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Drug Dosing in PCRRT. Deb Pasko, Pharm.D Pharmacy Clinical Specialist, PICU University of Michigan Health System. CRRT Solute Removal. Lots of things removed by CRRT! Drugs, nutrients… FD&C Blue dye #1… Crit Care Med, Mar 2002. Dialysate is used (lactated Ringers, PD solution, etc)

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Drug dosing in pcrrt

Drug Dosing in PCRRT

Deb Pasko, Pharm.D

Pharmacy Clinical Specialist, PICU

University of Michigan Health System


Crrt solute removal
CRRT Solute Removal

  • Lots of things removed by CRRT!

  • Drugs, nutrients… FD&C Blue dye #1…

  • Crit Care Med, Mar 2002


Diffusive therapies

Dialysate is used (lactated Ringers, PD solution, etc)

Good for small solute removal (<500 Da)

diffusion rate inversely proportional to MW

Efficiency of solute removal dependent on

Blood flow

Dialysate flow

Filter type

Solute molecular weight

Less good for larger solutes (MM, Vancomycin?)

Diffusive Therapies



Rrt drug removal mechanisms
RRT Drug Removal Mechanisms 1998;31:1019-27

  • Diffusion

  • Convection

  • Adsorption

    • May be important for 2 Microglobulin removal

      • Especially for PMMA membranes

    • Rarely important for drugs


Vancomycin overdose
Vancomycin overdose 1998;31:1019-27

  • 16 day old full-term infant presented to OSH hypothermia, bradycardia, and hypovolemia. Progressed to develop cardiac arrest, transferred to U of M. Dry wt. 2kg.

  • Received 3 doses of vancomycin 100mg/kg

  • Initial vancomycin serum concentration was 195.5 mg/L (desired peak conc ~35mg/L)


Vancomycin overdose case
Vancomycin overdose case 1998;31:1019-27


Hemodialyzer differences are they important in cvvhd
Hemodialyzer differences: Are they important in CVVHD? 1998;31:1019-27

Most published drug dosing guidelines assume they are all equal in terms of drug removal

most hemofilters are high-permeability with large pores

frequently high flux hemodialyzers were used for CRRT

Vancomycin CVVHD clearance differences between different hemodialyzers

Joy MS, et al. Am J Kidney Dis 1998 Jun;31(6):1019-27


Convective therapies hemofiltration

No dialysate, removes plasma water as it seeps through membrane

Removes small and large molecules easily

as long as they can fit through membrane

Protein binding important determinant – sieving coefficient

<15,000 Da has potential to be removed substantially

Drug removal easy to calculate

based on sieving coefficient – usually a function of PPB

ultrafiltrate concentration/plasma concentration

Convective Therapies (Hemofiltration)


Doses derived via sieving coefficient
Doses Derived Via Sieving Coefficient membrane

  • Sieving Coefficient (SC) known for many drugs

  • SC= UF/A

  • Comes from CAVH or CVVH data

  • Assumption often made that SC can be used CVVHD when dialysate rate is low.

    • Saturation coefficient (Sa) more properly used in CVVHD

  • SC related to protein binding of drugs

    • Protein binding may differ in critically ill vs. normals



Drug dosing recommendations based on sieving coefficient sc
Drug Dosing recommendations based on Sieving Coefficient (SC)

  • Clearance total = ClCRRT + Cl residual renal + Cl non-renal

  • SC equations only account for ClCRRT

  • What about other clearances?

  • Cl residual renal usually not an issue in CRRT patients

  • Cl non-rena l not always available for drugs



Crrt challenges drug dosing
CRRT Challenges: Drug Dosing normal renal function and ESRD

Does CVVH removal = CVVHDF = CVVHD???

Molecular weight determines whether solute diffuses well

Vancomycin (MW 1450 Da)

Aminoglycosides (MW ~450 Da)

High dialysate flow rates don’t allow sufficient time for diffusion

Probably not an issue when flow = ~1000ml/1.73m2/hr

Does Sieving Coefficient (CVVH) = Saturation Coefficient (CVVHD)???


Crrt challenges drug dosing1
CRRT Challenges: Drug Dosing normal renal function and ESRD

NO PEDIATRIC DOSING!!!!!!!

Most CRRT dosing guidelines based on CVVH @ UFR of 1000 mL/hr

Trend is for higher UFR and HD flows

UM uses 2L/1.73m2/hr

Higher flow rates now achievable with new machines

solute removal (H, HD, HDF) mechanisms


Pediatric crcl
Pediatric CrCl normal renal function and ESRD

  • CLCR = K x L/SCR

    • Where ClCR = creatinine clearance in ml/min/1.73m2

      K = constant of proportionality age specific

      AgeK

      LBW ≤ 1yo 0.33

      Full-term ≤ 1yo 0.45

      2-12 0.55

      13-21 female 0.55

      13-21 male 0.70


Calculating total clearance
Calculating Total Clearance normal renal function and ESRD

  • Example:

    • 2yo, 15kg, L = 60cm, SCR = 1.0 mg/dL, K = 0.55

    • CrCl = 0.55 x 60/1 = 33ml/min/1.73m2

    • However, if anuric renal clearance = zero

    • PCRRT = CVVHD of 2L/1.73m2/hr, BSA of 0.5

      • Qd = ~578ml/hr

        • (38.5ml/kg, or 9.6ml/min/0.5 BSA, or 33.2ml/min/1.73ml/min)

        • If this patient was not anuric and had renal fxn as above = 66ml/min/1.73m2, and we need to adjust accordingly


Adjusting doses based on cl
Adjusting doses based on Cl normal renal function and ESRD

  • Using the previous example for vancomycin:

    • >50ml/min/1.73m2 = q6-8h dosing

    • 30-50ml/min/1.73m2 = q12h dosing

      It is easy to under-dose or possibly overdose using this method, need to be careful

      Is CrCl the most reliable method for children?


What drugs do we care about
What drugs do we care about? normal renal function and ESRD

  • Drugs are “dialyzable” if:

    • Small MW

    • Small volume of distribution

    • Not highly protein bound

    • Water soluble


Drug dosing in pcrrt
Case normal renal function and ESRD

  • 10mof, ALL s/p chemo & BMT x60days, now admitted to unit for increased O2 needs requiring vent support, GVHD gut/liver stage IV and in septic shock.

  • PE: T 39.1, HR 180, BP 60/30, wt. 8.5kg, Ht 60cm

  • I/O: 900/50 over past 24hrs (0.24cc/kg/hr)

  • Baseline Scr = 0.3mg/dL, now 0.6mg/dL

  • Meds: Dopamine, Cefepime, Gentamicin, Linezolid, Voriconazole, Pentamidine, Hydrocortisone, Protonix, TPN/lipids, Dilaudid/Ativan, Phenobarb


Case con t
Case con’t normal renal function and ESRD

  • AM BC shows Pseudomonas aer. and VRE

  • Order written to start CVVH @ 2L/1.73m2/hr,

    • Calc. clearance: BSA = 0.38m2 (7.24ml/min, or 33ml/min/1.73m2)

    • What drugs do we care about?

    • If you can titrate we don’t necessarily care

    • For this patient antibiotics are going to save her life


So what drugs need adjustment

Dopamine? normal renal function and ESRD

Cefepime?

Gentamicin?

Linezolid?

Voriconazole?

Pentamidine?

Hydrocortsione?

Protonix?

TPN?

Dilaudid?

Ativan?

So what drugs need adjustment?


Antibiotic guidelines um
Antibiotic Guidelines UM normal renal function and ESRD


Linezolid clearance during cvvhdf
Linezolid Clearance During CVVHDF normal renal function and ESRD

  • 85 yo 90 kg anuric male in the SICU with documented abdominal VRE infection

  • Linezolid 600 mg IV q12

  • No published literature on CRRT removal

  • CVVHDF regimen:

    • dialysate flow rate 2000 mL/hr

    • mean ultrafiltrate production rate of 775 mL/hr


Linezolid calculations
Linezolid Calculations normal renal function and ESRD

Half-life, elimination rate, and volume of distribution

  • Sieving coefficient (SC) was calculated:

    SC= CE / Cp, Cp = (CA + CV) / 2

  • The clearance from CRRT (Cl CRRT) calculated as:

    Cl CRRT = (QD + QF) x SC

    • CE = the concentration in the effluent

    • Cp is the linezolid concentration in the plasma

    • CA is the linezolid concentration in the plasma drawn from the pre-filter sampling port

    • CV is the linezolid concentration in the plasma drawn from the post-filter sampling port.


Linezolid results
Linezolid Results normal renal function and ESRD

  • Vd = 60L (normal 40-60L)

  • T1/2 = 7.5-9 hrs during CVVHDF (8hrs)

  • SC = 0.77– 0.81 (PPB 30%)

  • ClCRRT = 36.5 mL/min with mean effluent flow rate of 46.2 mL/min

    • (normal ClR 40mL/min)

  • No dosage change necessary

  • First measured linezolid CRRT report

  • Kraft MK, Pasko DA, DePestel DD, Ellis JJ, Peloquin CA, Mueller BA. Linezolid clearance during continuous venovenous hemodiafiltration: A case report. Pharmacotherapy. 2003 Aug;23(8):1071-5.


So what drugs need adjustment1

Dopamine? normal renal function and ESRD

Cefepime?

Gentamicin?

Linezolid?

Voriconazole?

Pentamidine?

Hydrocortsione?

Protonix?

TPN?

Dilaudid?

Ativan?

So what drugs need adjustment?


Gentamicin pharmacokinetics
Gentamicin pharmacokinetics normal renal function and ESRD

  • This patient weighing 8.5kg receives a gent dose of 21mg (2.5mg/kg)

  • What peak concentration (mg/L) can be expected?

  • Volume of distribution of gent is 0.2-0.4L/kg

  • 0.25L/kg is normal, but in fluid overloaded patients, expect higher values. If 0.3L/kg =

    • 2.55 Liters = Vd

    • 21mg/2.55L = 8.2 mg/L assuming no drug removal


Gent kinetics con t
Gent kinetics con’t normal renal function and ESRD

  • 30 min after the 21mg dose is done a peak is done = 4.0mg/L

  • What is the patients actual volume of distribution?

    • 5.1 Liters = 0.6L/kg (actually double!!!!)


Gent kinetics con t1
Gent kinetics con’t normal renal function and ESRD

  • Peak was 4.0 mg/L

  • 12 hours later a random level was done

    • 1.0 mg/L

    • What is the half-life (t1/2) of gentamicin?

    • 4.0mg/L → 2.0mg/L → 1.0mg/L in 12 hours

    • 6 hour half-life

    • Ln 4 – ln 1 = kel = 0.115

      • 12hrs


Gent kinetics final
Gent kinetics FINAL normal renal function and ESRD

  • Half-life = 0.693 / 0.115 = 6 hours


So what drugs need adjustment2

Dopamine? normal renal function and ESRD

Cefepime?

Gentamicin?

Linezolid?

Voriconazole?

Pentamidine?

Hydrocortsione?

Protonix?

TPN?

Dilaudid?

Ativan?

So what drugs need adjustment?


Phenobarbital case
Phenobarbital case normal renal function and ESRD

  • 2 wof transferred to UM w/ severe CHF w/ AV valve regurgitation and seizure dx

  • 1/20 had cleft AV valve repair w/ PDA ligation, went on VA ECMO, developed ARF

  • 1/24 went on CVVHD in-line w/ECMO circuit

  • Wt 3.45kg (dry), Ht 47cm, BSA 0.21m2

  • Qd set at 300ml/hr (~2400ml/1.73m2/hr)

  • Quf at 69ml/hr (drips + no net loss)

  • Hemodiafilter = Mini-Plus, 0.08m2


Phenobarbital case1
Phenobarbital case normal renal function and ESRD

  • Phenobarbital dose pre dialysis initiation = 25mg q24h = 7.2mg/kg = 35.5mg/L serum concentration

  • CVVHD started 1/24

    • 1/25 Pb = 14.2 mg/L

    • 1/26 Pb = 9.6

    • 1/28 Pb = 13.9 @ 0700

    • 1/28 1400 sequential levels done


Phenobarbital case2
Phenobarbital case normal renal function and ESRD


Drug dosing problems in high volume hemofiltration
Drug dosing problems in normal renal function and ESRDhigh volume hemofiltration

Most drugs have > 2 compartments (pools)

like urea measurements during HD

high volume hemofiltration removes drug from peripheral compartment rapidly

how fast can drug transfer from deeper compartment?

Many drugs rapidly stripped from first pool


Phenobarb case final
Phenobarb case final normal renal function and ESRD

  • SC = 0.44

  • ClCRRT =

    • 2.7ml/0.21m2/min or 22.3ml/1.73m2/min (40)

    • Vd = 3.24L/kg (0.9L/kg, normal 0.6)

    • New maintenance dose to maintain level of 25mg/L =

      • 32.4mg (~10mg/kg) IV q8hrs

      • Original maintenance dose 25mg q24hrs



Iv drug administration drug removed as it is infused

Drug is infused into compartment being filtered/dialyzed normal renal function and ESRD

reduced ability to distribute into tissues (k12)

serum concentrations during infusion higher than usual “therapeutic” serum concentration

6L/hr = 1L/10 min = entire plasma volume/hr

Qb 150 ml/min Quf/hd 33 mL/min =

22% of volume removed

“first-pass” effect

IV drug administration: Drug removed as it is infused


Drug prescribing in renal failure edited by george aronoff et al
Drug Prescribing in Renal Failure normal renal function and ESRDedited by George Aronoff et al

  • Commonly carried text by pharmacists

  • http://www.kdp-baptist.louisville.edu/renalbook/

  • New edition to come out soon

  • Recommendations for new drugs

  • IHD and CRRT recommendations

  • Pediatric recommendations


Strength of evidence
Strength of Evidence normal renal function and ESRD

  • Controlled studies in humans or large case series experience

  • Small Case Series or Human Uncontrolled Trials

  • Animal or In Vitro Data

  • Known Drug Characteristics

    • Vast majority are of this type

58 drugs are A->C


D known drug characteristics
D. “Known drug characteristics“ normal renal function and ESRD

  • These recommendations made by panel of nephrologists and pharmacists

  • Based on:

    • Protein Binding Information

    • Volume of Distribution

    • Molecular Weight


When in doubt start here
When in doubt, start here… normal renal function and ESRD

  • Blood flow, filter type are not very important.

  • Find out

    • In CVVHD: Dialysate flow rate (ml/hr)

      • Usually 2 L/1.73m2/hr (33 mL/1.73m2/min)

    • In CVVH: Substitution Fluid rate (ml/hr)

      • Usually 2L/1.73m2/hr (33 mL/1.73m2/min)

  • Add this to patient’s native Cr Cl (ml/1.73m2/min)

  • This is patient’s new Cr Cl  dose accordingly

  • Works in most cases…is good enough for initial estimates. Follow up with drug level monitoring.


Pcrrt roller pump
PCRRT & Roller pump normal renal function and ESRD


Future research needed
Future research needed normal renal function and ESRD

  • ECMO/PCRRT

  • MARS

  • RAD


Crrt dosing should not be confusing
CRRT Dosing should not be confusing! normal renal function and ESRD