Drug Dosing in PCRRT

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Drug Dosing in PCRRT

• Deb Pasko, Pharm.D
• Pharmacy Clinical Specialist, PICU
• University of Michigan Health System

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CRRT Solute Removal

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

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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?)

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Joy MS, Matzke GR, Frye RF, Palevsky PM. AJKD
1998311019-27.
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RRT Drug Removal Mechanisms

• Diffusion
• Convection
• Adsorption
• May be important for ?2 Microglobulin removal
• Especially for PMMA membranes
• Rarely important for drugs

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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)

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Vancomycin overdose case
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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

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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

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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

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Sieving Coefficient Protein Binding
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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

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Non-renal clearance rates of selected drugs in
patients with normal renal function and ESRD
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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)???

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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

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(No Transcript)
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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

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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

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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?

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What drugs do we care about?

• Drugs are dialyzable if
• Small MW
• Small volume of distribution
• Not highly protein bound
• Water soluble

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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

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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

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So what drugs need adjustment?

• Dopamine?
• Cefepime?
• Gentamicin?
• Linezolid?
• Voriconazole?
• Pentamidine?

• Hydrocortsione?
• Protonix?
• TPN?
• Dilaudid?
• Ativan?

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Antibiotic Guidelines UM
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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

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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.

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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.

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So what drugs need adjustment?

• Dopamine?
• Cefepime?
• Gentamicin?
• Linezolid?
• Voriconazole?
• Pentamidine?

• Hydrocortsione?
• Protonix?
• TPN?
• Dilaudid?
• Ativan?

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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

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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!!!!)

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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

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Gent kinetics FINAL

• Half-life 0.693 / 0.115 6 hours

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So what drugs need adjustment?

• Dopamine?
• Cefepime?
• Gentamicin?
• Linezolid?
• Voriconazole?
• Pentamidine?

• Hydrocortsione?
• Protonix?
• TPN?
• Dilaudid?
• Ativan?

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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

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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

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Phenobarbital case
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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

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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

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Mueller BA, Pasko DA. Artif Organs 200327808-14.
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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

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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

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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
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D. Known drug characteristics

• These recommendations made by panel of
  nephrologists and pharmacists
• Based on
• Protein Binding Information
• Volume of Distribution
• Molecular Weight

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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.

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PCRRT Roller pump
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Future research needed

• ECMO/PCRRT
• MARS
• RAD

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CRRT Dosing should not be confusing!