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? 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 Impact of Acute Kidney Injury in the ICU Dose-outcome relationships & IRRT v CRRT Mechanisms of solute clearance Therapies in brief IRRT, CRRT & Hybrid therapies e.g. SLEDD Solute clearance with IRRT v CRRT v SLEDD Extracorporeal blood purification in sepsis Putting it together – making a rational choice

AKI classification systems 1: RIFLE

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

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) 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 AKI is not an innocent bystander in ICU We must ensure adequate dosing of RRT Choice of RRT mode may not be critical Septic AKI may be a different beast We must strive to avert acute kidney injury

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 Techniques Intermittent Hybrid Continuous IHD Intermittent haemodialysis SLEDD Sustained (or slow) low efficiency daily dialysis CVVH Continuous veno-venous haemofiltration IUF Isolated Ultrafiltration CVVHD Continuous veno-venous haemodialysis SLEDD-F Sustained (or slow) low efficiency daily dialysis with filtration 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 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 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 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 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 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 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 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 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 Continuous TPE Therapeutic plasma exchange HVHF High volume haemofiltration UHVHF 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 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 Cathecholamine resistant septic shock Daily IHD Daily IHD? HVHF 60-120 ml/kg/hour for 96 hours Daily SLEDD Daily SLEDD? CVVHD/F ? dose EBT PHVHF 60-120 ml/kg/hour for 6-8 hours then CVVH > 35 ml/kg/hour CVVH @ 35ml/kg/hour CVVH > 35ml/kg/hour ? 50-70 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