Preliminary Results of a Phase I Trial Evaluating an Extracorporeal Hepatic Support Device Utilizing Albumin Dialysis

Background: Toxins such as ammonia, aromatic amino acids, free fatty acids and bilirubin have been implicated as the cause of hepatic encephalopathy and cerebral edema in patients with acute liver failure. We have previously reported clearance of these toxins, using a non-cell based extracorporeal hepatic support device (ECHS).

Objective: To evaluate the safety and efficacy of ECHS through a phase I clinical trial.

Our hypothesis was that continuous veno-venous hemodiafiltration with albumin dialysis would: 1) decrease elevated levels of hepatic toxins, 2) reverse the ratio of branched chain to aromatic amino acids (Fischer ratio), 3) reverse hepatic encephalopathy, 4) maintain stable hemodynamics.

Methods: Patients with acute hepatic failure who were UNOS Status I, IIA or 7 were enrolled into a protocol approved by the FDA and the IRB. These patients were placed on continuous veno-venous hemodiafiltration (Blood flow rate = 10cc/kg/min) with continuous countercurrent dialysis using a 10 % albumin solution flowing through an activated charcoal sorbent cartridge (Dialysate flow rate = 10cc/kg/min). Mean arterial blood pressure (MAP), heart rate (HR), systemic venous oxygen saturation (SVO2), intracranial pressure (ICP), and hepatic encephalopathy score were recorded at baseline and throughout treatment. Serial blood samples were collected and evaluated for total bilirubin, ammonia, aromatic and branched chain amino acids, factor 7, and free fatty acids. Comparisons were made using Student’s t test.

Results: Nine patients were enrolled into this phase I study (Status I: n = 5, Status IIA: n = 4). During treatment there were there was no significant change in MAP, heart rate, or SVO2 when compared to baseline with no adverse mechanical effects (MAP: Pre = 81 ± 5.6 mmHg, Post = 79 ± 5.9 mmHg, p = 0.70; HR: Pre = 104 ± 5.2 bpm, Post = 107 ± 6.2 bpm, p = 0.62; SVO2: Pre = 72 ± 3.5, Post = 71 ± 1.7, p = 0.77, Figure [1]). There was a significant decrease in the ammonia levels (NH3: Pre = 129.8 ± 23.8 mg/dl, Post = 63.9 ± 16.1 mg/dl, p = 0.01, Figure [2]), and a trend of decreasing total bilirubin (Total Bili: Pre = 20.3 ± 2.5 mg/dl, Post = 17.6 ± 2.7 mg/dl, p = 0.4).

Figure 1

Figure 2

Also, there was a significant reversal of the Fischer ratio (Fischer ratio: Pre = 0.98 ± 0.2, Post = 2.17 ± 0.5, p = 0.038, Figure [3]) and a significant increase in the factor 7 levels (Factor 7: Pre = 13.9 ± 4.9, Post = 23.2 ± 4.8, p = 0.015, Figure [4]). There was a significant improvement in the hepatic encephalopathy score (HES: Pre = 3.8 ± 0.1, Post = 2 ± 0.7, p = 0.02). Of the five Status I patients, one recovered native hepatic function and three were successfully bridged to transplantation, one of which was anhepatic for 70 hours.

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Conclusion: Results of this phase I study suggest that an ECHS device which utilizes selective hemodiafiltration with albumin dialysis is effective in clearing some of the toxins that have been implicated as the cause of hepatic encephalopathy and cerebral edema with an associated decrease in the hepatic encephalopathy score. There were minimal hemodynamic effects and no mechanical complications. This study provides evidence that this device is safe with preliminary encouraging efficacy data that warrants further investigation.