Renal Replacement Therapy

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Renal Replacement Therapy

• Childrens Healthcare of Atlanta

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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.

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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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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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• 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.

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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

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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

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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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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

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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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How is it done?

• Peritoneal Dialysis
• Hemodialysis
• Hemofiltration
• The choice of which modality to use depends on
• Patients clinical status
• Resources available

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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

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Peritoneal dialysis
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

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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

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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

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SCUFSlow 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
Control rate of fluid removal
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SCUFSlow 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

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CVVH
Blood is pushed through a hemofilter Pressure
within filter (convection) Solvent Drag
Replacement fluid given back to patient
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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

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CVVHD
Blood is pushed through a hemofilter
Water and Solutes move across concentration
gradients (diffusion)
Dialysis fluid flows counter- current to blood
flow
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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

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

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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

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Indications for Renal Replacement Therapy

• Intractable acidosis
• Fluid overload or pulmonary edema
• BUN gt 150 mg/dL
• Symptomatic uremia (encephalopathy, pericarditis)
• Hyperkalemia (serum K gt 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
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Indicators of Circuit Function
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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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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 gt 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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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 gt 100 ml/min is usually
  unnecessary
• High BFR may contribute to increased hemolysis
  within the CVVH circuit

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Pediatric CRRT Vascular AccessPerformance
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

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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 pts BSA
• In CVVH, ultrafiltrate urea concentration and BUN
  are the same, canceling out of the equation,
  which becomes
• C urea UFR x 1.73
• pts BSA
• C urea (ml/min/1.73 m2 BSA)

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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 / pts 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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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

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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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Replacement Fluids

• Ultrafiltrate can be replaced with a combination
  of
• Custom physiologic solutions
• Ringers 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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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

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Anticoagulation

• To prevent clotting within the CVVH circuit,
  active anti-coagulation is often needed
• Heparin
• Citrate
• Local vs. systemic

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

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No Heparin
Systemically Heparinized
NO surface - heparinized
NO surface - no heparin
Compliments of Dr. Gail Annich, University
of Michigan
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Unfractionated Heparin
Hoffbauer R et al. Kidney Int. 1999561578-1583.
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Sites of Action of Citrate
TISSUE FACTOR TFVIIa
CONTACT PHASE XII activation XI IX
monocytes / platelets / macrophages
X
Va VIIIa Ca platelets
Xa
Phospholipid surface
prothrombin
CITRATE
THROMBIN
NATURAL ANTICOAGULANTS (APC, ATIII)
FIBRINOLYSIS ACTIVATION FIBRINOLYSIS INHIBITION
fibrinogen
CLOT
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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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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 lt
  0.3, while the systemic calcium concentration is
  maintained by the infusion.

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Citrate
Hoffbauer R et al. Kidney Int. 1999561578-1583.
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Citrate Problems

• Metabolic alkalosis
• 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

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Experimental High Flow

• High-volume CVVH might
• Improve hemodynamics
• Increase organ blood flow
• Decrease blood lactate and nitrite/nitrate
  concentrations.

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

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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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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

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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?

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Clinical Applications in Pediatric ARF Disease
and Survival
Bunchman TE et al Ped Neph 161067-1071, 2001
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Clinical Applications in Pediatric ARF Disease
and Survival

• Patient survival on pressors (35) lower survival
  than without pressors (89) (plt0.01)
• Lower survival seen in CRRT than in patients who
  received HD for all disease states

Bunchman TE et al Ped Neph 161067-1071, 2001
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Pediatric CRRT in the PICU

• 22 pt (12 male/10 female) received 23 courses
  (3028 hrs) of CVVH (n10) or CVVHD (n12) 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
  (pNS).
• 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
Jun107(6)1309-12
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Percent Fluid Overload Calculation


Fluid In - Fluid Out ICU Admit Weight
100
FO at CVVH initiation
Goldstein SL et al Pediatrics 2001
Jun107(6)1309-12
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Renal Replacement Therapy in the PICU Pediatric
Literature

• Lesser FO at CVVH (D) initiation was associated
  with improved outcome (p0.03)
• Lesser FO at CVVH (D) initiation was also
  associated with improved outcome when sample was
  adjusted for severity of illness (p0.03
  multiple regression analysis)

Goldstein SL et al Pediatrics 2001
Jun107(6)1309-12
59
PRISM at CRRT Initiation and Outcome
P lt 0.0005
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Fluid Overload and Outcome Renal Failure Only
P lt 0.05
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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

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These slides created from presentations by...

• Joseph DiCarlo, MD
• Stanford University
• Steven Alexander, MD
• Stanford University
• Catherine Headrick, RN
• Childrens Medical Center Dallas
• Patrick D. Brophy, MD
• University of Michigan

• Peter Skippen, MD
• British Columbia Childrens Hospital
• Stuart L. Goldstein, MD
• Baylor College of Medicine
• Timothy E. Bunchman, MD
• University of Alabama