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Drug dosing in continuous renal replacement therapy （ CRRT ） : general rules

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 Adequate dosing increase the efficacy minimize toxicity

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Drug dosing in continuous renal replacement therapy （ CRRT ） : general rules

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  1. Drug dosing in continuous renal replacement therapy（CRRT）:general rules

  2. Introduction • Acute kidney injury, AKI + RRT 5% of ICU patients. • unstable hemodynamic • multiple organ dysfunction • multiple drugs • Adequate dosing • increase the efficacy • minimize toxicity General Principles

  3. In the critically ill－Pharmacokinetics • increased Vd of water-soluble drugs • altered protein binding • decreased clearance • hyperdynamic circulation in early sepsis （may result in supranormal renal clearances）

  4. In the critically ill－Pharmacodynamics • pattern of bactericidal activity • postantibiotic effect（PAE）

  5. Extracorporeal removal • 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

  6. Factors determining extracorporeal drug removal • Drug–membrane interactions（minor） • Drug’s charge • Gibbs-Donan effect • Membrane adsorption • Diffusion or Convection（major）

  7. Diffusion or Convection（major） • Convective (hemofiltration, HF) • Diffusive (hemodialysis, HD) • Diffusion ＋Convection （hemodiafiltration, HDF)

  8. Convective transport • S＝Cf / Cp（definition） ＝1－PB（practical purposes） • 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

  9. Convective transport • Post-dilution hemofiltration • ClHFpost＝S × Qf • filtration rate (Qf) • Pre-dilution hemofiltration • ClHFpre＝S × Qf × Qb /（Qb＋Qspre） • blood flow (Qb) • predilution substitution rate (Qspre)

  10. Diffusive transmembrane transport • Sd＝Cd/Cp（definition） ＝1－PB （continuous dialysis, small solutes） • sieving coefficient in dialysis (Sd) • drug concentration in the dialysate outflow (Cd) • drug concentration in the plasma(Cp)

  11. Diffusive transmembrane transport • continuous dialysis • ClHD＝Sd × Qd • dialysate flow rate (Qd) • ClHD＝Sd × Qd × Kdrel • dialysate flow rate (Qd) • Kdrel＝Kd / Kdcreat＝(MWdrug/113)-0.42

  12. Convection ＋Diffusion • in HDF • further complicates • 1＋1＞2

  13. Extracorporeal Drug Clearance • filtrate flow rate(Qf) /dialysate flow rate(Qd) • protein binding extracorporeal drug clearance • normal protein binding • no membrane interactions • Not for diffusive transport （MW, membrane properties）

  14. Fractional extracorporeal clearance FrEC＝ClEC/（ClEC＋ClNR＋ClR） Extracorporeal drug clearance  Notbe clinically relevant for drugs with： • low ClEC（high protein binding or low Qf or Qd） • high ClNR（predominant hepatic/enzymatic clearance） • high ClR（if used in nonrenal indications）

  15. Micafungin： protein binding of 99.8%、 extensively metabolized in the liver • Amphotericin B lipid complexes： insoluble in water、 highly protein binding

  16. Practical approach: steps • loading dose：target plasma level and Vd （ no adaptation for extracorporeal removal ） • maintenance dose (before RRT)： for reduced renal function • maintenance dose (after RRT)： for clinically important extracorporeal elimination (FrEC＞0.25).

  17. Approaches to drug dosing (1) • Consult the available literature • 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 • Extracorporeal Ccr (low-volume CRRT:10-25ml/min) (high-volume CRRT:25-50ml/min) • Endogenous Ccr (estimated / calculated)

  18. Approaches to drug dosing (2) • DoseCVVH＝Dn × [ClNR＋(Qf × S) /Cln] • normal dose (Dn) • normal total clearance (Cln) • nonrenal clearance (ClNR) • Extracorporeal clearance (Qf × S) • Based on the FrEC • Maintenance dose ＝anuric dose / (1-FrEC) • Dosing interval ＝anuric dosing interval / (1-FrEC)

  19. Approaches to drug dosing (3) • Monitoring of drug levels • Dose＝target Cp × Cl × timing • Dose＝(target－actual Cp) × Cl × timing • Based on clinical effect

  20. Special considerations ‘semi-continuous’ high efficiency treatments （Ex: SLED） • Drug dosing • beta-lactam • aminoglycosides • Phenomenon of rebound after treatment interruption

  21. Conclusion • Clearance accuracy： convective transport＞diffusive transport • The simplest method of Drug dosing during CRRT based on total creatinine clearance. • volume of distribution • protein binding • nonrenal clearance rely more on drug monitoring

  22. Conclusion • For antibiotics with low toxicity • In the absence of drug monitoring • the consequences of underdosing are much more dangerous than the adverse effects of overdosing clinicians should prefer overdose

  23. 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

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