Pharmacist Considerations for Continuous Renal Replacement Therapy

This week’s clinical pearl is a brief overview of the methods of continuous renal replacement therapy (CRRT), and the drug properties we should consider when deciding if dosing adjustments are necessary.

 

There are two modes of solute removal utilized for the different methods of CRRT: DIFFUSION and CONVECTION. Both methodologies involve passing blood across a semi-permeable membrane, but the difference is in the way solutes are removed from the blood. Diffusion is the method used in traditional dialysis which involves passage of a solute through a membrane from a high to low concentration (the countercurrent dialysate flow rate keeps a consistently lower concentration for diffusion of solute from blood into dialysate). On the other hand, convection is independent of concentration and relies on a hydrostatic pressure gradient causing solutes to be removed with water from the blood, this is known as the filtrate.

 

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There are three main types of CRRT that we will usually hear about:

1.       CVVH (continuous veno-venous hemofiltration) – the method usually used at UCH. This method utilizes convection only and removes solutes up to a molecular weight of 20-30,000 Daltons (because this is the size of the pores in the semi-permeable membrane). The molecular weight of the solute does not matter much as long as it is below the threshold of membrane. There is no “dialysate” in CVVH, only replacement fluid. Replacement fluid is also sometimes referred to as therapy fluid. The replacement fluid can be delivered either pre- or post-filtration.

 

2.       CVVHD (continuous veno-venous hemodialysis) – This method utilizes diffusion only. While the pore size of the membrane may be similar to that of CVVH, larger solutes diffuse slower. Therefore the molecular weight can be thought of as inversely proportional to the diffusivity of the molecule. Small molecules such as potassium and phosphate will be easily removed, but larger molecules will not be as easily removed as in CVVH. Other things that can affect solute removal is the dialysate flow rate and composition of the dialysate. 

 

3.       CVVHDF (continuous veno-venous hemodiafiltration) – This method utilizes a combination of convection and diffusion. There is a countercurrent dialysate flowing in addition to a hydrostatic pressure gradient.

 

Drug properties considerations

1.       Molecular Weight – The majority of medications are < 500 Daltons molecular weight, which is significantly lower than the threshold for removal by CVVH. Antibiotics are some of the larger drug molecules (vancomycin ~1500) but still relatively small in comparison to the filter pore size. Therefore molecular weight is not a major consideration in CVVH, but it can reduce removal by CVVHD as larger molecules (>500 Daltons) may have some reduced clearance as they diffuse slower.

 

2.       Volume of Distribution – In order for drug to be removed by CRRT, it must be in the blood. Therefore it makes sense that medications that have a high volume of distribution will be removed less by CRRT. While true, this phenomenon affects intermittent hemodialysis (IHD) more so than continuous treatments. While IHD only takes place for a short period of time and therefore only clears solutes in the blood filtered in a matter of a few hours, continuous renal replacement therapy is able to clear drug as it redistributes from fluids and tissues back into the blood because of the continuous nature. 

 

3.       Degree of Protein Binding – In terms of drug properties, this is one of the more important ones to take into account when determining if a drug will be removed by CRRT. The molecular weight of albumin is around 68,000 Da, which means that it will never be removed by CRRT. Therefore if a drug has a high degree of protein binding (>90%), it will be minimally removed by CRRT. However, it is important to remember than protein binding can be altered in malnourished patients, those with uremia, and in the critically ill in general.

 

4.       Primary Route of Drug Clearance – The last property is one that is fairly intuitive. Since CRRT is replacing function of the kidney, a drug that has a high degree of renal clearance will be cleared much more than a drug with primarily hepatic or other routes of metabolism. 

 

How to assess a patient on CRRT

Screen shot from Epic found in Doc Flowsheets – the CVVH therapy fluid rate can be used as an estimate of CrCl to use when making dose adjustments. The 3 in this case is in L/hour = ~50 mL/min. Therefore you could review the patients medications and adjust for an estimated CrCl of 50 mL/min if applicable.

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Final thoughts

Some literature is available for guidance in drug dosing in CRRT – primarily for antibiotics. This is an area where adequate dosing is a must since there are relatively few objective parameters to reassure us that we are dosing adequately. The CVVH machines are very efficient and can substantially remove drugs that have the ideal properties for removal (low protein binding and volume of distribution with a high degree of renal clearance), so it can be easy to inadequately dose these medications in particular. Therapeutic drug monitoring is crucial for medications where it is available.  Loading doses are NOT affected by CRRT and should be delivered as you would a patient with normal organ function. Subsequent doses can then be adjusted if necessary.

 

Happy New Year!

 

References

1. Awdishu L and Bouchard J. How to optimize drug delivery in renal replacement therapy. Sem in Dialysis 2011 24(2): 176-182.

2. Dager W and Spencer A. Acute Renal Failure. In Pharmacotherapy 7th Ed. 723-743.

3. Pea F, Viale P, Pavan F et al. Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet 2007; 46(12): 997-1038.

4. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy 2009;29(5):562–577.

 

 

Charles J. Foster, PharmD, BCPS