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… FD&C Blue dye #1…
Crit Care Med, Mar 2002

3. 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?)

4. Joy MS, Matzke GR, Frye RF, Palevsky PM. AJKD 1998;31:1019-27.

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 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 Jun;31(6):

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
<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

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
Drug
Reported SC
Free Fraction
Amikacin
0.93
0.95
Imipenem
0.78
0.80
Metronidazole
0.84
Penicillin
0.68
0.50
Ranitidine
0.85
Vancomycin
0.90
Valproic Acid
0.22
0.10

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 don’t 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 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

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
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 con’t AM BC shows Pseudomonas aer. and VRE
Order written to start 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

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 = hrs during CVVHDF (8hrs)
SC = 0.77– (PPB 30%)
ClCRRT = 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 Aug;23(8):

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 L/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 con’t
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 con’t 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 =
12hrs

32. Gent kinetics FINAL
Half-life = / = 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 = 0700
1/ sequential levels done

36. Phenobarbital case Site Concentration (mg/L) Pre-oxygenator 26.5
Post-oxygenator
24.7
Pre-hemodiafilter
26.2
Post-hemodiafilter
25.9
Effluent
11.4

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 2003;27:808-14.

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 Failure edited by George Aronoff et al
Commonly carried text by pharmacists
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 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.

45. PCRRT & Roller pump

46. Future research needed
ECMO/PCRRT
MARS
RAD

47. CRRT Dosing should not be confusing!