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Published on 1 September 2005

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Drug dosing in renal replacement therapies

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Mariann D Churchwell
PharmD
Assistant Professor
University of Toledo College of Pharmacy
Toledo, OH
USA
E:mdchurchw@comcast.net

Renal replacement therapy (RRT) is the cornerstone in the treatment of patients with acute renal failure (ARF). There are two types of RRT: continuous renal replacement therapy (CRRT) and intermittent haemodialysis (IHD). By its nature, CRRT removes drugs differently from IHD. CRRT utilises slower blood flow, ultrafiltration and/or dialysate flow rates (Quf/Qd) in addition to different haemodiafilter membranes and 24-hour-a-day therapy.(1–3) CRRT has the ability to remove drugs, solutes and nutrients, but information is lacking on how much of these drugs and solutes are removed during this therapy.

CRRT removes drugs by different mechanisms. Drugs are removed by convection, diffusion and adsorption, with the primary means being convection and diffusion.(1–3)

Convective drug removal
Continuous venovenous haemofiltration (CVVH) uses convection for fluid and drug removal.(3,4) CVVH does not use dialysate. Plasma water and dissolved solutes are removed as they seep across the haemodiafilter membrane. This process removes small (<500 daltons) and large (>1,000 daltons) molecular weight (MW) drugs.(5) Protein binding (PB) is an important determinant as to what drugs are able to cross the haemodiafilter membrane. The PB of a drug is used to estimate the sieving coefficient (SC), which is inversely proportional to the PB of a drug.(3,6,7) SC represents the fraction of a drug that crosses the haemodiafilter membrane. SC ranges from 0 to 1.0,  with ≥0.9 considered a high amount of drug crossing the haemodiafilter membrane. Estimating the SC by subtracting the fraction protein bound (fpb) of the drug from 1.0 would equal the fraction unbound to protein (fup; see Equation 1).(8)

[[HPE22_equation1_82]]

SC can be used to calculate the removal of a drug by CVVH (see Equation 2).

[[HPE22_equation2_82]]

This equation can be used, for example, to determine how much gentamicin is crossing the haemodiafilter membrane for a patient on CVVH and receiving gentamicin. The SC of gentamicin can be determined by obtaining an ultrafiltrate sample from the ultrafiltration port and a blood sample from the prefilter port. Each sample is analysed for gentamicin concentration, and these concentrations are placed into Equation 2. This SC fraction could be used to determine the transmembrane clearance of ­gentamicin for a patient during CVVH using Equation 3.(3,6)

[[HPE22_equation3_82]]

Diffusive drug removal
Continuous venovenous haemodialysis (CVVHD) uses diffusion to facilitate drug removal.(3,9) Drugs diffuse from an area of higher concentration to an area of lower concentration to create equilibrium between the dialysate and blood.

During CVVHD, small-MW drugs are easily removed, and the rate of diffusion is inversely proportional to MW.(3) The saturation coefficient (SA) reflects what is crossing the haemodiafilter membrane and saturating the dialysate during diffusion. SA is used to calculate the amount of a drug crossing the haemodiafilter membrane during CVVHD.(3) SA is dependent on blood flow rate (Qb), Qd, PB, MW and haemodiafilter type (see Equation 4).(3,7)

[[HPE22_equation4_82]]

This equation can be used, for example, to determine how much vancomycin is crossing the haemo‑diafilter membrane for a patient receiving vancomycin and CVVHD. The SA of vancomycin can be determined by obtaining an effluent sample from the effluent/spent dialysate port, a blood sample from the pre- and postfilter ports. Each sample is analysed for vancomycin concentration, and these concentrations are placed into Equation 4. SA is a fraction, where an SA of 0.01 represents a small fraction of drug and an SA of 0.9 corresponds to a high amount of the drug crossing the haemodiafilter membrane. SA can be used to determine the transmembrane clearance of vancomycin for a patient during CVVHD using Equation 5.

[[HPE22_equation5_83]]

Drug dosing during CRRT must also account for total drug clearance. Total drug clearance includes the nonrenal clearance(10) and any residual renal clearance the patient may have in addition to any drug loss during CRRT (see Equation 6).(7)

[[HPE22_equation6_83]]

Nonrenal clearance differs in normal healthy patients as compared with patients with chronic kidney disease (CKD), but little is known about nonrenal clearance in patients with ARF.(11) An example of a practical use for SC and SA would be in a patient receiving CVVHD at a rate of 2 litres/h with a ­vancomycin serum concentration of 20mg/l. What would you do with this information? Start by determining the SA either from published literature (SA: 0.8)(7,13,14) or from the patient using the previously mentioned SA calculation. Calculate the vancomycin lost in one hour of CVVHD by using Equation 7.(2,3)

[[HPE22_equation7_83]]

Then add this to drug loss by renal and nonrenal clearance to aid in drug dosing.

When no CRRT drug dosing information is available, one approach would be to consider Quf or Qd as the patient’s creatinine clearance (Clcr) provided by the CRRT system. This approach is usually valid because creatinine has SC and SA values of 1.0; consequently, all effluent contains creatinine at the same concentration as plasma. Add the CRRT Clcr to any native Clcr and dose the drug in question using this derived Clcr. Monitor serum drug concentrations closely. Drug dosing information is available on the internet (see Resource).

References

  1. Daugirdas JT, Blake PG, Ing TS. Handbook of dialysis. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.
  2. Subach R, Marx M. Drug dosing in acute renal failure: the role of renal replacement therapy in altering drug pharmacokinetics. Adv Ren Replace Ther 1998;5:141-7.
  3. Nissenson AR, Fine RN, Gentile DE. Clinical dialysis. 3rd ed. Norwalk, CN: Appleton and Lange; 1995.
  4. Macias WL, Mueller BA, Scarim SK. Continuous venovenous hemofiltration: an alternative to continuous arteriovenous hemofiltration and hemodiafiltration in acute renal failure. Am J Kidney Dis 1991;18:451-8.
  5. Golper TA, Marx MA. Drug dosing during continuous renal replacement therapies. Kidney Int Supp 1998;66:S165-8.
  6. Golper TA. Drug dosing during continuous hemofiltration and hemodialysis. Contrib Nephrol 1991;93:110-6.
  7. Joy M, Matzke GR Armstrong DK. A primer on continuous renal replacement therapy for critically ill patients. Ann Pharmacother 1998;32:362-75.
  8. Roland M, Towzer TN. Clinical pharmacokinetics concepts and applications. 3rd ed. Philadelphia, PA: Williams and Wilkins Media; 1995.
  9. Sigler MH, Teehan BP. Solute transport in continuous hemodialysis: a new treatment for acute renal failure. Kidney Int 1987;32:562-71.
  10. Touchette MA, Slaughter RL. The effect of renal failure on hepatic drug clearance. Ann Pharmacother 1991;25:1214-22.
  11. Macias WL, Mueller BA, Scarim SK. Vancomycin pharmacokinetics in acute renal failure: preservation of nonrenal function. Clin Pharmacol Ther 1991;50:688-94.
  12. Aronoff G, Berns JS, Brier ME. Drug prescribing in renal failure. Dosing guidelines for adults. 4th ed. Philadelphia, PA: American College of Physicians–American Society of Internal Medicine; 1999.
  13. Joy MS, Matzke GR, Frye RF. Determinants of vancomycin clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Am J Kidney Dis 1998;31:1019-27.
  14. Golper TA, Wedel SK, Kaplan AA. Drug removal during continuous arteriovenous hemofiltration: theory and clinical observations. Int J Artif Organs 1985;8:307-12.

Resource
The Renal Drug Book
W:www.kdp-baptist.louisville.edu/renalbook



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