Renal Replacement Therapy Children’s Healthcare of Atlanta

Renal Replacement Therapy What is it? The medical approach to providing the electrolyte balance, fluid balance, and toxin removal functions of the kidney. How does it work? Uses concentration and pressure gradients to remove solutes (K, Urea, etc…) and solvents (water) from the human body.

Tetralogy of Fallot 21.9.98 Where did it come from? In Germany during 1979, Dr. Kramer inadvertently cannulated the femoral artery of a patient which led to a spontaneous experiment with CAVH (continuous arteriovenous hemofiltration) The patient's cardiac function alone is capable of driving the system Large volumes of ultrafiltrate were produced through the highly permeable hemofilter Continuous arteriovenous hemofiltration could provide complete renal replacement therapy in an anuric adult All-Net Internet Textbook 4

History of Pediatric Hemofiltration Tetralogy of Fallot 21.9.98 History of Pediatric Hemofiltration USA, 1985: Dr. Liebermann used SCUF (slow continuous ultrafiltration) to successfully support an anuric neonate with fluid overload Italy, 1986: Dr. Ronco described the successful use of CAVH in four neonates USA, 1987: Dr. Leone described CAVH in older children 1993: A general acceptance of pump-driven CVVH was seen as less problematic than CAVH All-Net Internet Textbook 5

In 1984, Dr. Claudio Ronco, treated this child with CAVH in Vicenza, Italy. This is the first patient purposely treated with CAVH in the world. The patient survived.

Mechanisms of Action: Convection Hydrostatic pressure pushes solvent across a semi-permeable membrane Solute is carried along with solvent by a process known as “solvent drag” Membrane pore size limits molecular transfer Efficient at removal of larger molecules compared with diffusion Pressure Na H2O H2O + Na

Mechanisms of Action: Diffusion Solvent moves up a concentration gradient Solute diffuses down an concentration gradient Solute movement occurs via Brownian motion The smaller the molecule (e.g. urea) the greater the kinetic energy The larger the concentration gradient the more drive for movement Therefore, smaller molecules with greater concentration gradients move more quickly across membrane Osmolarity H2O Osmolarity Urea Uremia

Semi-permeable Membranes Tetralogy of Fallot 21.9.98 Semi-permeable Membranes Allow easy transfer of solutes less than 100 Daltons Urea Creatinine Uric acid Sodium Potassium Ionized calcium Phosphate Almost all drugs not bound to plasma proteins Bicarbonate Interleukin-1 Interleukin-6 Endotoxin Vancomycin Heparin Pesticides Ammonia Are impermeable to albumin and other solutes of greater than 50,000 Daltons All-Net Internet Textbook 14

Semi-permeable Membranes Sieving Coefficient Defines amount (clearance) of molecule that crosses semi-permeable membrane Sieving Coefficient is “1” for molecules that easily pass through the membrane and “0” for those that do not

Semi-permeable Membranes Tetralogy of Fallot 21.9.98 Semi-permeable Membranes Continuous hemofiltration membranes consist of relatively straight channels of ever-increasing diameter that offer little resistance to fluid flow Intermittent hemodialysis membranes contain long, tortuous inter-connecting channels that result in high resistance to fluid flow All-Net Internet Textbook 13

How is it done? Peritoneal Dialysis Hemodialysis Hemofiltration Tetralogy of Fallot 21.9.98 How is it done? Peritoneal Dialysis Hemodialysis Hemofiltration The choice of which modality to use depends on Patient’s clinical status Resources available All-Net Internet Textbook 51

Peritoneal Dialysis Fluid placed into peritoneal cavity by catheter Glucose provides solvent gradient for fluid removal from body Can vary concentration of electrolytes to control hyperkalemia Can remove urea and metabolic products Can be intermittent or continuously cycled

Peritoneal dialysis Simple to set up & perform Easy to use in infants Advantages Disadvantages Simple to set up & perform Easy to use in infants Hemodynamic stability No anti-coagulation Bedside peritoneal access Treat severe hypothermia or hyperthermia Unreliable ultrafiltration Slow fluid & solute removal Drainage failure & leakage Catheter obstruction Respiratory compromise Hyperglycemia Peritonitis Not good for hyperammonemia or intoxication with dialyzable poisons

Intermittent Hemodialysis Advantages Disadvantages Maximum solute clearance of 3 modalities Best therapy for severe hyperkalemia Limited anti-coagulation time Bedside vascular access can be used Hemodynamic instability Hypoxemia Rapid fluid and electrolyte shifts Complex equipment Specialized personnel Difficult in small infants

Continuous Hemofiltration Advantages Disadvantages Easy to use in PICU Rapid electrolyte correction Excellent solute clearances Rapid acid/base correction Controllable fluid balance Tolerated by unstable patients Early use of TPN Bedside vascular access routine Systemic anticoagulation (except citrate) Frequent filter clotting Vascular access in infants

SCUF:Slow Continuous Ultrafiltration Blood is pushed through a hemofilter Pressure generated within filter pushes solvent (serum) through semi-permeable membrane (convection) Solutes are carried through membrane by a process known as “solvent drag” Urea Creatinine K Na H2O Blood Ultrafiltrate Pressure Control rate of fluid removal

SCUF:Slow Continuous Ultrafiltration Pros Filters blood effectively Control fluid balance by regulating transmembrane pressures No replacement fluid therefore less pharmacy cost Cons No replacement fluid given so electrolyte abnormalities can occur Low ultrafiltration rates that keep electrolytes balanced do not remove urea effectively

CVVH Blood is pushed through a hemofilter Tetralogy of Fallot 21.9.98 CVVH Blood is pushed through a hemofilter Pressure within filter (convection) Solvent Drag Urea Creatinine K Na H2O Ultrafiltrate Replacement Fluid Blood Pressure Replacement fluid given back to patient All-Net Internet Textbook 2

Continuous Venovenous Hemofiltration Filtration occurs by convection Mimics physiology of the mammalian kidney Provides better removal of middle molecules (500-5000 Daltons) thought to be responsible clinical state of uremia Ultrafiltrate is replaced by a sterile solution (replacement solution) Patient fluid loss (or gain) results from the difference between ultrafiltration and replacement rates

CVVHD Blood is pushed through a hemofilter Tetralogy of Fallot 21.9.98 CVVHD Blood is pushed through a hemofilter Water and Solutes move across concentration gradients (diffusion) Urea Creatinine K Na H2O Dialysate Blood Dialysis Fluid Dialysis fluid flows counter- current to blood flow All-Net Internet Textbook 2

Continuous Venovenous Hemodialysis Diffusion (predominantly) Some convection occurs due to transmembrane pressure created by roller-head pump Dialysate flow rate is slower than BFR and is the limiting factor to solute removal Therefore, solute removal is directly proportional to dialysate flow rate

CVVHDF Blood is pushed through a hemofilter Water and Solutes move across concentration gradients (diffusion) Pressure within filter (convection) Solvent Drag Urea Creatinine K Na H2O Replacement Fluid Blood Dialysis Fluid Dialysate Pressure Replacement fluid given back to patient Dialysis fluid flows counter- current to blood flow

Continuous Venovenous Hemodialysis with Ultrafiltration Pros Can provide both ultrafiltration (removal of medium size molecules) and dialysis (removal of small molecules) Can remove toxins Cons Toxin removal is slow Overly complicated to set-up for small clinical benefits

Is there a “Best” Method? The greatest difference between modalities is most likely related to the membrane utilized and their specific characteristics. There are no data available assessing patient outcomes using diffusive (CVVHD) and convective (CVVH) therapies

Indications for Renal Replacement Therapy Intractable acidosis Fluid overload or pulmonary edema BUN > 150 mg/dL Symptomatic uremia (encephalopathy, pericarditis) Hyperkalemia (serum K > 7 mEq/L) Hyperammonemia Ultrafiltration for nutritional support or excessive transfusions Exogenous toxin removal Hyponatremia or hypernatremia Adapted From Rogers’ Textbook of Pediatric Intensive Care, Table 38.7

Indicators of Circuit Function

Tetralogy of Fallot 21.9.98 Filtration Fraction The degree of blood dehydration can be estimated by determining the filtration fraction (FF) The fraction of plasma water removed by ultrafiltration FF(%) = (UFR x 100) / QP where QP is the filter plasma flow rate in ml/min QP = BFR* x (1-Hct) *BFR: blood flow rate All-Net Internet Textbook 17

Ultrafiltrate Rate FF(%) = (UFR x 100) / QP QP = BFR x (1-Hct) Tetralogy of Fallot 21.9.98 Ultrafiltrate Rate FF(%) = (UFR x 100) / QP QP = BFR x (1-Hct) For example... When BFR = 100 ml/min & Hct = 0.30 (i.e. 30%), the QP = 70 ml/min A filtration fraction > 30% promotes filter clotting In this example, when the maximum allowable FF is set at 30%, a BFR of 100 ml/min yields a UFR = 21 ml/min QP: the filter plasma flow rate in ml/min All-Net Internet Textbook 18

Blood Flow Rate & Clearance Tetralogy of Fallot 21.9.98 Blood Flow Rate & Clearance A child with body surface area = 1.0 m2, BFR = 100 ml/min and FF = 30% Small solute clearance is 36.3 ml/min/1.73 m2 (About one third of normal renal small solute clearance) Target CVVH clearance of at least 15 ml/min/1.73 m2 For small children, BFR > 100 ml/min is usually unnecessary High BFR may contribute to increased hemolysis within the CVVH circuit All-Net Internet Textbook 19

Pediatric CRRT Vascular Access: Performance = Blood Flow!!! Minimum 30 to 50 ml/min to minimize access and filter clotting Maximum rate of 400 ml/min/1.73m2 or 10-12 ml/kg/min in neonates and infants 4-6 ml/kg/min in children 2-4 ml/kg/min in adolescents

Tetralogy of Fallot 21.9.98 Urea Clearance Urea clearance (C urea) in hemofiltration, adjusted for the patient's body surface area (BSA), can be calculated as follows: C urea =  UF [urea] x UFR x 1.73 BUN pt’s BSA In CVVH, ultrafiltrate urea concentration and BUN are the same, canceling out of the equation, which becomes: C urea = UFR x 1.73 pt’s BSA C urea: (ml/min/1.73 m2 BSA) All-Net Internet Textbook 20

Tetralogy of Fallot 21.9.98 Urea Clearance When target urea clearance (C urea) is set at 15 ml/min/1.73 m2, the equation can be solved for UFR 15 = UFR x 1.73 / pt’s BSA UFR = 15 / 1.73 = 8.7 ml/min Thus, in a child with body surface area = 1.0 m2, a C urea of about 15 ml/min/1.73 m2 is obtained when UFR = 8.7 ml/min or 520 ml/hr. This same clearance can be achieved in the 1.73 m2 adolescent with a UFR = 900 ml/hr. All-Net Internet Textbook 22

Solute Molecular Weight and Clearance Solute (MW) Convective Coefficient Diffusion Coefficient Urea (60) 1.01 ± 0.05 1.01 ± 0.07 Creatinine (113) 1.00 ± 0.09 1.01 ± 0.06 Uric Acid (168) 1.01 ± 0.04 0.97 ± 0.04 Vancomycin (1448) 0.84 ± 0.10 0.74 ± 0.04 Cytokines (large) adsorbed minimal clearance Drug therapy can be adjusted by using frequent blood level determinations or by using tables that provide dosage adjustments in patients with altered renal function

Tetralogy of Fallot 21.9.98 Fluid Balance Precise fluid balance is one of the most useful features of CVVH Each hour, the volume of filtration replacement fluid (FRF) is adjusted to yield the desired fluid balance. All-Net Internet Textbook 24

Tetralogy of Fallot 21.9.98 Replacement Fluids Ultrafiltrate can be replaced with a combination of: Custom physiologic solutions Ringer’s lactate Total parenteral nutrition solutions In patients with fluid overload, a portion of the ultrafiltrate volume is simply not replaced, resulting in predictable and controllable negative fluid balance. All-Net Internet Textbook 25

Physiologic Replacement Fluid Tetralogy of Fallot 21.9.98 Physiologic Replacement Fluid Na 135-145 mEq/L K 2.5-4.5 mEq/L HCO3 25-35 mEq/l Cl Balance Ca 2.5 mEq/L Mg 1.5 mEq/L Glucose 100 mg/dL All-Net Internet Textbook 26

Tetralogy of Fallot 21.9.98 Anticoagulation To prevent clotting within the CVVH circuit, active anti-coagulation is often needed Heparin Citrate Local vs. systemic All-Net Internet Textbook 32

Mechanisms of Filter Thrombosis TISSUE FACTOR TF:VIIa CONTACT PHASE XII activation XI IX monocytes / platelets / macrophages Ca++ X Va VIIIa Ca++ platelets Xa Phospholipid surface prothrombin THROMBIN NATURAL ANTICOAGULANTS (APC, ATIII) FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION fibrinogen CLOT

Sites of Action of Heparin TISSUE FACTOR TF:VIIa CONTACT PHASE XII activation XI IX Ca++ monocytes platelets macrophages X Va VIIIa Ca++ platelets Xa ATIII Phospholipid surface prothrombin UF HEPARIN THROMBIN NATURAL ANTICOAGULANTS (APC, ATIII) FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION fibrinogen CLOT

Heparin - Problems Bleeding Unable to inhibit thrombin bound to clot Unable to inhibit Xa bound to clot Ongoing thrombin generation Direct activation of platelets Thrombocytopenia Extrinsic pathway unaffected If you review the literature on anticoagulation with heparin for CRRT, the incidence of hemorrhagic complications is impressive and remains the most common complication. Most of the research on the effects of heparin have come from cardiac surgery and the need to anticoagulate patients for CPB. It is absolutely critical to prevent clotting in these patients undergoing cardiac surgery. The doses of heparin and the desired ACT levels are far in excess of what we try to achieve during CRRT. Even massive doses of unfractionated heparin are unable to inhibit clot bound thrombin. Clot bound thrombin, we know, cleaves pro-thrombin generating more thrombin. Hence, there is ongoing thrombin generation in the presence of heparin and ongoing activation of the coagulation and fibrinolytic cascade. NEXT SLIDE

Systemically Heparinized No Heparin Systemically Heparinized In addition, heparin damages platelets, as can be demonstrated in this slide. Thanks to Dr. Gail Annich in Ann Arbor at University of Michigan for allowing me to use this slide. The slide represents scanning electron microscopy of the surface of extracorporeal circuits from an animal study. The right side of each image is a x 5 magnification of the area selected. Figure A = a circuit that was not heparinized. Note the clumping of platelets and fibrin strands. Figure B = represents a heparinized circuit - note the shape of the platelets Figure C = a circuit where the clotting was prevented by a special circuit material that Dr. Annich and her colleagues have been working on, and heparin was NOT used - note the shape of the platelets now. NO surface - no heparin NO surface - heparinized Compliments of Dr. Gail Annich, University of Michigan

Unfractionated Heparin Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.

Sites of Action of Citrate TISSUE FACTOR TF:VIIa CONTACT PHASE XII activation XI IX monocytes / platelets / macrophages Ca++ X Va VIIIa Ca++ platelets Xa Phospholipid surface prothrombin CITRATE THROMBIN NATURAL ANTICOAGULANTS (APC, ATIII) FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION fibrinogen CLOT

Anticoagulation: Citrate Tetralogy of Fallot 21.9.98 Anticoagulation: Citrate Citrate regional anticoagulation of the CVVH circuit may be employed when systemic (i.e., patient) anticoagulation is contraindicated for any reason (usually, when a severe coagulopathy pre-exists). CVVH-D helps prevent inducing hypernatremia with the trisodium citrate solution All-Net Internet Textbook 35

Anticoagulation: citrate Tetralogy of Fallot 21.9.98 Anticoagulation: citrate Citrate regional anticoagulation of the CVVH circuit: 4% trisodium citrate ‘pre-filter’ Replacement fluid: normal saline Calcium infusion: 8% CaCl in NS through a distal site Ionized calcium in the circuit will drop to < 0.3, while the systemic calcium concentration is maintained by the infusion. All-Net Internet Textbook 36

Citrate Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.

Citrate: Problems Metabolic alkalosis Electrolyte disorders metabolized in liver / skeletal muscle / other tissues Electrolyte disorders Hypernatremia Hypocalcemia Hypomagnesemia May not be able to use in Congenital metabolic diseases Severe liver disease / hepatic failure May be issue with massive blood transfusions There are a number of problems that can occur if you are not careful. Metabolic alkalosis will occur in every case. This can be dealt with by adjusting the replacement fluids and dialysate. An added complication that can be added to the list from our recent clinical experience is hyperglycemia. The solution we use is a 3% citrate solution, which also contains 2.5% of dextrose in solution as well.

Experimental: High Flow Tetralogy of Fallot 21.9.98 Experimental: High Flow High-volume CVVH might… Improve hemodynamics Increase organ blood flow Decrease blood lactate and nitrite/nitrate concentrations. All-Net Internet Textbook 37

Ronco et al. Lancet 2000; 351: 26-30 35 mL/kg/hr ~ 40 cc/min/1.73 m2

Ronco et al. Lancet 2000; 351: 26-30 Conclusions: Minimum UF rates should reach at least 35 ml/kg/hr (40 mL/min/1.73 m2) Survivors in all their groups had lower BUNs than non-survivors prior to commencement of hemofiltration

Experimental: septic shock Tetralogy of Fallot 21.9.98 Experimental: septic shock Zero balance ultrafiltration (ZBUF) performed 3L ultrafiltrate/h for 150 min then 6 L/h for an additional 150 min. Rogers et al: Effects of CVVH on regional blood flow and nitric oxide production in canine endotoxic shock. All-Net Internet Textbook 38

What are the targets? Most known mediators are water soluble Possible contenders 500-60,000D (“middle molecules”) cytokines anti/pro-coagulants Other molecules complement phospholipase A-2 dependent products Likely many unknown contenders

Unknowns of Hemofiltration for Sepsis Interaction of immune system with foreign surface of the circuit? Complement activation Bradykinin generation Leukocyte adhesion Clearance of anti-inflammatory mediators? Clearance of unknown good mediators? What do plasma levels of mediators really mean? Is animal sepsis clinically applicable to human sepsis?

Clinical Applications in Pediatric ARF: Disease and Survival Bunchman TE et al: Ped Neph 16:1067-1071, 2001

Clinical Applications in Pediatric ARF: Disease and Survival Patient survival on pressors (35%) lower survival than without pressors (89%) (p<0.01) Lower survival seen in CRRT than in patients who received HD for all disease states Bunchman TE et al: Ped Neph 16:1067-1071, 2001

Pediatric CRRT in the PICU 22 pt (12 male/10 female) received 23 courses (3028 hrs) of CVVH (n=10) or CVVHD (n=12) over study period. Overall survival was 41% (9/22). Survival in septic patients was 45% (5/11). PRISM scores at ICU admission and CVVH initiation were 13.5 +/- 5.7 and 15.7 +/- 9.0, respectively (p=NS). Conditions leading to CVVH (D) Sepsis (11) Cardiogenic shock (4) Hypovolemic ATN (2) End Stage Heart Disease (2) Hepatic necrosis, viral pneumonia, bowel obstruction and End-Stage Lung Disease (1 each) Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12

Percent Fluid Overload Calculation [ ] Fluid In - Fluid Out ICU Admit Weight % FO at CVVH initiation = * 100% Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12

Renal Replacement Therapy in the PICU Pediatric Literature Lesser % FO at CVVH (D) initiation was associated with improved outcome (p=0.03) Lesser % FO at CVVH (D) initiation was also associated with improved outcome when sample was adjusted for severity of illness (p=0.03; multiple regression analysis) Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12

PRISM at CRRT Initiation and Outcome

Fluid Overload and Outcome: Renal Failure Only P < 0.05

Final Thoughts on Hemofiltration Medical Therapy that can perform the functions of the kidney and provide precise electrolyte and fluid balance Unknown which method (CVVH vs. CVVHD vs. CVVHDF) is best Many applications in the PICU No perfect method of coagulation High flow replacement fluids may be beneficial in sepsis Earlier use in fluid overloaded patients with lower PRISM scores may improve mortality

These slides created from presentations by... Joseph DiCarlo, MD Stanford University Steven Alexander, MD Catherine Headrick, RN Children’s Medical Center Dallas Patrick D. Brophy, MD University of Michigan Peter Skippen, MD British Columbia Children’s Hospital Stuart L. Goldstein, MD Baylor College of Medicine Timothy E. Bunchman, MD University of Alabama