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Drug Kinetics and CRRT: Parameters and Principles

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

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Drug Kinetics and CRRT: Parameters and Principles

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  1. Drug Kinetics and CRRT: Parameters and Principles Morgan R. Cole, Pharm.D., BCPS Manager, HDVCH Pharmacy Services Clinical Pharmacy Specialist, Pediatric Critical Care

  2. 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

  3. CRRT Principles

  4. 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

  5. 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

  6. Ultrafiltration • Movement of fluid through a semi-permeable membrane caused by a pressure gradient • 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

  7. 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

  8. 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

  9. Pharmacokinetic Parameters

  10. 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

  11. 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

  12. Sample sieving coefficients (S) 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 Adapted from 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

  13. 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

  14. 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) Convective + Diffusive Clearance

  15. Clinical Pearls • Medications unaffected by CRRT • Ceftriaxone • Metronidazole • Clindamycin • Lansoprazole • Pantoprazole • Cyclosporin • Phenytoin

  16. 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

  17. 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.

  18. 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

  19. 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

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