Transcript Drug dosing in continuous renal replacement therapy （CRRT

Drug dosing in
continuous renal replacement therapy
（CRRT）:
general rules
Introduction

Acute kidney injury, AKI + RRT
5% of ICU patients.
 unstable hemodynamic
 multiple organ dysfunction
 multiple drugs
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Adequate dosing
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increase the efficacy
minimize toxicity
General Principles
In the critically ill－Pharmacokinetics
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increased Vd of water-soluble drugs
altered protein binding
decreased clearance
hyperdynamic circulation in early sepsis
（may result in supranormal renal clearances）
In the critically ill－Pharmacodynamics
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pattern of bactericidal activity
postantibiotic effect（PAE）
Most Abx
Time-dependent
continuous infusions
No PAE
（except Carbapenems）
Aminoglycosides Conc.-dependent
Quinolones
With PAE
Metronidazole
high doses with
prolonged dosing interval
Extracorporeal removal
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only the drug in the central compartment（plasma）
is available for extracorporeal removal
drugs with a large Vd have less access to the
hemofilter or dialyzer
Extracorporeal treatmentdeeper compartments
 the rate of extracorporeal removal
 the rate of transfer between the peripheral and
central compartment.
Ex: Intermittent vs Contineous
Factors determining
extracorporeal drug removal
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Drug–membrane interactions（minor）
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Drug’s charge
Gibbs-Donan effect
Membrane adsorption
Diffusion or Convection（major）
Diffusion or Convection（major）
Convective (hemofiltration, HF)
 Diffusive (hemodialysis, HD)
 Diffusion ＋Convection
（hemodiafiltration, HDF)
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Convective transport
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S＝Cf / Cp（definition）
＝1－PB（practical purposes）
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sieving coefficient (S)
drug concentration in the ultrafiltrate (Cf)
drug concentration in the plasma(Cp)
Swith wide variation,
no matter in health and critical ill patient
Convective transport
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Post-dilution hemofiltration
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ClHFpost＝S × Qf
filtration rate (Qf)
Pre-dilution hemofiltration
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ClHFpre＝S × Qf × Qb /（Qb＋Qspre）
blood flow (Qb)
predilution substitution rate (Qspre)
Diffusive transmembrane transport
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Sd＝Cd/Cp（definition）
＝1－PB
（continuous dialysis, small solutes）
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sieving coefficient in dialysis (Sd)
drug concentration in the dialysate outflow (Cd)
drug concentration in the plasma(Cp)
Diffusive transmembrane transport
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continuous dialysis
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ClHD＝Sd × Qd
dialysate flow rate (Qd)
ClHD＝Sd × Qd × Kdrel
dialysate flow rate (Qd)
Kdrel＝Kd / Kdcreat＝(MWdrug/113)-0.42
Convection ＋ Diffusion
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in HDF
 further complicates
 1＋1＞2
Extracorporeal Drug Clearance
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filtrate flow rate(Qf) /dialysate flow rate(Qd)
protein binding
extracorporeal drug clearance
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normal protein binding
no membrane interactions
Not for diffusive transport
（MW, membrane properties）
Fractional extracorporeal clearance
FrEC＝ClEC/（ClEC＋ClNR＋ClR）
Extracorporeal drug clearance
 Not be clinically relevant for drugs with：
1.
2.
3.
low ClEC（high protein binding or low Qf or Qd）
high ClNR（predominant hepatic/enzymatic clearance）
high ClR（if used in nonrenal indications）
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Micafungin：
protein binding of 99.8%、
extensively metabolized in the liver
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Amphotericin B lipid complexes：
insoluble in water、
highly protein binding
Practical approach: steps
1. loading dose：target plasma level and Vd
（ no adaptation for extracorporeal removal ）
2. maintenance dose (before RRT)：
for reduced renal function
3. maintenance dose (after RRT)：
for clinically important extracorporeal elimination
(FrEC＞0.25).
Approaches to drug dosing (1)
1. Consult the available literature
 Antibiotic Dosing in Critically Ill Adult Patients
Receiving CRRT
Clinical Infectious Diseases 2005; 41:1159–66
2. Based on total creatinine clearance
 Extracorporeal Ccr+ endogenous Ccr
 Extracorporeal Ccr
(low-volume CRRT:10-25ml/min)
(high-volume CRRT:25-50ml/min)
 Endogenous Ccr (estimated / calculated)
Approaches to drug dosing (2)
3. DoseCVVH＝Dn × [ClNR ＋(Qf × S) /Cln]
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normal dose (Dn)
normal total clearance (Cln)
nonrenal clearance (ClNR)
Extracorporeal clearance (Qf × S)
4. Based on the FrEC
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Maintenance dose
＝anuric dose / (1-FrEC)
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Dosing interval
＝anuric dosing interval / (1-FrEC)
Approaches to drug dosing (3)
5. Monitoring of drug levels
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Dose＝target Cp × Cl × timing
Dose＝(target－actual Cp) × Cl × timing
6. Based on clinical effect
Special considerations
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‘semi-continuous’ high efficiency treatments
（Ex: SLED）
Drug dosing
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beta-lactam
aminoglycosides
Phenomenon of rebound after treatment
interruption
Conclusion
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Clearance accuracy：
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convective transport＞diffusive transport
The simplest method of Drug dosing during CRRT
based on total creatinine clearance.
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volume of distribution
protein binding
nonrenal clearance
rely more on drug monitoring
Conclusion
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For antibiotics with low toxicity
In the absence of drug monitoring
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the consequences of underdosing are much more
dangerous than the adverse effects of overdosing
clinicians should prefer overdose
Take Home Message
 Antibiotic Dosing in Critically Ill Adult Patients
Receiving CRRT
Clinical Infectious Diseases 2005; 41:1159–66
 Based on total creatinine clearance
 Extracorporeal Ccr+ endogenous Ccr
 Monitoring of drug levels
 Based on clinical effect