Transcript No Slide Title - Pediatric Continuous Renal Replacement Therapy

Drug Kinetics and CRRT:
Parameters and Principles
Morgan R. Cole, Pharm.D., BCPS
Manager, HDVCH Pharmacy Services
Clinical Pharmacy Specialist,
Pediatric Critical Care
Objectives
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Describe CRRT principles
Understand basic pharmacokinetic (Pk)
parameters
Describe CRRT principles and effects on Pk
Describe variances in Pk parameters
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Critically ill
Pediatrics & Neonates
Understand assumptions to estimate dosing
regimens in pediatric CRRT
CRRT Principles
CRRT Principles
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Heparin Anticoagulation
Citrate Anticoagulation
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Calcium Chloride Replacement
Convective Clearance
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Acid Citrate Dextrose –
Anticoagulation (ACD-A)
Hemofiltration ~ Ultrafiltration
Filter Replacement Fluid (FRF)
Diffusive Clearance
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Hemodialysis
Dialysate
CRRT Principles
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Usual circuit priming
volume ~ 100-150mL
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Blood, Saline, & Albumin
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Usual Blood Flow Rate
~ 3-5mL/kg/min
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Tubing and Membrane
Filter impact
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Adsorption
Adapted with permission from:
Gambro Training Manual 1 and 2 Slides from Gambro Training package Last
Update: February, 2008
Ultrafiltration
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Movement of fluid
through a semipermeable membrane
caused by a pressure
gradient
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Positive, negative and
osmotic pressure from
non-permeable solutes
Adapted with permission from:
Gambro Training Manual 1 and 2 Slides from Gambro Training package Last
Update: February, 2008
Convective Clearance
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Movement of solutes
with water flow, “solvent
drag”.
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The more fluid moved
through a semipermeable membrane,
the more solutes that are
removed.
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Replacement Fluid is
used to create
convection
Adapted with permission from:
Gambro Training Manual 1 and 2 Slides from Gambro Training package Last
Update: February, 2008
Diffusive Clearance
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Movement of solutes
from an area of
higher concentration
to an area of lower
concentration.
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Dialysate is used to
create a concentration
gradient across a
semi-permeable
membrane.
Adapted with permission from:
Gambro Training Manual 1 and 2 Slides from Gambro Training package Last
Update: February, 2008
Pharmacokinetic
Parameters
CRRT Impact on Kinetic Parameters
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Usual circuit priming volume ~ 100-150mL
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Tubing binds drug
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Increases Volume of Distribution (Vd)
Usual adult blood volume ~5000mL (0.07L/kg or 70mL/kg)
Usual pediatric blood volume ~80mL/kg
Increases Vd
Adsorption
Membrane Filter binds drug by “Gibbs-Donnan Effect”
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Increases Vd
Adsorption
CRRT Impact on Kinetic Parameters
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Usual Blood Flow Rate ~ 3-5mL/kg/min
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Ultrafiltrate Rate ~ Filter Replacement Fluid
(FRF) Rate if the patient is kept in even fluid
balance ~ 35-40mL/kg/hr (2.5L/m2/hr)
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Higher the rate leads to increased Clearance (Cl)
Higher the rate leads to increased Cl
Dialysate Rate ~ 35-40mL/kg/hr (2.5L/m2/hr)
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Higher the rate leads to increased Cl
Sample sieving coefficients (S)
Medication
Gentamicin
Tobramycin
Amikacin
S
~0.8
~0.8
~0.9
Medication
Levofloxacin
Moxifloxacin
Ciprofloxacin
S
~0.8
~0.85
~0.75
Ceftazidime
Cefepime
Imipenem
~0.85
~0.85
~0.8
Pip / Tazo
Linezolid
Daptomycin
~>1
~0.8
~0.15
Meropenem
~0.8
Vancomycin
~0.7
Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885
Adapted from Golper, Dialysis Transpl 1993;22:185-188
Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704
DelDot, Br J Clin Pharmacol 2004;58:3,259-268
Kraft, Pharmacotherapy 2003;23(8):1071-1075
Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155
Churchwell, Blood Purif 2006;24(5-6):548-554
Mariat, Crit Care 2006;10:1,R26
Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780-784
Guenter, Pharmacotherapy 2002;2:175-83
Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12):2640-2645
CRRT Impact on Kinetic Parameters
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Combined hemofiltration plus dialysis (Cldf)
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Convective Clearance (Filter Replacement Fluid (FRF))
Diffusive Clearance (Dialysate)
Cldf = Qf * S + Qd * Sd
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Native clearance must be taken into account if
the patient maintains renal function despite
CRRT support
Convective + Diffusive Clearance
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Ultrafiltrate Rate ~
Filter Replacement
Fluid (FRF) Rate
~ 35-40mL/kg/hr
(2.5L/m2/hr)
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Dialysate Rate
~ 35-40mL/kg/hr
(2.5L/m2/hr)
Clinical Pearls
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Medications unaffected by CRRT
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Ceftriaxone
Metronidazole
Clindamycin
Lansoprazole
Pantoprazole
Cyclosporin
Phenytoin
Clinical Pearls
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Due to extracorporeal clearance provided by
CRRT remember to hold the following if
CRRT circuit goes down and consult the
primary service /nephrology service
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Total Parenteral Nutrition / Enteral Nutrition
Antibiotics except ceftriaxone, clindamycin,
metronidazole
Potassium, and Phosphorus supplementation
H2 receptor antagonists
Clinical Pearls
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Due to extracorporeal clearance provided by CRRT
remember to monitor closely for toxicity + reduce the
dose for the following if CRRT circuit goes down and
consult the primary service /nephrology service
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Sedation (Midazolam, Lorazepam, Fentanyl, & Morphine)
Pressors (Norepinephrine, Epinephrine, & Dopamine)
Inotropes (Milrinone, Dobutamine, & Epinephrine)
If a new circuit is initiated, a reloading phase will
occur until complete adsorption occurs and a new
steady state with the circuit is reached.
Summary
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Understand CRRT principles
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
Understand basic pharmacokinetic (Pk) parameters
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

Critically ill
Pediatrics & Neonates
Understand CRRT principles and effects on Pk
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
Vd / Pb / Cl / t1/2
Describe variances in Pk parameters
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Ultrafiltration / Convective vs Diffusive Clearance
Adsorption /  Vd /  Cl
Understand assumptions to estimate dosing regimens in
pediatric CRRT
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Pb / MW / S / Sd / Clf / Cld / Cldf
References
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Gambro Renal Products, Intensive Care Division, 14143 Denver
West Parkway Lakewood, Co. 80401
Golper, Dialysis Transpl 1993;22:185-188
DelDot, Br J Clin Pharmacol 2004;58:3,259-268
Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155
Mariat, Crit Care 2006;10:1,R26
Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780784
Guenter, Pharmacotherapy 2002;2:175-83
Tegeder, Antimicrobial Agents and Chemotherapy
1997;41(12):2640-2645
Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885
Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704
Kraft, Pharmacotherapy 2003;23(8):1071-1075
Churchwell, Blood Purif 2006;24(5-6):548-554