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Drug Dosing in PCRRT

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... always available for drugs ... Most drugs have 2 compartments (pools) like urea ... Recommendations for new drugs. IHD and CRRT recommendations ... – PowerPoint PPT presentation

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Title: Drug Dosing in PCRRT


1
Drug Dosing in PCRRT
  • Deb Pasko, Pharm.D
  • Pharmacy Clinical Specialist, PICU
  • University of Michigan Health System

2
CRRT Solute Removal
  • Lots of things removed by CRRT!
  • Drugs, nutrients FDC Blue dye 1
  • Crit Care Med, Mar 2002

3
Diffusive Therapies
  • Dialysate is used (lactated Ringers, PD solution,
    etc)
  • Good for small solute removal (
  • 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?)

4
Joy MS, Matzke GR, Frye RF, Palevsky PM. AJKD
1998311019-27.
5
RRT Drug Removal Mechanisms
  • Diffusion
  • Convection
  • Adsorption
  • May be important for ?2 Microglobulin removal
  • Especially for PMMA membranes
  • Rarely important for drugs

6
Vancomycin overdose
  • 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)

7
Vancomycin overdose case
8
Hemodialyzer differences Are they important in
CVVHD?
  • 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
    Jun31(6)1019-27

9
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
  • substantially
  • Drug removal easy to calculate
  • based on sieving coefficient usually a function
    of PPB
  • ultrafiltrate concentration/plasma concentration

10
Doses Derived Via Sieving Coefficient
  • 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

11
Sieving Coefficient Protein Binding
12
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

13
Non-renal clearance rates of selected drugs in
patients with normal renal function and ESRD
14
CRRT Challenges Drug Dosing
  • Does CVVH removal CVVHDF CVVHD???
  • Molecular weight determines whether solute
    diffuses well
  • Vancomycin (MW 1450 Da)
  • Aminoglycosides (MW 450 Da)
  • High dialysate flow rates dont allow sufficient
    time for diffusion
  • Probably not an issue when flow
    1000ml/1.73m2/hr
  • Does Sieving Coefficient (CVVH) Saturation
    Coefficient (CVVHD)???

15
CRRT Challenges Drug Dosing
  • NO PEDIATRIC DOSING!!!!!!!
  • Most CRRT dosing guidelines based on CVVH _at_ 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

16
(No Transcript)
17
Pediatric CrCl
  • CLCR K x L/SCR
  • Where ClCR creatinine clearance in
    ml/min/1.73m2
  • K constant of proportionality age specific
  • Age K
  • LBW 1yo 0.33
  • Full-term 1yo 0.45
  • 2-12 0.55
  • 13-21 female 0.55
  • 13-21 male 0.70

18
Calculating Total Clearance
  • 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

19
Adjusting doses based on Cl
  • 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?

20
What drugs do we care about?
  • Drugs are dialyzable if
  • Small MW
  • Small volume of distribution
  • Not highly protein bound
  • Water soluble

21
Case
  • 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

22
Case cont
  • AM BC shows Pseudomonas aer. and VRE
  • Order written to start CVVH _at_ 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 dont necessarily care
  • For this patient antibiotics are going to save
    her life

23
So what drugs need adjustment?
  • Dopamine?
  • Cefepime?
  • Gentamicin?
  • Linezolid?
  • Voriconazole?
  • Pentamidine?
  • Hydrocortsione?
  • Protonix?
  • TPN?
  • Dilaudid?
  • Ativan?

24
Antibiotic Guidelines UM
25
Linezolid Clearance During CVVHDF
  • 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

26
Linezolid Calculations
  • 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.

27
Linezolid Results
  • 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
    Aug23(8)1071-5.

28
So what drugs need adjustment?
  • Dopamine?
  • Cefepime?
  • Gentamicin?
  • Linezolid?
  • Voriconazole?
  • Pentamidine?
  • Hydrocortsione?
  • Protonix?
  • TPN?
  • Dilaudid?
  • Ativan?

29
Gentamicin pharmacokinetics
  • 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

30
Gent kinetics cont
  • 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!!!!)

31
Gent kinetics cont
  • 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

32
Gent kinetics FINAL
  • Half-life 0.693 / 0.115 6 hours

33
So what drugs need adjustment?
  • Dopamine?
  • Cefepime?
  • Gentamicin?
  • Linezolid?
  • Voriconazole?
  • Pentamidine?
  • Hydrocortsione?
  • Protonix?
  • TPN?
  • Dilaudid?
  • Ativan?

34
Phenobarbital case
  • 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

35
Phenobarbital case
  • 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 _at_ 0700
  • 1/28 1400 sequential levels done

36
Phenobarbital case
37
Drug dosing problems in high 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

38
Phenobarb case final
  • 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

39
Mueller BA, Pasko DA. Artif Organs 200327808-14.
40
IV drug administration Drug removed as it is
infused
  • Drug is infused into compartment being
    filtered/dialyzed
  • 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

41
Drug Prescribing in Renal Failureedited 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

42
Strength of Evidence
  • 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
43
D. Known drug characteristics
  • These recommendations made by panel of
    nephrologists and pharmacists
  • Based on
  • Protein Binding Information
  • Volume of Distribution
  • Molecular Weight

44
When in doubt, start here
  • 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 patients native Cr Cl
    (ml/1.73m2/min)
  • This is patients new Cr Cl ? dose accordingly
  • Works in most casesis good enough for initial
    estimates. Follow up with drug level monitoring.

45
PCRRT Roller pump
46
Future research needed
  • ECMO/PCRRT
  • MARS
  • RAD

47
CRRT Dosing should not be confusing!
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