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Extracorporeal Liver Support Devices
Objectives
This chapter will:
- 1.
Discuss the theoretical basis for the use of extracorporeal liver support devices (ECLSDs) in acute and chronic liver failure.
- 2.
Describe the structure and function of current artificial and bioartificial ECLSDs.
- 3.
Review the current the literature regarding the effectiveness of ECLSDs in the management of acute and chronic liver failure.
The last 50 years have seen the increasingly successful use of extracorporeal devices to support failing organ systems. There are proven extracorporeal therapies for use in renal failure and more recently, cardiac and respiratory failure. However, the development of a proven extracorporeal support device for liver failure remains elusive. Mortality and morbidity from acute and chronic liver failure remain high, and transplantation remains the most effective treatment. The liver is a complex organ intimately involved in maintaining body-wide homeostasis. Specifically, the liver has key detoxification, synthetic, and immunologic roles. The development of liver failure results in loss of all three functions. Although the synthetic and immunologic roles, to a degree, can be supported medically, replication of the detoxification role is more difficult to achieve.
The literature suggests that there up to 500 different toxins produced in liver failure, the most important being ammonia, urea, bile acids, branch-chained aromatic amino acids, reactive nitrate, and nitrite species and proinflammatory mediators such as the tumor necrosis factor (TNF) and interleukin families. The combination of these toxins contributes to the characteristic findings in liver disease of a systemic inflammatory response and encephalopathy. The difficulty developing an effective extracorporeal liver support device (ECLSD) has been most likely the result of the complexity in the magnitude, variation in molecular weights, degree of protein binding, and volumes of distribution exhibited by this toxic milleu.
Despite these difficulties there has been continued impetus for research into an ECLSD, largely because of a shortage of appropriate transplantable organs and recently, increasing recognition of the liver's unique ability to regenerate in the setting of an acute insult. Subsequently, the rationale for an ECLSD is now clearer; to act as a bridge to transplantation, a bridge to recovery, or potentially providing symptom relief. There are currently two main approaches being pursued: an artificial liver support system, using or adapting preexisting renal replacement technology with adsorbent or detoxifying capacity or a bioartificial support system with the integration of living hepatocytes into an extracorporeal circuit, with provision of metabolism and synthetic function (see Box 130.1 and Table 130.1 ).
Box 130.1
Indications for Extracorporeal Support
-
Bridge to transplantation
-
Bridge to recovery
-
Potential symptom relief
TABLE 130.1
Selected Extracorporeal Devices
| LIVER SUPPORT DEVICE | TECHNIQUE | CLINICAL STUDIES |
|---|---|---|
| Artificial Devices | ||
| Single-pass dialysis | Albumin dialysis via 2%–5% albumin | Equivalent biochemical parameters compared with MARS, possible concerns with citrate anticoagulation |
| Molecular adsorbent recirculating system | Albumin dialysis via 20% albumin | Improved toxin clearance, improved hemodynamics, no evidence of improved survival in acute or chronic liver failure |
| Prometheus | Plasma separation, adsorption, resin, and anion adsorbent | Limited survival data in acute or chronic liver failure |
| Therapeutic plasma exchange | Removal of patients’ plasma and replacement with fresh frozen plasma | Improved hemodynamics, clinical and biochemical parameters, increased transplant-free survival |
| Select plasma exchange therapy | Plasma filtration, higher filter membrane cutoff | No current studies |
| Bioartificial Devices | ||
| HepatAssist | Plasma separation, adsorption, porcine hepatocytes | Improved clinical and biochemical parameters in acute liver failure and primary graft nonfunction, no survival benefit |
| Modular extracorporeal liver system | Albumin dialysis human hepatocytes | Successfully used as bridge to transplantation |
| Academic Medical Centre bioartificial liver | Porcine hepatocytes, new human cell line | Improved biochemical and clinical parameters as a bridging therapy |
| Extracorporeal liver assist device | Hemodialysis, human hepatocytes | Trials currently in progress Safe in acute and chronic liver failure |
| Spheroid reserve bioartificial liver | Porcine hepatocytes, spheroid reservoir | Animal studies only—improved survival, decreased ammonia, decreased intracranial pressure |
MARS, Molecular adsorbent recirculating system.
Artificial Systems
Artificial liver support systems are based upon the concept that pathophysiology of liver failure is secondary to impaired hepatic detoxification and the subsequent accumulation of normally cleared toxins. Artificial support systems have been developed from the success of renal replacement technology in correcting the metabolic and electrolyte disturbances of renal failure. Correspondingly, they use various combinations of dialysis, filtration, and adsorption. The main approaches are discussed later in this chapter (see Fig. 130.1 and Table 130.1 ).
Hemofiltration and Hemodiafiltration
Hemofiltration and hemodiafiltration involve the use of traditional continuous renal replacement therapy (CRRT) apparatus in patients with liver failure and currently has only limited application. The process involves the exposure of blood to a dialysate moving in a countercurrent direction via a hollow fiber membrane, allowing toxins and electrolytes to move either via convection or diffusion down their concentration gradient. The membrane used in CRRT has a pore size of approximately 60 kilodaltons (kDa), allowing the removal of small and mid-sized water-soluble molecules. The membrane pore size does not allow the transfer albumin, therefore prohibiting the removal of albumin-bound toxins.
However, there is increased interest in the use of CRRT in liver failure patients for two reasons. First, because there are potential similarities between the SIRS response in both populations, high-volume filtration has been proposed to modulate the impact of inflammatory cytokines. Evidence from pediatric liver failure suggests that it can improve hemodynamics and neurologic state and possibly is considered standard of care. However, in the general adult critical care population, high-volume filtration has not been shown to affect patient outcomes. Second, ammonia, a key mediator of neurotoxicity associated with liver failure, is water soluble and has a molecular weight similar to urea; therefore it is removed easily by traditional CRRT. Indeed, a study from the United Kingdom demonstrated that CRRT at 35 mL/kg/hr and 90 mL/kg/hr was very effective at removing this important toxin; however, survival data in this setting are currently lacking.
Plasma Exchange
Plasmapheresis, or plasma exchange, involves the use of CRRT apparatus along with a plasma filter membrane or centrifuge to separate blood into its plasma and cellular components and replace the discarded plasma 1:1 with fresh frozen plasma. Consistent with the use of plasma exchange in other critical care populations, plasma replacement is empirically weight based at approximately 15% to 20% body weight and is repeated daily for up to 3 days. This approach has had increased interest in the management of acute liver failure. The rationale behind plasma exchange is that by the removal of circulating cytokines and toxins, multi-organ failure may be limited or prevented. In addition, this process may be assisted by the replacement of depleted substances via the provision of fresh frozen plasma. Indeed, plasma exchange has been shown to improve hemodynamics and grade of encephalopathy and decrease vasopressor requirements. In the largest randomized control trial to date, 182 patients were randomized to standard care or high-volume exchange, with plasma exchange cohort showing a significant improvement in transplant-free survival, which was most marked in patients who did not receive a transplant. In addition, plasma exchange was shown to decrease significantly the markers of the innate immune response. One theoretical concern with plasma exchange is that the removal of cytokines and growth factors may include those that have an important role in hepatic regeneration. Recently, the Li-ALS system has been introduced, which uses the combination of low-volume plasma exchange—exchanges approximating 2.5% body weight—coupled with high-flux hemodiafiltration and, although only in a pig model of acute liver failure, there is evidence of improved survival.
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