Acute Kidney Injury and Kidney Replacement Therapy in the Critically Ill Patient

Solutes are considered to have a small MW (less than 1000 Da), middle MW (1000-30,000 Da),

or large MW (greater than 30,000 Da). Most unbound drugs have an MW less than 500 Da (e.g.,

cefepime = 480 Da). Diffusive clearance (as with IHD and CVVHD) readily removes small MW

drugs to a greater extent than middle MW drugs, whereas convective clearance modalities (as

with CVVH) remove both small and middle MW drugs well. Highly protein bound drugs, as with

albumin binding (67,000 Da), appear to have a high MW because of the association with the plasma

protein. This large size would exceed the typical pore size of a high-flux, high-efficiency dialyzer,

which is standard of care, and lead to reduced drug clearance.

Vd is inversely related to extracorporeal removal, wherein a larger Vd decreases elimination through

the circuit because the drug is distributed throughout the body compartments. For continuous KRT,

the slower rates allow for steady redistribution between body compartments, which can facilitate

removal of drugs with a larger Vd to a greater degree than with IHD. Medications are generally

considered to have a large Vd when greater than 1 L/kg and a small Vd when less than 0.3 L/kg.

Continuous KRT modalities and their influence during therapy

CVVH

Solute removal during CVVH is by convection. Convection is influenced by the membrane pore

size; the free fraction of drug, as discussed earlier; and the ultrafiltration rate.

ii.

The ability of a substance to pass through a membrane by convection is termed the sieving

coefficient (SC). The SC ranges from 0 to 1. A SC of 1 represents free movement, whereas a SC

of 0 represents no movement across a filter.

iii.

SC is best obtained from the primary literature or from patient-specific values. It can be

calculated using a ratio of measured drug or other solute in the ultrafiltrate to its concentration

in the plasma, SC = CUF/Cp, where CUF is concentration in the ultrafiltrate and Cp is concentration

in the plasma.

protein, SC = 1 − fb, where fb is fraction bound (i.e., percent protein bound).

iv.

Site of replacement fluid administration can influence solute clearance. Adding replacement

fluids pre-filter will dilute the blood entering the dialyzer. This diluted blood will have decreased

drug concentrations; thus, less drug will be removed than if the replacement solution is infused

after the filter.

If pre-dilution (i.e., before the filter) fluids are used, clearance across the membrane is reduced.

Clearance can be estimated using the following equation:

CVVHpre-dilution = QUF x SC x Qb/(Qb + Qrf)

where QUF is ultrafiltration flow rate, Qb is blood flow rate, and Qrf is pre-dilution replacement

fluid flow rate. For pre-dilution fluid replacement to affect overall clearance, the rate must be

high.

If replacement fluids are administered postfilter (i.e., post-dilution), the clearance rate can be

estimated using the following equation:

CVVHpost-dilution = QUF x SC

CVVHD

Solute removal during CVVHD occurs by passive diffusion. The flow of dialysate is

countercurrent to that of the blood. Movement of solute across the semipermeable membrane

occurs because of a concentration gradient, with movement from an area of higher concentration

(blood) to an area of lower concentration (dialysate). This process occurs until equilibrium is

established.