The Author Replies

Abstract

Two letters to the editor raise important issues about drug dosing and extracorporeal drug clearance in intensive care unit patients.1.Keller F. Drug use in the intensive care unit.Kidney Int. 2012; 82: 936Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,2.Barrantes F. Horwedel T. Drug use and nephrotoxicity in the intensive care unit: are we under-dosing antimicrobials in patients with acute kidney injury with the need of extended dialysis?.Kidney Int. 2012; 82: 935-936Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Critically ill patients often suffer from acute kidney injury (AKI) and multi-organ failure; they are the most complicated group for whom nephrologists must provide care.3.Perazella M.A. Drug use and nephrotoxicity in the intensive care unit.Kidney Int. 2012; 81: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar By the nature of their acute and chronic disease processes, they require numerous pharmaceutical agents. Calculating the appropriate dose is challenging and fraught with difficulty, as most pharmacokinetic parameters are disrupted in critically ill patients with AKI, especially when there is coexistent liver injury. Changes in volume of distribution and altered drug metabolism can lead to either lack of efficacy or overt toxicity. In addition, renal drug excretion is frequently abnormal, difficult to predict, quite dynamic, and further altered when renal replacement therapy is added to the mix. Dr Keller astutely points out the limitations of creatinine clearance and its use as a ratio to determine drug dose adjustments. I concede this point, but emphasize that my intent was to bring the reader's attention to the need for dose adjustment in these patients because of their underlying pharmacokinetic disturbances.3.Perazella M.A. Drug use and nephrotoxicity in the intensive care unit.Kidney Int. 2012; 81: 1172-1178Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar All glomerular filtration rate (GFR) estimates in critically ill patients with AKI and/or multi-organ failure perform poorly, thereby limiting their utility in accurately dosing drugs. The Kidney Disease: Improving Global Outcomes drug dosing recommendations, which were published after my paper was written, are very helpful.4.Matzke G.R. Aronoff G.R. Atkinson A.J. et al.Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2011; 80: 1122-1137Abstract Full Text Full Text PDF PubMed Scopus (302) Google Scholar However, these formulas often significantly overestimate GFR, and the GFR ranges utilized for drug dose adjustment are anything but granular (<10, 10–50, >50). Many of these problems would disappear if we could simply measure drug concentrations. Until this is available for all drugs, the goal of my drug-dosing guides was to familiarize the reader with pharmacokinetic concepts and provide a simple approach to dose adjustment (loading vs. maintenance dose). Most importantly, I emphasize the need for a collaborative working relationship between clinical pharmacists and critical-care nephrologists. Barrantes and Horwedel appropriately note that attentive care must be undertaken when dosing antibiotics in patients on extended dialysis (ED). While pharmacokinetic drug studies are limited for most continuous renal replacement therapy modalities, ED is an even more understudied area, although it has received recent interest.5.Mueller B.A. Scoville B.A. Adding to the armamentarium: antibiotic dosing in extended dialysis.Clin J Am Soc Nephrol. 2012; 7: 373-375Crossref PubMed Scopus (14) Google Scholar As the authors point out, drug efficacy and toxicity are related not only to the dose administered, but also to the timing of the dose in relation to ED. They wisely note that efficacy should also be assessed by monitoring pharmacodynamic drug effects, such as antimicrobial killing.