Renal Replacement Therapies in Critical Care

Rosie KalsiRegional teaching October2014

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

Renal failure of any cause

Many physiologic derangements:• Homeostasis of water and electrolytes as the

excretion of the daily metabolic load of fixedhydrogen ions is no longer possible.

• Toxic end-products of nitrogen metabolism (urea,creatinine, uric acid, among others) accumulatein blood and tissue.

• Endocrine organ dysfunction and failingproduction of erythropoietin and 1,25dihydroxycholecalciferol (calcitriol).

Evaluating ARF

Severity of ARF/AKI should not be estimatedfrom measurements of blood urea or creatininealone .

Cockcroft & Gault equation or MDRD eGFR orreciprocal creatinine plots should not be usedwhen the GFR is <30 mL/min or to determinethe need for acute RRT.

AKI classification systems 1: RIFLE

Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the second International Consensus Conference of the Acute Dialysis Initiative (ADQI) group. Crit Care 2004; 8: R204–R212.

AKI classification systems 2: AKIN

Stage Creatinine criteria Urine output criteria

11.5 - 2 x baseline (or rise > 26.4

mmol/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 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

Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.

The ‘evolving’ evidence says…

• Early initiation of RRT and utilization of RIFLE criteria. Minimal dose 35ml/kg/hr (ie for 70kg person 2450ml/hr exchange)(1)

• But results of RENAL and ATN suggest 25mg/kg/hr

• Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int2012;2(Suppl):S1-138.

(1)Effects of different doses in CVVH on outcomes of ARF – C. Ronco M.D., R. Bellomo M.D. Lancet 2000; 356:26-30

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 (pericarditis, nausea, vomiting, poor appetite, hemorrhage, lethargy, malaise, somnolence, stupor, coma, delirium, asterixis, tremor, seizures)

• Dysnatraemias > 155 or < 120 mmol/L• Hyper/(hypo)thermia• Drug overdose with dialysable drug• Refractory hypertension

Lameire, N et al. Lancet 2005; 365: 417-430

“Non-renal” indications

• Substances with higher degrees of protein binding and is sometimes substances with very long plasma half-lives.

• In general, the size of the molecule and the degree of protein binding determines the degree to which the substance can be removed (smaller, nonprotein bound substances are easiest to remove).

• Techniques such as sorbent hemoperfusion may also be used.

• These substances include drugs, poisons, contrast agents, and cytokines.

Acute Kidney Injury in the ICU

• AKI is 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

CRRT Treatment Goals

• The concept behind CRRT is to dialyse patients in a more physiologic way, slowly, over 24 hours, just like the kidney

• Tolerated well by hemodynamically unstable patients

• Maintain fluid, electrolyte, acid/base balance

• Prevent further damage to kidney tissue

• Promote healing and total renal recovery

• Allow other supportive measures; nutritional support

Determinants of Outcome

• Initiation of Therapy– Ronco Study (2000)

– Gettings Study (2000)

– ADQI Consensus Initiative - Rifle Criteria (2004)

• Dose– Ronco Study (2000)

– Kellum Meta-Analysis (2002)

– Saudan Study (2006)

– RENAL and ATN studies (2007)

– IVOIRE (2013)

RRT for Acute Renal Failure

• Newer evidence from RENAL and ATN trials suggest no difference between higher therapy CRRT dose and better outcome

• 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

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

ATN (2007)

large numbersmixed RRT20 vs 35ml/kg/hr60 days

RENAL (2007)

Large numbers

20 vs 40ml/kg/hr

CVVHDF

90 days

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

Outcome with high vs low dose CRRT (1)

Min Jun et al. Intensities of Renal Replacement Therapy in Acute Kidney Injury: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol. Jun 2010; 5(6): 956–963.

Outcome with high vs low dose CRRT (2)

Implications of the available data

ARF is not an innocent bystander in ICU

We must ensure adequate dosing of RRT

Choice of RRT mode may not be critical

Septic ARF may be a different beast

We must strive to avert acute renal failure

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 (?)

Intermittent Therapies - PROS

(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 - CONS

Hypotension 30-60%

Cerebral oedemaLimited therapy duration

Renal injury & ischaemia

Gut/coronary ischaemia

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 - PROS

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 - CONS

Anticoagulation requirements

Higher potential for filter clotting

Expense – fluids etc.

Immobility & Transport issues

Increased bleeding risk

High heparin exposure

Comparison of IHD and CVVH

John, S & Eckardt K-U. Seminars in Dialysis 2006; 19: 455-464

PrismaFlex

Basic CRRT Principles

Continuous Renal Replacement

Therapy (CRRT)

““Any extracorporeal blood purification therapy intended to substitute for impaired renal function over an extended period of time and applied for or aimed at being applied for 24 hours/day.”

Bellomo R., Ronco C., Mehta R, Nomenclature for Continuous Renal Replacement Therapies, AJKD, Vol 28, No. 5, Suppl 3, Nov 1996

Anatomy of a Haemofilter• 4 External ports

– blood and dialysis fluid

• Potting material

– support structure

• Hollow fibers

– Semi-permeable membrane

• Outer casing

Semi-permeable Membranes

• Semi-permeable membranes are the basis of all blood purification therapies.

• They allow water and some solutes to pass through the membrane, while cellular components and other solutes remain behind.

• The water and solutes that pass through the membrane are called ultrafiltrate.

• The membrane and its housing are referred to as the filter.

RRT Molecular Transport Mechanisms

• Ultrafiltration

• Diffusion

• Convection

• Adsorption

Fluid Transport

Solute Transport}

Ultrafiltration

• Ultrafiltration is the passage of fluid through a membrane under a pressure gradient.

• Pressures that drive ultrafiltration can be positive, that is the pressure pushes fluid through the filter.

• They can also be negative, there may be suction applied that pulls the fluid to the other side of the filter.

• Also osmotic pressure from non-permeable solutes.• The rate of UF will depend upon the pressures applied to

the filter and on the rate at which the blood passes through the filter.

• Higher pressures and faster flows increase the rate of ultrafiltration.

• Lower pressures and slower flows decrease the rate of ultrafiltration.

Blood Out

Blood Into waste

(to patient)

(From patient)

HIGH PRESSLOW PRESS

Fluid VolumeReduction

Ultrafiltration

Diffusion

• Diffusion is the movement of a solute across a membrane via a concentration gradient.

• For diffusion to occur, another fluid must flow on the opposite side of the semi-permeable membrane. In blood purification this fluid is called dialysate.

• Solutes always diffuse across a membrane from an area of higher concentration to an area of lower concentration until equilibration.

Haemodialysis: Diffusion

Dialysate In

Dialysate Out(to waste)

Blood Out

Blood In

(to patient)

(from patient)

HIGH CONCLOW CONC

Convection

• Convection is the movement of solutes through a

membrane by the force of water (“solvent drag”).

• Convection is able to move very large molecules if the

flow of fluid through the membrane is fast enough.

• In CRRT this property is maximized by using replacement

fluids.

• Replacement fluids are crystalloid fluids administered at a

fast rate just before or just after the blood enters the

filter.

to waste

HIGH PRESSLOW PRESS

Repl.Solution

Haemofiltration: Convection

Blood Out

Blood In

(to patient)

(from patient)

Adsorption

• Adsorption is the removal of solutes from the blood because they cling to the membrane.

• In blood purification. High levels of solute/molecule adsorption can cause filters to clog and become ineffective.

Adsorption

• Molecular adherence to the surface or interior of the membrane.

Molecular WeightsDaltons

Inflammatory Mediators (1,200-40,000)

“small”

“middle”

“large”

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 clearanceInulin represents middle molecule and b2 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

0

20

40

60

80

100

Cle

aran

ce in

%

35.000 55.00020.0005.0002.500Urea(60)

Albumin(66.000)

Myoglobin(17.000)

65.000Creatinine

(113)

Kidney

Convection

Diffusion

Small vs. Large Molecules Clearance

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

Major Renal Replacement TechniquesIntermittent ContinuousHybrid

IHDIntermittent

haemodialysis

IUFIsolated

Ultrafiltration

SLEDDSustained (or slow) low efficiency daily

dialysis

SLEDD-FSustained (or slow) low efficiency daily

dialysis with filtration

CVVHContinuous veno-venous

haemofiltration

CVVHDContinuous veno-venous

haemodialysis

CVVHDFContinuous veno-venous

haemodiafiltration

SCUFSlow continuous

ultrafiltration

CRRT Modes of Therapy

• SCUF - Slow Continuous Ultrafiltration

• CVVH - Continuous Veno-Venous Hemofiltration

• CVVHD - Continuous Veno-Venous HemoDialysis

• CVVHDF - Continuous Veno-Venous HemoDiaFiltration

Vascular Access and the Extracorporeal Circuit

• There are two options for vascular access for CRRT, venovenous and arteriovenous.

• Venovenous access is by far the most commonly used in the modern ICU.

Electrolytes & pH Balance

• Another primary goal for CRRT, specifically:– Sodium

– Potassium

– Calcium

– Glucose

– Phosphate

– Bicarbonate or lactate buffer

• Dialysate and replacement solutions are used in CRRT to attain this goal.

Dialysate Solutions

• Dialysate is a crystalloid solution containing various amounts of electrolytes, glucose, buffers and other solutes.

• Flows counter-current to blood flow between 600 –

1800mL/hour

• Remains separated by a semi-permeable membrane

• Drives diffusive transport

– dependent on concentration gradient and flow rate

• Facilitates removal of small solutes

• Contains physiologic electrolyte levels

• Components adjusted to meet patient needs

Replacement Solutions

• Infused directly into the blood at points along the blood pathway

• Replacement fluids are used to increase the amount of convective solute removal in CRRT

• Facilitates the removal of small middle and large solutes

• Contains electrolytes at physiological levels

• Important to understand that despite their name, Replacement fluids do not replace anything.

Effluent Flow Rate

Effluent = Total Fluid Volume:

• Patient Fluid Removal

• Dialysate Flow

• Replacement Flow

• Pre-Blood Pump Flow

Anticoagulation & CRRT

• Anticoagulation is needed as the clotting cascades are activated when the blood touches the non-endothelial surfaces of the tubing and filter.

• CRRT can be run without anticoagulation

SCUFSlow Continuous Ultra-Filtration

Primary therapeutic goal:

– Safe and effective management of fluid removal from the patient

• No dialysate or replacement fluid is used

• Primary indication is fluid overload without uremia or significant electrolyte imbalance.

• Removes water from the bloodstream through ultrafiltration.

• The amount of fluid in the effluent bag is the same as the amount removed from the patient.

• Fluid removal rates are typically closer to 100-300 mL/hour.

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

SCUFSlow Continuous UltraFiltration

Effluent

Pump

Infusion or

Anticoagulant

Blood Pump

PBP

Pump

Effluent

Access

Return

CVVHContinuous VV Hemofiltration

• Primary Therapeutic Goal: - Removal of small, middle and large sized solutes - Safe fluid volume management

• Blood is run through the filter with a replacement fluid added either before or after the filter.

• No dialysate is used.• Extremely effective method of solute removal and is indicated

for uremia or severe pH or electrolyte imbalance with or without fluid overload.

• Removes solutes via convection, and is particularly good at removal of large molecules.

• Ideal in severe renal impairment combined with a need to maintain or increase fluid volume status.

• The amount of fluid in the effluent bag is equal to the amount of fluid removed from the patient plus the volume of replacement fluids administered.

CA/VVH

• 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

CVVHContinuous VV Hemofiltration

Effluent

Pump

Blood

Pump

Effluent

Access

Return

Replacement

Pump 1

Replacement

Pump 2

Replacement 1Replacement 2 Infusion or

Anticoagulant

PBP

Pump

Pre-Dilution Replacement Solution

• Decreases risk of clotting

• Higher UF capabilities

• Decreases Hct

Hemofilter

Effluent

Pump

Blood

Pump

PBP

Pump

Effluent

Access

Return

Replacement

Pump

Replacement

Fluid

Infusion or

Anticoagulant

Post-Dilution Replacement Solution

• Consider lowering replacement rates (filtration %)

• Higher BFR (filtration %)

• Higher anticoagulation

• More efficient clearance (>15%)

Hemofilter

Effluent

Pump

Blood

Pump

Effluent

Access

Return

Replacement

Pump

Replacement

Fluid

Replacement

Pump

Replacement

Fluid

PBP

Pump

Infusion or

Anticoagulant

CVVHDContinuous VV HemoDialysis

• Primary therapeutic goal:– Small solute removal by diffusion– Safe fluid volume management

• Dialysate is run on the opposite side of the filter, no replacement fluid is used.

• Similar to traditional hemodialysis, and is effective for removal of small to medium sized molecules.

• Solute removal due to diffusion• Dialysate can be tailored to promote diffusion of specific

molecules. • CVVHD can be configured to allow a positive or zero fluid

balance, it is more difficult than with CVVH because the rate of solute removal is dependent upon the rate of fluid removal from the patient.

• The amount of fluid in the effluent bag is equal to the amount of fluid removed from the patient plus the dialysate.

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

CVVHDContinuous VV HemoDialysis

Hemofilter

Effluent

Pump

Effluent

Access

Return

Dialysate

Pump

Dialysate

Fluid

Blood

Pump

Infusion or

Anticoagulant

PBP

Pump

CVVHDFContinuous VV HemoDiaFiltration

• Primary therapeutic goal:– Solute removal by diffusion and convection

– Safe fluid volume management

– Efficient removal of small, middle and large molecules

• Dialysate and replacement fluid either before or after the filter.

• Combines the benefits of diffusion and convection for solute removal.

• The amount of fluid in the effluent bag equals the fluid removed from the patient plus the dialysate and the replacement fluid.

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

CVVHDFContinuous VV HemoDiaFiltration

Effluent

Pump

Effluent

Access

Return

Dialysate

Pump

Dialysate

Fluid

Blood

Pump

Replacement

Pump

Replacement

Fluid

PBP

Pump

Infusion or

Anticoagulant

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

Complications of CRRT

• Bleeding

• Hypothermia

• Electrolyte Imbalances

• Acid-Base Imbalances

• Infection

• Appropriate Dosing of Medications

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

Beyond renal replacement…RRT as blood purification

therapy

Extracorporeal Blood Purification Therapy (EBT)

Intermittent Continuous

TPETherapeutic plasma

exchange

HVHFHigh volume

haemofiltration

UHVHFUltra-high volume

haemofiltration

PHVHFPulsed high volume

haemofiltration

CPFACoupled 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 Haemofiltration

• 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)

High-volume versus standard-volume haemofiltration for septic shock patients with

acute kidney injury (IVOIRE study): a multicentre randomized controlled trial

Intensive Care Med. 2013 Sep;39(9):1535-46.

No evidence that HVHF at 70 mL/kg/h, when compared with contemporary SVHF at 35 mL/kg/h, leads to a reduction of 28-day mortality or contributes to early improvements in haemodynamic profile or organ function. HVHF, as applied in this trial, cannot be recommended for treatment of septic shock complicated by AKI

Towards Targeted Therapy

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

Non-septic ARF Septic ARFCathecholamineresistant 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

EBT

Cerebral oedema