Page 104 - Biomedical Engineering and Design Handbook Volume 2, Applications

OVERVIEW OF CARDIOVASCULAR DEVICES 83

encompasses the spectrum of molecules encountered in an uremic state at the appropriate flow con-
ditions. Mock circulatory circuits can approximate hemofiltration and hemodialysis flow environ-
ments, generating ultrafiltration rates, sieving coefficients (larger molecules), and clearances (smaller
molecules) for sample fluids as simple as salt solutions up to uremic human blood (Leypoldt and
Cheung, 1996). Many of the toxins responsible for uremia are unknown and are approximated with
marker molecules spanning a large-size spectrum, including small solutes, middle molecules, and
albumin (Leypoldt and Cheung, 1996). Small solutes used for in vitro studies include the clinically
relevant compounds urea and creatinine, while middle molecules such as 2 microglobulin can be
approximated with inulin and dextrans (Leypoldt and Cheung, 1996). Albumin is used to approxi-
mate high-molecular-weight oncotic substances in the blood, and its clearance is believed to be
negligible (Leypoldt and Cheung, 1996). The transport properties derived using mock circulatory
loops may not reflect clinical performance due to complex solute—carrier protein interactions and
membrane surface fouling by plasma proteins (Leypoldt and Cheung, 1996).
Computational and in silico experiments have also been used for the design and analysis of both
artificial kidneys (Eloot et al., 2004) and their associated access devices (De Wachter and Verdonck,
2002; Mareels et al., 2004). Researchers continue to develop computational models of various
devices, complete with experimental validation (Mareels et al., 2007). Although validation of com-
putational findings remains important, progress in the area of artificial organ simulation could reduce
the need for exhaustive experimental testing.

3.6.4 Complications and Patient Management

Complications that occur during hemodialysis and hemofiltration can be divided into problems
related to vascular access and those due to exposure of the blood to the exchange circuit. Depending
upon the method used, most vascular access problems associated with renal replacement therapy are
similar to those experienced in patients with vascular grafts or catheters and are covered in those
respective sections. However, patients with progressive renal disease require particular consideration
as a lack of vascular access leads to rapid patient demise.
The complications associated with blood exposure to the dialysis or filtration membrane are related to
the activation and upregulation of various homeostatic systems. Inflammatory and hemostatic cascades
can become activated by protein adsorption onto the significant surface area that these devices necessarily
present to the blood. As part of the inflammatory response to dialyzer perfusion, activation of the
complement system results in the generation of anaphylatoxins C3a and C5a and can potentiate activation
of polymorphonuclear leukocytes and monocytes (Johnson, 1994; Grooteman and Nube, 1998). These
activated leukocytes release cytotoxic compounds and inflammatory mediators that normally would be
reserved for the killing of bacteria and infectious agents. The release of these inflammatory mediators is
implicated in sequelae such as fever, cardiovascular instability, and increased catabolism of muscle
protein (Pertosa et al., 2000). Since the nature and extent of protein adsorption impacts the inflammatory
response, the surface properties of dialyzer membranes are of interest as a means to limit this response.
In studying surface properties and complement activation, the presence of surface hydroxl groups has
been implicated as a potential trigger for pathway activation (Chenoweth, 1984).
Activation of the coagulation cascade and platelet deposition in the artificial kidney circuit are
obviously undesirable, leading to reduced device performance or failure. To minimize this phenom-
ena, patients on hemodialysis are usually anticoagulated with heparin during the dialysis session on
either a systemic or regional (extracorporeal circuit only) level (Denker et al., 2000). Patients with a
sensitivity or contraindication to heparin therapy can be anticoagulated regionally with citrate as well
(Denker et al., 2000). Minimizing the potential of membrane surfaces to activate both the hemosta-
tic and inflammatory pathways is of interest to device manufacturers as they seek to reduce compli-
cations associated with artificial kidney use.

3.6.5 Future Trends
Artificial kidney designs will likely continue to experience incremental improvements in the materials
and hemodynamic areas. New developments in biocompatible materials, superior transport methods