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Renal Replacement Therapies in Critical Care Dr. Andrew Ferguson Consultant in Intensive Care Medicine & Anaesthesia Craigavon Area Hospital, United Kingdom.

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Presentation on theme: "Renal Replacement Therapies in Critical Care Dr. Andrew Ferguson Consultant in Intensive Care Medicine & Anaesthesia Craigavon Area Hospital, United Kingdom."— Presentation transcript:

1 Renal Replacement Therapies in Critical Care Dr. Andrew Ferguson Consultant in Intensive Care Medicine & Anaesthesia Craigavon Area Hospital, United Kingdom

2 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? 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?

3 Overview

4 AKI classification systems 1: RIFLE

5 AKI classification systems 2: AKIN StageCreatinine criteriaUrine output criteria 1 1.5 - 2 x baseline (or rise > 26.4 mol/L) 6 hours 2>2 - 3 x baseline 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

6 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 APACHE underestimates ROD 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 ** AKIis common: 3-35%* of admissions AKI is associated with increased mortality Minor rises in Cr associated with worse outcome APACHE underestimates ROD 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

7 Mortality by AKI Severity (1) Clermont, G et al. Kidney International 2002; 62: 986-996

8 Mortality by AKI Severity (2) Bagshaw, S et al. Am J Kidney Dis 2006; 48: 402-409

9 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** nodefinitive evidence 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 No definitive evidence on timing of RRT 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** nodefinitive evidence 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 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

10 Therapy Dose in IRRT p = 0.01 p = 0.001 Schiffl, H et al. NEJM 2002; 346: 305-310

11 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

12 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

13 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

14 Outcome with IRRT vs CRRT (3) Vinsonneau, S et al. Lancet 2006; 368: 379-385

15 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 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

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

17 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 (?) 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 (?)

18 Solute Clearance - Diffusion Small (< 500d) molecules cleared efficiently Concentration gradient critical Gradient achieved by countercurrent flow Principal clearance mode of dialysis techniques

19 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) 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

20 Major Renal Replacement Techniques Intermittent Continuous Hybrid IHD Intermittent haemodialysisIHD IUF Isolated UltrafiltrationIUF SLEDD Sustained (or slow) low efficiency daily dialysisSLEDD SLEDD-F Sustained (or slow) low efficiency daily dialysis with filtrationSLEDD-F CVVH Continuous veno-venous haemofiltrationCVVH CVVHD Continuous veno-venous haemodialysisCVVHD CVVHDF Continuous veno-venous haemodiafiltrationCVVHDF SCUF Slow continuous ultrafiltrationSCUF

21 Intermittent Therapies - PRO (Relatively) InexpensiveFlexible timing allows for mobility/transportRapid correction of fluid overloadRapid removal of dialyzable drugsRapid correction of acidosis & electrolyte abnormalityMinimises anticoagulant exposure

22 Intermittent Therapies - CON Hypotension 30-60% Cerebral oedema Limited therapy duration Renal injury & ischaemiaGut/coronary ischaemia

23 Intradialytic Hypotension: Risk Factors or 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

24 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

25 Continuous Therapies - PRO Haemodynamic stability => ??? better renal recoveryStable and predictable volume controlStable and predictable control of chemistryStable intracranial pressureDisease modification by cytokine removal (CVVH)?

26 Continuous Therapies - CON Anticoagulation requirementsHigher potential for filter clotting Expense – fluids etc.Immobility & Transport issues Increased bleeding risk High heparin exposure

27 SCUF High flux membranes Up to 24 hrs per day Objective VOLUME control Not Not suitable for solute clearance Blood flow 50-200 ml/min UF rate 2-8 ml/min High flux membranes Up to 24 hrs per day Objective VOLUME control Not Not suitable for solute clearance Blood flow 50-200 ml/min UF rate 2-8 ml/min

28 CA/VVH Extended duration up to weeks High flux membranes convective Mainly convective clearance UF > volume control amount replaced Excess UF replaced Replacement pre- or post-filter Blood flow 50-200 ml/min UF rate 10-60 ml/min Extended duration up to weeks High flux membranes convective Mainly convective clearance UF > volume control amount replaced Excess UF replaced Replacement pre- or post-filter Blood flow 50-200 ml/min UF rate 10-60 ml/min

29 CA/VVHD Mid/high flux membranes Extended period up to weeks Diffusive 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 Mid/high flux membranes Extended period up to weeks Diffusive 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

30 CVVHDF High flux membranes Extended period up to weeks Diffusive& convective Diffusive & convective solute clearance Countercurrent dialysate UF exceeds volume control Replacement 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 High flux membranes Extended period up to weeks Diffusive& convective Diffusive & convective solute clearance Countercurrent dialysate UF exceeds volume control Replacement 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

31 SLED(D) & SLED(D)-F : Hybrid therapy Conventional dialysis equipment Online dialysis fluid preparation Excellent 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 Conventional dialysis equipment Online dialysis fluid preparation Excellent 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

32 Kinetic Modelling of Solute Clearance CVVH (predilution)Daily IHDSLED Urea TAC (mg/ml)40.364.643.4 Urea EKR (ml/min)33.821.131.3 Inulin TAC (mg/L)25.455.599.4 Inulin EKR (ml/min)11.85.43.0 2 microglobulin TAC (mg/L) 9.424.240.3 2 microglobulin EKR (ml/min) 18.27.04.2 TAC = time-averaged concentration (from area under concentration-time curve) EKR = equivalent renal clearance Inulin represents middle molecule and 2 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

33 Uraemia Control Liao, Z et al. Artificial Organs 2003; 27: 802-807

34 Large molecule clearance Liao, Z et al. Artificial Organs 2003; 27: 802-807

35 Comparison of IHD and CVVH John, S & Eckardt K-U. Seminars in Dialysis 2006; 19: 455-464

36 renal blood purification therapy Beyond renal replacement… RRT as blood purification therapy

37 Extracorporeal Blood Purification Therapy (EBT) Intermittent Continuous TPE Therapeutic plasma exchangeTPE HVHF High volume haemofiltration HVHF High volume haemofiltrationUHVHF Ultra-high volume haemofiltrationUHVHF PHVHF Pulsed high volume haemofiltrationPHVHF CPFA Coupled plasma filtration and adsorptionCPFA

38 Peak Concentration Hypothesis Removes cytokines from blood compartment during pro-inflammatory phase of sepsis Assumes blood cytokine level needs to fall 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 unknown But tissue/interstitial cytokine levels unknown Removes cytokines from blood compartment during pro-inflammatory phase of sepsis Assumes blood cytokine level needs to fall 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 unknown But tissue/interstitial cytokine levels unknown Ronco, C & Bellomo, R. Artificial Organs 2003; 27: 792-801

39 Threshold Immunomodulation Hypothesis More dynamic view of cytokine system but blood level does not need to fall 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 dont know when such a point is reached More dynamic view of cytokine system but blood level does not need to fall 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 dont know when such a point is reached Honore, PM & Matson, JR. Critical Care Medicine 2004; 32: 896-897

40 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 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

41 High Volume Hemofiltration unbound May reduce unbound fraction of cytokines Removes – endothelinI – endothelin-I (causes early pulm hypertension in sepsis) – endogenous cannabinoids – endogenous cannabinoids (vasoplegic in sepsis) – myodepressant factor – PAI-I – PAI-I so may eventually reduce DIC Reduces post-sepsis immunoparalysis (CARS) Reduces inflammatory cell apoptosis too low a dose Human trials probably using too low a dose (40 ml/kg/hour vs 100+ ml/kg/hour in animals) unbound May reduce unbound fraction of cytokines Removes – endothelinI – endothelin-I (causes early pulm hypertension in sepsis) – endogenous cannabinoids – endogenous cannabinoids (vasoplegic in sepsis) – myodepressant factor – PAI-I – PAI-I so may eventually reduce DIC Reduces post-sepsis immunoparalysis (CARS) Reduces inflammatory cell apoptosis too low a dose Human trials probably using too low a dose (40 ml/kg/hour vs 100+ ml/kg/hour in animals)

42 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 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

43 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

44 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 ? 50-70 ml/kg/hour CVVH @ 35ml/kg/hour Daily IHD? Daily SLEDD? HVHF 60-120 ml/kg/hour for 96 hours HVHF 60-120 ml/kg/hour for 96 hours PHVHF 60-120 ml/kg/hour > for 6-8 hours then CVVH > 35 ml/kg/hour 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

45 You should listen to your heart, and not the voices in your head Marge Simpson


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