Renal Replacement Renal Replacement Therapies in Critical CareTherapies in Critical Care

Dr. Andrew FergusonDr. Andrew FergusonConsultant in Intensive Care Medicine & AnaesthesiaConsultant in Intensive Care Medicine & Anaesthesia

Craigavon Area Hospital, United KingdomCraigavon Area Hospital, United Kingdom

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?

Overview

AKI classification systems 1: RIFLE

AKI classification systems 2: AKINStage Creatinine criteria Urine output criteria

1 1.5 - 2 x baseline (or rise > 26.4 mol/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 mol/L with acute rise > 44 mol/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

• 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

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 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 nono definitive evidence definitive evidence for superiority

of one therapy over another, and wide practice variation exists***

• Accepted indications for RTT vary• No definitive evidence 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 IRRTp = 0.01

p = 0.001

Schiffl, H et al. NEJM 2002; 346: 305-310

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

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”

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

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”• 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 TechniquesIntermittent ContinuousHybrid

IHDIHDIntermittent

haemodialysis

IUFIUFIsolated

Ultrafiltration

SLEDDSLEDDSustained (or slow) low efficiency daily

dialysis

SLEDD-FSLEDD-FSustained (or slow) low efficiency daily

dialysis with filtration

CVVHCVVHContinuous veno-venous

haemofiltration

CVVHDCVVHDContinuous veno-venous

haemodialysis

CVVHDFCVVHDFContinuous veno-venous

haemodiafiltration

SCUFSCUFSlow continuous

ultrafiltration

Intermittent Therapies - PRO

Intermittent Therapies - CON

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

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 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

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

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

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

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 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 ClearanceCVVH (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

2 microglobulin TAC (mg/L) 9.4 24.2 40.3

2 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 clearanceInulin represents middle molecule and 2 microglobulin large molecule.

CVVH has marked effects on middle and large molecule clearance not seen with IHD/SLEDSLED and CVVH have equivalent small molecule clearanceDaily 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 renalrenal replacement…RRT as blood purification blood purification

therapytherapy

Extracorporeal Blood Purification Therapy (EBT)

Intermittent Continuous

TPETPETherapeutic plasma

exchange

HVHFHigh volume

haemofiltration

UHVHFUHVHFUltra-high volume

haemofiltration

PHVHFPHVHFPulsed high volume

haemofiltration

CPFACPFACoupled plasma

filtration and adsorption

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

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 but blood level does not need to falllevel 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 unboundunbound fraction of cytokines• Removes

– endothelinendothelin-II (causes early pulm hypertension in sepsis)– endogenous cannabinoids endogenous 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 dose 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 outcomeHerrera-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

Cathecholamine resistant septic

shock

Daily IHD

Daily SLEDD

CVVHD/F ? dose

CVVH >> 35ml/kg/hour

? 50-70 ml/kg/hour

CVVH @ 35ml/kg/hour

Daily IHD?

Daily SLEDD?

HVHF 60-120 ml/kg/hourfor 96 hours

PHVHF 60-120 ml/kg/hour

for 6-8 hours then CVVH >> 35

ml/kg/hour

EBTEBT

Honore, PM et al. Int J Artif Organs 2006; 29: 649-659

Cerebral oedema

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

Marge Simpson