Transcript 05-20-08 Kinetics CRRT - Pediatric Continuous Renal

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



Calcium Chloride Replacement
Convective Clearance



Acid Citrate Dextrose –
Anticoagulation (ACD-A)
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

Movement of fluid
through a semipermeable 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
Convective Clearance

Movement of solutes
with water flow, “solvent
drag”.

The more fluid moved
through a semipermeable 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
Pharmacokinetic Parameters

Volume of Distribution (Vd) = Volume a drug
would occupy if one compartment model
exists (conceptual) L / Total Body Weight (TBW) kg
Vd L/kg = Volume L / TBW kg
Loading Dose (LD) mcg/kg = Vd L/kg * serum concentration mcg/mL

Protein Binding (Pb) describes the bound
fraction of drug but infers the free fraction of
drug available for pharmacological action

Albumin is the largest contributor to protein
binding, though other proteins contribute
Pharmacokinetic Parameters

Clearance describes the elimination of drug
(volume) mL from the body per unit time min
Cl mL/min = Volume mL / Time min
Maintenance Dose (MD) mcg = Cl mL/min * serum concentration
mcg/mL * dosing interval min

Terminal elimination half life (t1/2) is the time
hours that it takes for the serum concentration
of a drug to be reduced by 50%
t1/2 hours = 0.693 * ke hours-1
ke hours-1 = Vd L * Cl mL/min
Pharmacokinetic Parameters
Pk
Parameter
Healthy
individual
Critically ill patient variation
Increases
Decreases
Vd
One compartment model
Two compartment model
Volume resuscitation
Ascites
Capillary leak
Edema
Dehydration
Volume loss
Diarrhea/Vomitting
Pb
Total protein = 5-7
Albumin = 3-5
IVIG administration
Albumin administration
Adequate nutrition
Hypoproteinemia
Hypoalbuminemia
Acidosis / Fever / Uremia
Medication competition
Cl
First order kinetics
Zero order kinetics
Hemodialysis
Peritoneal dialysis
CRRT
Oliguric renal failure
Anuric renal failure
Shock states
t1/2
First order kinetics
Zero order kinetics
Hemodialysis
Peritoneal dialysis
CRRT
Oliguric renal failure
Anuric renal failure
Shock states
CRRT Impact on Kinetic Parameters

Usual circuit priming volume ~ 100-150mL




Tubing binds drug



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”


Increases Vd
Adsorption
CRRT Impact on Kinetic Parameters

Usual Blood Flow Rate ~ 3-5mL/kg/min


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 Clearance (Cl)
Higher the rate leads to increased Cl
Dialysate Rate ~ 35-40mL/kg/hr (2.5L/m2/hr)

Higher the rate leads to increased Cl
CRRT Impact on Kinetic Parameters

Convective Clearance (Filter Replacement Fluid (FRF))


Hemofiltration = Ultrafiltration
Clearance (Clf) depends on the sieving coefficient
(S), small molecules (S = 1) and low protein bound
drugs pass freely through the membrane filter
based on pressure
S=
Drug concentration in filtrate (Cf)
Drug concentration in plasma (Cp)
*Clearance depends on Protein binding (Pb), independent from Molecular weight

Clf mL/min = Qf mL/min * S
**Qf is the ultrafiltrate rate mL/min = FRF rate mL/min and depends on
membrane surface area and transmembrane pressure
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

Diffusive Clearance (Dialysate)


Hemodialysis
Clearance (Cld) depends on the dialysate saturation
(Sd), small molecules including small, low protein
bound drugs pass through the membrane filter
based on diffusion & pressure
Sd =
Drug concentration in dialysate (Cd)
Drug concentration in plasma (Cp)
*Clearance depends on Protein binding (Pb) & Molecular weight <40,000 daltons

Cld mL/min = Qd mL/min * Sd
**Qd is the dialysate rate mL/min and depends on membrane surface
area, pore size, and blood flow rate and dialysate rate
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 unaaffected 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


Understand basic pharmacokinetic (Pk) parameters



Critically ill
Pediatrics & Neonates
Understand CRRT principles and effects on Pk


Vd / Pb / Cl / t1/2
Describe variances in Pk parameters


Ultrafiltration / Convective vs Diffusive Clearance
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;54,780784
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