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Renal Replacement Therapies in Critical Care

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?

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Renal Replacement Therapies in Critical Care

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  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? • 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?

  3. 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

  4. AKI classification systems 1: RIFLE

  5. AKI classification systems 2: AKIN 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 • 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 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 nodefinitive evidence forsuperiority 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

  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 45 ml/kg/hr 35 ml/kg/hr 25 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 “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

  13. 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

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

  16. Implications of the available data

  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 (?)

  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) * In post-dilution haemofiltration

  20. 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

  21. Intermittent Therapies - PRO

  22. Intermittent Therapies - CON

  23. 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

  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

  26. Continuous Therapies - CON

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. Kinetic Modelling of Solute Clearance 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

  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. Beyond renal replacement…RRT as blood purification therapy

  37. Extracorporeal Blood Purification Therapy (EBT) Continuous Intermittent TPE Therapeutic plasma exchange HVHF High volume haemofiltration UHVHF Ultra-high volume haemofiltration PHVHF Pulsed high volume haemofiltration CPFA Coupled plasma filtration and adsorption

  38. 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

  39. 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

  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 Di Carlo, JV & Alexander, SR. Int J Artif Organs 2005; 28: 777-786

  41. 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)

  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 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 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

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

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