
Septic ARF resistant septic
resistant septic
shock
shock

Daily
DailyIHD
IHD Daily
DailyIHD?
IHD? HVHF
HVHF 60-120
60-120
ml/kg/hour
ml/kg/hour
Daily
DailySLEDD
SLEDD Daily
DailySLEDD?
SLEDD? for
for 96
96 hours
hours
CVVHD/F
CVVHD/F??dose
dose EBT
EBT
PHVHF
PHVHF 60-120
60-120
CVVH
CVVH@@ CVVH>>
CVVH ml/kg/hour
ml/kg/hour
35ml/kg/hour
35ml/kg/hour 35ml/kg/hour for
for 6-8
6-8 hours
hours
35ml/kg/hour
??50-70
50-70 then CVVH >> 35
then CVVH 35
ml/kg/hour
ml/kg/hour ml/kg/hour
ml/kg/hour
Cerebral oedema
Cerebral oedema

Honore, PM et al. Int J Artif Organs 206; 29: 649-659

“You should listen to your heart, and
not the voices in your head”
Marge Simpson
Questions?