Drug Kinetics and CRRT: Parameters and Principles
Morgan R. Cole, Pharm.D., BCPS
Manager, HDVCH Pharmacy Services
Clinical Pharmacy Specialist,
Pediatric Critical Care
Objectives
Describe CRRT principles Understand basic pharmacokinetic (Pk)
parameters Describe CRRT principles and effects on Pk Describe variances in Pk parameters
Critically ill Pediatrics & Neonates
Understand assumptions to estimate dosing regimens in pediatric CRRT
CRRT Principles
CRRT Principles
Heparin Anticoagulation Citrate Anticoagulation
Acid Citrate Dextrose – Anticoagulation (ACD-A)
Calcium Chloride Replacement Convective Clearance
Hemofiltration ~ Ultrafiltration Filter Replacement Fluid (FRF)
Diffusive Clearance Hemodialysis Dialysate
CRRT Principles
Usual circuit priming volume ~ 100-150mL Blood, Saline, & Albumin
Usual Blood Flow Rate
~ 3-5mL/kg/min
Tubing and Membrane Filter impact Adsorption
Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008
Ultrafiltration
Adapted with permission from: Gambro Training Manual 1 and 2 Slides from Gambro Training package Last Update: February, 2008
Movement of fluid through a semi-permeable membrane caused by a pressure gradient
Positive, negative and osmotic pressure from non-permeable solutes
Convective Clearance
Movement of solutes with water flow, “solvent drag”.
The more fluid moved through a semi-permeable membrane, the more solutes that are removed.
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
Movement of solutes from an area of higher concentration to an area of lower concentration.
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
Usual circuit priming volume ~ 100-150mL Increases Volume of Distribution (Vd) Usual adult blood volume ~5000mL (0.07L/kg or 70mL/kg) Usual pediatric blood volume ~80mL/kg
Tubing binds drug Increases Vd Adsorption
Membrane Filter binds drug by “Gibbs-Donnan Effect” Increases Vd Adsorption
CRRT Impact on Kinetic Parameters
Usual Blood Flow Rate ~ 3-5mL/kg/min Higher the rate leads to increased Clearance (Cl)
Ultrafiltrate Rate ~ Filter Replacement Fluid (FRF) Rate if the patient is kept in even fluid balance ~ 35-40mL/kg/hr (2.5L/m2/hr) Higher the rate leads to increased Cl
Dialysate Rate ~ 35-40mL/kg/hr (2.5L/m2/hr) Higher the rate leads to increased Cl
Sample sieving coefficients (S)
Medication S
Gentamicin ~0.8
Tobramycin ~0.8
Amikacin ~0.9
Ceftazidime ~0.85
Cefepime ~0.85
Imipenem ~0.8
Meropenem ~0.8
Medication S
Levofloxacin ~0.8
Moxifloxacin ~0.85
Ciprofloxacin ~0.75
Pip / Tazo ~>1
Linezolid ~0.8
Daptomycin ~0.15
Vancomycin ~0.7Adapted from Golper, Dialysis Transpl 1993;22:185-188DelDot, Br J Clin Pharmacol 2004;58:3,259-268Malone, Antimicrobial Agents and Chemotherapy 2001;3148-3155Mariat, Crit Care 2006;10:1,R26Fuhrmann, Journal of Antimicrobial Chemotherapy 2004;54,780-784Guenter, Pharmacotherapy 2002;2:175-83Tegeder, Antimicrobial Agents and Chemotherapy 1997;41(12):2640-2645
Valtonen, Journal of Antimicrobial Chemotherapy 2001;48,881-885Valtonen, Journal of Antimicrobial Chemotherapy 2000;45,701-704Kraft, Pharmacotherapy 2003;23(8):1071-1075Churchwell, Blood Purif 2006;24(5-6):548-554
CRRT Impact on Kinetic Parameters
Combined hemofiltration plus dialysis (Cldf) Convective Clearance (Filter Replacement Fluid (FRF))
Diffusive Clearance (Dialysate)
Cldf = Qf * S + Qd * Sd
Native clearance must be taken into account if the patient maintains renal function despite CRRT support
Convective + Diffusive Clearance
Ultrafiltrate Rate ~
Filter Replacement Fluid (FRF) Rate
~ 35-40mL/kg/hr
(2.5L/m2/hr)
Dialysate Rate
~ 35-40mL/kg/hr
(2.5L/m2/hr)
Clinical Pearls
Medications unaffected by CRRT Ceftriaxone Metronidazole Clindamycin Lansoprazole Pantoprazole Cyclosporin Phenytoin
Clinical Pearls
Due to extracorporeal clearance provided by CRRT remember to hold the following if CRRT circuit goes down and consult the primary service /nephrology service Total Parenteral Nutrition / Enteral Nutrition Antibiotics except ceftriaxone, clindamycin,
metronidazole Potassium, and Phosphorus supplementation H2 receptor antagonists
Clinical Pearls
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 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
Understand CRRT principles Ultrafiltration / Convective vs Diffusive Clearance
Understand basic pharmacokinetic (Pk) parameters Vd / Pb / Cl / t1/2
Describe variances in Pk parameters Critically ill Pediatrics & Neonates
Understand CRRT principles and effects on Pk Adsorption / Vd / Cl
Understand assumptions to estimate dosing regimens in pediatric CRRT Pb / MW / S / Sd / Clf / Cld / Cldf
References
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;54,780-
784 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