Drug removal in continuous renal replacement therapy
- Bruce A Mueller, PharmD, FCCP, FASN, FNKF
Bruce A Mueller, PharmD, FCCP, FASN, FNKF
- Professor and Associate Dean of Academic Affairs
- University of Michigan College of Pharmacy
- Thomas A Golper, MD
Thomas A Golper, MD
- Section Editor — Dialysis
- Professor of Medicine
- Vanderbilt University Medical Center
- Section Editors
- Jeffrey S Berns, MD
Jeffrey S Berns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Dialysis
- Professor of Medicine
- Perelman School of Medicine at the University of Pennsylvania
- Paul M Palevsky, MD
Paul M Palevsky, MD
- Section Editor — Renal Failure
- Professor of Medicine
- University of Pittsburgh
- VA Pittsburgh Healthcare System
Continuous renal replacement therapy (CRRT) is occasionally required for critically ill patients with acute kidney injury (AKI) . Some, but not all, drugs are removed by CRRT. For patients treated with CRRT, it is important to understand the factors that determine drug removal to permit optimal drug dosing . This is particularly true for antibiotics since subtherapeutic levels are commonly observed in patients on CRRT [3-6] and associated with antibiotic failure [3,7].
This topic reviews drug clearance and an approach to drug dosing in patients on CRRT. The general mechanisms underlying solute clearance by RRTs are discussed elsewhere. (See "Mechanisms of solute clearance and ultrafiltration in peritoneal dialysis".)
Other issues related to CRRT, including optimal prescription, and anticoagulation are discussed elsewhere. (See "Continuous renal replacement therapy in acute kidney injury (acute renal failure)" and "Anticoagulation for continuous renal replacement therapy".)
The effectiveness and potential toxicity of drugs are related to their concentration. Drug concentration is determined by absorption, volume of distribution, and clearance, all which may be altered among critically ill patients .
In patients on CRRT, drug clearance is the sum of metabolisms and excretion by the liver and gastrointestinal tract, removal by residual renal function that may be present, and removal by RRT. Drug clearance is difficult to estimate and may change from day to day among critically ill patients, particularly as kidney function deteriorates and CRRT is initiated, and as kidney function begins to improve and CRRT is discontinued or the patient is transitioned to other RRT modalities [9-13].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Manns M, Sigler MH, Teehan BP. Continuous renal replacement therapies: an update. Am J Kidney Dis 1998; 32:185.
- Joy MS, Matzke GR, Armstrong DK, et al. A primer on continuous renal replacement therapy for critically ill patients. Ann Pharmacother 1998; 32:362.
- Lewis SJ, Mueller BA. Antibiotic dosing in critically ill patients receiving CRRT: underdosing is overprevalent. Semin Dial 2014; 27:441.
- Bauer SR, Salem C, Connor MJ Jr, et al. Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT. Clin J Am Soc Nephrol 2012; 7:452.
- Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 2009; 37:840.
- Seyler L, Cotton F, Taccone FS, et al. Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Crit Care 2011; 15:R137.
- Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest 1999; 115:462.
- Zamoner W, de Freitas FM, Garms DS, et al. Pharmacokinetics and pharmacodynamics of antibiotics in critically ill acute kidney injury patients. Pharmacol Res Perspect 2016; 4:e00280.
- Udy AA, Baptista JP, Lim NL, et al. Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*. Crit Care Med 2014; 42:520.
- Udy AA, Roberts JA, Shorr AF, et al. Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients. Crit Care 2013; 17:R35.
- Claus BO, Hoste EA, Colpaert K, et al. Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. J Crit Care 2013; 28:695.
- Bakke V, Sporsem H, Von der Lippe E, et al. Vancomycin levels are frequently subtherapeutic in critically ill patients: a prospective observational study. Acta Anaesthesiol Scand 2017; 61:627.
- Hirai K, Ishii H, Shimoshikiryo T, et al. Augmented Renal Clearance in Patients With Febrile Neutropenia is Associated With Increased Risk for Subtherapeutic Concentrations of Vancomycin. Ther Drug Monit 2016; 38:706.
- Vilay AM, Churchwell MD, Mueller BA. Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury. Crit Care 2008; 12:235.
- Mueller BA, Scarim SK, Macias WL. Comparison of imipenem pharmacokinetics in patients with acute or chronic renal failure treated with continuous hemofiltration. Am J Kidney Dis 1993; 21:172.
- Macias WL, Mueller BA, Scarim SK. Vancomycin pharmacokinetics in acute renal failure: preservation of nonrenal clearance. Clin Pharmacol Ther 1991; 50:688.
- Ulldemolins M, Roberts JA, Rello J, et al. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet 2011; 50:99.
- De Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin Pharmacokinet 2002; 41:1135.
- Vilay AM, Grio M, Depestel DD, et al. Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis. Crit Care Med 2011; 39:19.
- Eyler RF, Vilay AM, Nader AM, et al. Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration. Antimicrob Agents Chemother 2014; 58:1320.
- Lewis SJ, Mueller BA. Antibiotic Dosing in Patients With Acute Kidney Injury: "Enough But Not Too Much". J Intensive Care Med 2016; 31:164.
- Roberts DM. The relevance of drug clearance to antibiotic dosing in critically ill patients. Curr Pharm Biotechnol 2011; 12:2002.
- Agarwal R, Cronin RE. Heterogeneity in gentamicin clearance between high-efficiency hemodialyzers. Am J Kidney Dis 1994; 23:47.
- De Bock V, Verbeelen D, Maes V, Sennesael J. Pharmacokinetics of vancomycin in patients undergoing haemodialysis and haemofiltration. Nephrol Dial Transplant 1989; 4:635.
- Rumpf KW, Rieger J, Ansorg R, et al. Binding of antibiotics by dialysis membranes and its clinical relevance. Proc Eur Dial Transplant Assoc 1977; 14:607.
- Kraft D, Lode H. Elimination of ampicillin and gentamicin by hemofiltration. Klin Wochenschr 1979; 57:195.
- Kronfol NO, Lau AH, Barakat MM. Aminoglycoside binding to polyacrylonitrile hemofilter membranes during continuous hemofiltration. ASAIO Trans 1987; 33:300.
- Markou N, Fousteri M, Markantonis SL, et al. Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study. J Antimicrob Chemother 2012; 67:2459.
- Patel JH, Churchwell MD, Seroogy JD, et al. Telavancin and hydroxy propyl-beta-cyclodextrin clearance during continuous renal replacement therapy: an in vitro study. Int J Artif Organs 2009; 32:745.
- Colton CK, Henderson LW, Ford CA, Lysaght MJ. Kinetics of hemodiafiltration. I. In vitro transport characteristics of a hollow-fiber blood ultrafilter. J Lab Clin Med 1975; 85:355.
- Golper TA, Wedel SK, Kaplan AA, et al. Drug removal during continuous arteriovenous hemofiltration: theory and clinical observations. Int J Artif Organs 1985; 8:307.
- Kronfol NO, Lau AH, Colon-Rivera J, Libertin CL. Effect of CAVH membrane types on drug-sieving coefficients and clearances. ASAIO Trans 1986; 32:85.
- Henderson, LW. Hemodialysis: Rationale and physical principles. In: The Kidney, 1st ed, Brenner, BM, Rector, FC (Eds), Saunders, Philadelphia 1976. p.1643-1671.
- Hofmann CL, Fissell WH. Middle-molecule clearance at 20 and 35 ml/kg/h in continuous venovenous hemodiafiltration. Blood Purif 2010; 29:259.
- Langsdorf LJ, Krankel LG, Zydney AL. Effect of blood-membrane interactions on solute clearance during hemodialysis. ASAIO J 1993; 39:M767.
- Langsdorf LJ, Zydney AL. Effect of blood contact on the transport properties of hemodialysis membranes: a two-layer membrane model. Blood Purif 1994; 12:292.
- Brunet S, Leblanc M, Geadah D, et al. Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis 1999; 34:486.
- Sprenger KG, Stephan H, Kratz W, et al. Optimising of hemodiafiltration with modern membranes? Contrib Nephrol 1985; 46:43.
- Thalhammer F, Schenk P, Burgmann H, et al. Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrob Agents Chemother 1998; 42:2417.
- Tegeder I, Neumann F, Bremer F, et al. Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration. Clin Pharmacol Ther 1999; 65:50.
- Golper TA, Cigarran-Guldris S, Jenkins RD, Brier ME. The role of convection during simulated continuous arteriovenous hemodialysis. Contrib Nephrol 1991; 93:146.
- European Best Practice Guidelines Expert Group on Hemodialysis, European Renal Association. Section I. Measurement of renal function, when to refer and when to start dialysis. Nephrol Dial Transplant 2002; 17 Suppl 7:7.
- Vilay AM, Shah KH, Churchwell MD, et al. Modeled dalbavancin transmembrane clearance during intermittent and continuous renal replacement therapies. Blood Purif 2010; 30:37.
- Messer J, Mulcahy B, Fissell WH. Middle-molecule clearance in CRRT: in vitro convection, diffusion and dialyzer area. ASAIO J 2009; 55:224.
- PHARMACOKINETICS OVERVIEW
- FACTORS THAT AFFECT CLEARANCE BY CRRT
- Drug characteristics
- - Protein binding
- - Volume of distribution
- - Molecular weight
- CRRT features
- - Characteristics of membrane
- - Modality and operating conditions (flow rate settings)
- Continuous venovenous hemofiltration (CVVH)
- Continuous venovenous hemodialysis (CVVHD)
- Continuous venovenous hemodiafiltration (CVVHDF)
- OUR APPROACH TO DETERMINING THE OPTIMAL DRUG DOSE
- Estimate of loading dose
- Estimate of maintenance dose
- SUMMARY AND RECOMMENDATIONS