RRT

Regional ICM Teaching - Renal
Dr Rosie Kalsi

1. Renal Replacement Therapies in Critical Care Rosie Kalsi Regional teaching October2014

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 vs 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. 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 ).

5. 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.

6. 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.

7. 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.

8. 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 Int 2012;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

9. 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, l ethargy , 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

10. “ 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.

11. 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

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

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

14. 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

15. 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)

16. 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

17. 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

18. ATN (2007) large numbers mixed RRT 20 vs 35ml/kg/hr 60 days

19. RENAL (2007) Large numbers 20 vs 40ml/kg/hr CVVHDF 90 days

20. 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 ”

21. 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

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

23. 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.

24. Outcome with high vs low dose CRRT (2)

25. Implications of the available data

26. 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 (?)

27. Intermittent Therapies - PROS

28. Intermittent Therapies - CONS

29. 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

30. 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

31. Continuous Therapies - PROS

32. Continuous Therapies - CONS

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

34. PrismaFlex Basic CRRT Principles

35. 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

36. Anatomy of a Haemofilter 4 External ports blood and dialysis fluid Potting material support structure Hollow fibers Semi-permeable membrane Outer casing

37. 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 .

38. RRT Molecular Transport Mechanisms Ultrafiltration Diffusion Convection Adsorption Fluid Transport Solute Transport }

39. 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.

40. Blood Out Blood In to waste (to patient) (From patient) HIGH PRESS LOW PRESS Fluid Volume Reduction Ultrafiltration

41. 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.

42. Haemodialysis : Diffusion Dialysate In Dialysate Out (to waste) Blood Out Blood In (to patient) (from patient) HIGH CONC LOW CONC

43. 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 .

44. to waste HIGH PRESS LOW PRESS Repl. Solution Haemofiltration : Convection Blood Out Blood In (to patient) (from patient)

45. 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.

46. Adsorption Molecular adherence to the surface or interior of the membrane.

47. Molecular Weights Daltons Inflammatory Mediators (1,200-40,000) “ small ” “ middle ” “ large ”

48. 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 b 2 microglobulin TAC (mg/L) 9.4 24.2 40.3 b 2 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

49. 20 40 60 80 100 Clearance in % 35.000 55.000 20.000 5.000 2.500 Urea (60) Albumin (66.000) Myoglobin (17.000) 65.000 Creatinine (113) Kidney Convection Diffusion Small vs. Large Molecules Clearance

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

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

52. Major Renal Replacement Techniques Intermittent Continuous Hybrid IHD Intermittent haemodialysis IUF Isolated Ultrafiltration SLEDD Sustained (or slow) low efficiency daily dialysis SLEDD-F Sustained (or slow) low efficiency daily dialysis with filtration CVVH Continuous veno -venous haemofiltration CVVHD Continuous veno -venous haemodialysis CVVHDF Continuous veno -venous haemodiafiltration SCUF Slow continuous ultrafiltration

53. CRRT Modes of Therapy SCUF - Slow Continuous Ultrafiltration CVVH - Continuous Veno -Venous Hemofiltration CVVHD - Continuous Veno -Venous HemoDialysis CVVHDF - Continuous Veno -Venous HemoDiaFiltration

54. 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.

55. 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.

56. 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

57. 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 I mportant to understand that despite their name, Replacement fluids do not replace anything.

58. Effluent Flow Rate Effluent = Total Fluid Volume: Patient Fluid Removal Dialysate Flow Replacement Flow Pre-Blood Pump Flow

59. 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

60. SCUF Slow 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. R emoves 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 .

61. 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

62. SCUF Slow Continuous UltraFiltration Effluent Pump Infusion or Anticoagulant Blood Pump PBP Pump Effluent Access Return

63. CVVH Continuous 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. E xtremely effective method of solute removal and is indicated for uremia or severe pH or electrolyte imbalance with or without fluid overload. R emoves 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.

64. 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

65. CVVH Continuous VV Hemofiltration Effluent Pump Blood Pump Effluent Access Return Replacement Pump 1 Replacement Pump 2 Replacement 1 Replacement 2 Infusion or Anticoagulant PBP Pump

66. 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

67. 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

68. CVVHD Continuous 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. S imilar to traditional hemodialysis, and is effective for removal of small to medium sized molecules. Solute removal due to diffusion D ialysate 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. T he amount of fluid in the effluent bag is equal to the amount of fluid removed from the patient plus the dialysate .

69. 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

70. CVVHD Continuous VV HemoDialysis Hemofilter Effluent Pump Effluent Access Return Dialysate Pump Dialysate Fluid Blood Pump Infusion or Anticoagulant PBP Pump

71. CVVHDF Continuous 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.

72. 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

73. CVVHDF Continuous VV HemoDiaFiltration Effluent Pump Effluent Access Return Dialysate Pump Dialysate Fluid Blood Pump Replacement Pump Replacement Fluid PBP Pump Infusion or Anticoagulant

74. 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

75. Complications of CRRT Bleeding Hypothermia Electrolyte Imbalances Acid-Base Imbalances Infection Appropriate Dosing of Medications

76. 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

77. 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

78. Beyond renal replacement… RRT as blood purification therapy

79. 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

80. 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

81. 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

82. 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

83. 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)

84. 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

85. Towards Targeted Therapy Honore, PM et al . Int J Artif Organs 206; 29: 649-659 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 Daily IHD? Daily SLEDD? 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 EBT Cerebral oedema