Transcript Renal Replacement Therapy Children’s Healthcare of Atlanta Renal Replacement Therapy • What is it? – The medical approach to providing the electrolyte balance, fluid.

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.
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
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
•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
H2O
Na
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
Uremia
Urea
Osmolarity
H2O
Urea
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
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
• Continuous hemofiltration
• Intermittent hemodialysis
membranes consist of
membranes contain long,
relatively straight channels
tortuous inter-connecting
of ever-increasing diameter
channels that result in high
that offer little resistance to
resistance to fluid flow
fluid flow
How is it done?
•
•
•
•
Peritoneal Dialysis
Hemodialysis
Hemofiltration
The choice of which modality to use depends on
– Patient’s clinical status
– Resources available
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
Advantages
•
•
•
•
•
•
Simple to set up & perform
Easy to use in infants
Hemodynamic stability
No anti-coagulation
Bedside peritoneal access
Treat severe hypothermia or
hyperthermia
Disadvantages
•
•
•
•
•
•
•
•
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
• Maximum solute
clearance of 3 modalities
• Best therapy for severe
hyperkalemia
• Limited anti-coagulation
time
• Bedside vascular access
can be used
Disadvantages
• Hemodynamic instability
• Hypoxemia
• Rapid fluid and electrolyte
shifts
• Complex equipment
• Specialized personnel
• Difficult in small infants
Continuous Hemofiltration
Advantages
•
•
•
•
•
•
•
•
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
Disadvantages
• 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
Pressure
K
Na
H2O
Control rate of fluid removal
Ultrafiltrate
Blood
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
Pressure within filter (convection)
Solvent Drag
Urea
Creatinine
Pressure
K
Na
Replacement Fluid
Blood
H2O
Replacement fluid given back to patient
Ultrafiltrate
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
Water and Solutes
move across
concentration
gradients
(diffusion)
Urea
Creatinine
Blood
Dialysis fluid
flows countercurrent to blood
flow
K
Na
Dialysis Fluid
H2O
Dialysate
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
Water and Solutes
move across
concentration
gradients
(diffusion)
Pressure within filter
(convection)
Solvent Drag
Urea
Creatinine
Pressure
K
Replacement Fluid
Na
Dialysis Fluid
Blood is pushed
through a hemofilter
Blood
H2O
Replacement
Dialysis fluid
fluid given
flows counterback to patient Dialysate
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
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
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
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
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
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)
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.
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
adsorbed
minimal clearance
Cytokines (large)
•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
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.
FRF
=
to be given
in next hour
total fluid out
in the previous
hour
- total fluid in desired
excluding
fluid balance
FRF
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.
Physiologic Replacement Fluid
•
•
•
•
•
•
•
Na
K
HCO3
Cl
Ca
Mg
Glucose
135-145 mEq/L
2.5-4.5 mEq/L
25-35 mEq/l
Balance
2.5 mEq/L
1.5 mEq/L
100 mg/dL
Anticoagulation
• To prevent clotting within the CVVH
circuit, active anti-coagulation is often
needed
– Heparin
– Citrate
– Local vs. systemic
Mechanisms of Filter Thrombosis
TISSUE FACTOR
TF:VIIa
CONTACT PHASE
XII activation
XI IX
monocytes /
X
Va
VIIIa
Ca++
platelets
Xa
prothrombin
platelets /
macrophages
Phospholipid
surface
Ca+
+ +
Ca
+
Ca+
+
Ca+
+
Ca+
+
Ca+
+
THROMBIN
NATURAL
ANTICOAGULANTS
(APC, ATIII)
fibrinogen
CLOT
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
Sites of Action of Heparin
TISSUE FACTOR
TF:VIIa
CONTACT PHASE
XII activation
XI IX
Va
VIIIa
Ca++
platelets
X
ATIII
Xa
prothrombin
monocytes
platelets
macrophages
Phospholipid
surface
Ca+
+ +
Ca
+
Ca+
+
Ca+
+
Ca+
+
Ca+
+
UF HEPARIN
THROMBIN
NATURAL
ANTICOAGULANTS
(APC, ATIII)
fibrinogen
CLOT
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
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
No Heparin
NO surface - no heparin
Systemically Heparinized
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
Va
VIIIa
Ca++
platelets
monocytes /
X
Xa
prothrombin
CITRATE
NATURAL
ANTICOAGULANTS
(APC, ATIII)
platelets /
macrophages
Phospholipid
surface
Ca+
+ +
Ca
+
Ca+
+
Ca+
+
Ca+
+
Ca+
+
THROMBIN
fibrinogen
CLOT
FIBRINOLYSIS ACTIVATION
FIBRINOLYSIS INHIBITION
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
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.
Citrate
Hoffbauer R et al. Kidney Int. 1999;56:1578-1583.
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
Experimental: High Flow
• High-volume CVVH might…
– Improve hemodynamics
– Increase organ blood flow
– Decrease blood lactate and nitrite/nitrate
concentrations.
Ronco et al. Lancet 2000; 351: 26-30
425 patients
Endpoint = survival 15 days after D/C HF
146 UF rate 20ml/kg/hr
survival significantly lower
in this group compared
to the others
139 UF rate 35ml/kg/hr
p=0.0007
140 UF rate 45ml/kg/hr
p=0.0013
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
• Zero balance ultrafiltration (ZBUF) performed
– 3L ultrafiltrate/h for 150 min then 6 L/h for an additional 150
min.
UF @
mean art. BP (mmHg)
cardiac index
(mL/min.kg)
stroke index (mL/kg)
6 L/min
77 ± 19
0.17 ± .04
1.0 ± 0.4
no UF
40 ± 15
p < .05
0.06 ± .04 p < .05
0.4 ± 0.3
p < .05
LV strokework index
1.0 ± 0.6
0.2 ± 0.2 p < .05
(g/m.kg)
hepatic blood flow
+226 ± 68 +70 ± 34
(% baseline)
Rogers et al: Effects of CVVH on regional
blood flow and nitric oxide production in
canine endotoxic shock.
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
Diagnosis
N
Survival Diagnosis
N
%Survival
BMT
26
42%
HUS
16
94%
TLS/Malig
17
58%
ATN
46
67%
CHD
47
39%
Liver Tx
22
17%
Heart Tx
13
67%
Sepsis
39
33%
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 EndStage Lung Disease (1 each)
Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
Percent Fluid Overload Calculation
[
% FO at CVVH initiation =
Fluid In - Fluid Out
ICU Admit Weight
Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
]
* 100%
Renal Replacement Therapy in the PICU
Pediatric Literature
4
5
4
0
3
5
3
0
p=
0
.0
3
2
5
%FOatCVVHInitiation
• 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)
2
0
1
5
1
0
5
0
M
e
a
n
+
S
E
M
e
a
n
-S
E
D
e
a
th
Goldstein SL et al: Pediatrics 2001 Jun;107(6):1309-12
O
U
T
C
O
M
E
S
u
rv
iv
a
l
M
e
a
n
PRISM at CRRT Initiation and Outcome
0
3
6
2
2
2
PRISMATCRRTInitiation
8
1
4
1
0
1
6
2
l
rviva
u
S
th
a
e
D
E
M
O
C
T
U
O
P < 0.0005
v.
e
.D
td
S
±
rr.
.E
td
S
±
n
a
e
M
Fluid Overload and Outcome: Renal Failure Only
4
0
3
5
3
0
2
5
PercentFluidOverloadatCRRTInitiation
2
0
1
5
1
0
5
0
-5
D
e
a
th
S
u
rviva
l
O
U
T
C
O
M
E
P < 0.05
±
S
td
.D
e
v.
±
S
td
.E
rr.
M
e
a
n
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
Peter Skippen, MD
Stanford University
British Columbia Children’s Hospital
Steven Alexander, MD
Stuart L. Goldstein, MD
Stanford University
Baylor College of Medicine
Catherine Headrick, RN
Timothy E. Bunchman, MD
Children’s Medical Center Dallas
University of Alabama
Patrick D. Brophy, MD
University of Michigan