1. Renal Replacement Therapy
Children’s Healthcare of Atlanta

2. 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.

3. Tetralogy of Fallot
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
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4. History of Pediatric Hemofiltration
Tetralogy of Fallot
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
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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.

6. 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

7. 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

8. Semi-permeable Membranes
Tetralogy of Fallot
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
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9. 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

10. Semi-permeable Membranes
Tetralogy of Fallot
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
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11. How is it done? Peritoneal Dialysis Hemodialysis Hemofiltration
Tetralogy of Fallot
How is it done?
Peritoneal Dialysis
Hemodialysis
Hemofiltration
The choice of which modality to use depends on
Patient’s clinical status
Resources available
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12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. CVVH Blood is pushed through a hemofilter
Tetralogy of Fallot
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
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19. Continuous Venovenous Hemofiltration
Filtration occurs by convection
Mimics physiology of the mammalian kidney
Provides better removal of middle molecules ( 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

20. CVVHD Blood is pushed through a hemofilter
Tetralogy of Fallot
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
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21. 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

22. 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

23. 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

24. 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

25. 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

26. Indicators of Circuit Function

27. Tetralogy of Fallot
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
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28. Ultrafiltrate Rate FF(%) = (UFR x 100) / QP QP = BFR x (1-Hct)
Tetralogy of Fallot
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
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29. Blood Flow Rate & Clearance
Tetralogy of Fallot
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
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30. 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

31. Tetralogy of Fallot
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
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
pt’s BSA
C urea: (ml/min/1.73 m2 BSA)
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32. Tetralogy of Fallot
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 / 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.
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33. Solute Molecular Weight and Clearance
Solute (MW) Convective Coefficient Diffusion Coefficient
Urea (60) 1.01 ± ± 0.07
Creatinine (113) 1.00 ± ± 0.06
Uric Acid (168) 1.01 ± ± 0.04
Vancomycin (1448) 0.84 ± ± 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

34. Tetralogy of Fallot
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.
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35. Tetralogy of Fallot
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.
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36. Physiologic Replacement Fluid
Tetralogy of Fallot
Physiologic Replacement Fluid
Na mEq/L
K mEq/L
HCO mEq/l
Cl Balance
Ca 2.5 mEq/L
Mg 1.5 mEq/L
Glucose 100 mg/dL
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37. Tetralogy of Fallot
Anticoagulation
To prevent clotting within the CVVH circuit, active anti-coagulation is often needed
Heparin
Citrate
Local vs. systemic
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38. 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

39. 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

40. 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

41. 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

42. Unfractionated Heparin
Hoffbauer R et al. Kidney Int. 1999;56:

43. 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

44. Anticoagulation: Citrate
Tetralogy of Fallot
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
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45. Anticoagulation: citrate
Tetralogy of Fallot
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.
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46. Citrate
Hoffbauer R et al. Kidney Int. 1999;56:

47. 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.

48. Experimental: High Flow
Tetralogy of Fallot
Experimental: High Flow
High-volume CVVH might…
Improve hemodynamics
Increase organ blood flow
Decrease blood lactate and nitrite/nitrate concentrations.
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49. Ronco et al. Lancet 2000; 351: 26-30
35 mL/kg/hr ~ 40 cc/min/1.73 m2

50. 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

51. Experimental: septic shock
Tetralogy of Fallot
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.
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52. 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

53. 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?

54. Clinical Applications in Pediatric ARF: Disease and Survival
Bunchman TE et al: Ped Neph 16: , 2001

55. 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: , 2001

56. 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 /- 5.7 and /- 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):

57. 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):

58. 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):

59. PRISM at CRRT Initiation and Outcome

60. Fluid Overload and Outcome: Renal Failure Only
P < 0.05

61. 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

62. 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