RENAL REPLACEMENT THERAPIES IN CRITICAL CARE

DR YOGESH RATHODCHRISTIAN MEDICAL COLLEGE, VELLORE.

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?

RENAL FAILURE OF ANY CAUSE

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

daily metabolic load of fixed hydrogen ions is no longer possible.

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

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

EVALUATING ARF

• Severity of ARF/AKI should not be estimated from measurements of blood urea or creatinine alone.

• Cockcroft & Gault equation or MDRD eGFR or reciprocal creatinine plots should not be used when the GFR is <30 mL/min or to determine the 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

1 1.5 - 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.

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

• TO GET RID OF Substances with higher degrees of protein binding and sometimes for 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 (i.e. smaller, nonprotein bound substances are easiest to remove).

• RRT can be used as sorbent hemoperfusion for substances that 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• 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

Clermont, G et al. Kidney International 2002; 62: 986-996

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) InexpensiveFlexible timing allows for mobility/transportRapid correction of fluid overloadRapid removal of dialyzable drugsRapid correction of acidosis & electrolyte abnormalityMinimises anticoagulant exposure

Intermittent Therapies - CONSHypotension 30-60%Cerebral oedema

Limited 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• 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

RRT MOLECULAR TRANSPORT MECHANISMS

• Ultrafiltration

• Diffusion

• Convection

• Adsorption

Fluid Transport

Solute Transport}

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.

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 WEIGHTS

Daltons

Inflammatory Mediators (1,200-40,000)

“small”

“middle”

“large”

MAJOR RENAL REPLACEMENT TECHNIQUES

Intermittent ContinuousHybrid

IHDIntermittent

haemodialysis

IUFIsolated

Ultrafiltration

SLEDDSustained (or slow) low efficiency daily

dialysis

SLEDD-F

Sustained (or slow) low efficiency daily

dialysis with filtration

CVVHContinuous veno-

venous haemofiltration

CVVHDContinuous veno-

venous haemodialysis

CVVHDFContinuous veno-

venous haemodiafiltration

SCUFSlow continuous

ultrafiltration

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

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

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.

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

SCUFPrimary 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

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

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)

SUMMARY

ARF is not an innocent bystander in ICU

We must ensure adequate dosing of RRTChoice of RRT mode may not be criticalSeptic ARF may be a different beast

We must strive to avert acute renal failure