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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 General Principles 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) In the critically ill-Pharmacodynamics 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 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 treatmentdeeper 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 Drug–membrane interactions(minor) 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) 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) Swith wide variation, no matter in health and critical ill patient 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) 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) 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 Convection + Diffusion in HDF further complicates 1+1>2 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) 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) Micafungin: protein binding of 99.8%、 extensively metabolized in the liver 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] normal dose (Dn) normal total clearance (Cln) nonrenal clearance (ClNR) Extracorporeal clearance (Qf × S) 4. Based on the FrEC Maintenance dose =anuric dose / (1-FrEC) Dosing interval =anuric dosing interval / (1-FrEC) Approaches to drug dosing (3) 5. Monitoring of drug levels Dose=target Cp × Cl × timing Dose=(target-actual Cp) × Cl × timing 6. Based on clinical effect Special considerations ‘semi-continuous’ high efficiency treatments (Ex: SLED) Drug dosing beta-lactam aminoglycosides Phenomenon of rebound after treatment interruption 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 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 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