Principles of Dosage Adjustment for Patients Receiving Continuous Renal Replacement Therapy (CRRT) Based on the Quantitative Estimation of Clearance by CRRT

Abstract

Continuous renal replacement therapy (CRRT) is often introduced to critically ill patients with hemodynamic instability to remove the uremic toxins or inflammatory cytokines. However, it is often the case that CRRT also removes drugs from the body and makes it difficult to maintain the therapeutic concentrations. Therefore, the dosage for patients receiving CRRT should be carefully determined. Although some guidelines recommend dosage for the patients receiving CRRT, most of these dosages are based on the reports of the limited number of clinical studies with limited CRRT conditions and may not be directly applied for daily clinical settings because of the significant inter-individual and/or inter-institutional difference in CRRT condition. Thus, to optimize the dosage for the patients receiving CRRT, it is necessary to understand the relationship between drug clearance by CRRT (CL_CRRT) and CRRT condition and to quantitatively evaluate the change in total body clearances (CL_tot) by application of CRRT.　Basically, removal of low molecular drugs by CRRT depends on filtration and diffusion through the dialyzer membrane, and only unbound drugs are removed from the body since the dialyzer membrane is impenetrable to albumin-bound drugs. Therefore, CL_CRRT can be calculated from plasma unbound fraction (f_U) of drugs and CRRT condition, and is approximately equivalent to creatinine clearance (CL_cr) of 10~35 mL/min at the standard CRRT condition (i.e., the sum of ultrafiltration rate and dialysate flow rate of 10~35 mL/min). On the other hand, it is quite important to consider the urinary excretion ratio of the unchanged drug (A_e) to adjust the dosage for patients receiving CRRT. In principle, suggested dosage for the patients receiving CRRT is equal to that for patients with CL_cr of 10~50 mL/min, which is described in authoritative references (i.e. “Sanford Guide” or “Drug Prescribing in Renal Failure” etc.) However in case of renally excreted drugs (i.e. drugs with large A_e values), individual CRRT condition should be considered to achieve the precise concentration control because the inter-individual difference in CRRT condition is significantly affect the CL_tot during CRRT when the residual renal function of the patients are negligible. In addition, the initial dosages for patients receiving CRRT should be equal to those for patients with normal renal function to rapidly increase the drug concentration. Furthermore, it should be taken into account that CRRT exclusively replaces the glomerular filtration of kidneys. This means that the unexpected pharmacokinetic changes can be occurred in drugs which extensively secreted or resorbed at the renal tubular. In this review, the principle for the quantitative estimation of drug clearances by CRRT and its application for dosage adjustment of antibiotics are discussed.