Introduction An effective liver support device to remove metabolic toxins is an unmet clinical need. We have demonstrated that in liver failure, albumin function is irreversibly damaged, preventing detoxification processes, and that bacterial endotoxins induce neutrophil dysfunction causing indiscriminate damage and immune failure. Previous generations of artificial devices were designed to remove toxins from patients’ plasma, but did not address albumin damage and/or inflammation. An albumin replacement system with a novel endotoxin ligation (ARSeNEL) component was developed to selectively filter plasma to adsorb endotoxin and replace damaged albumin.
Method The device consists of three components; plasmapheresis, endotoxin and high cut-off (100 kDa) cartridges; with fresh frozen plasma replacing ultrafiltered plasma. We tested the device in a model of acetominophen-induced acute liver failure (ALF). Sixteen female landrace pigs (3 sham, 8 ALF, 5 ALF+UCL-ARSeNEL) were studied. ALF was induced via intra-gastric acetaminophen administration, confirmed by deranged clotting function (ca. 20hrs to ALF). Animals were treated with UCL-ARSeNEL or haemofiltration control within 2 h of ALF confirmation. Endpoints were: survival; ICP; standard biochemistry; cytokines; albumin damage; and plasma endotoxin levels.
Results Survival post ALF was significantly increased using UCL-ARSeNEL (ALF 15.8±2.4 h vs UCL-ARSeNEL 23.8±1.9 h; p=0.02). No haematological or biocompatibility issues were observed. Endotoxin reduced by a quarter (1.99±0.18 Eu/ml vs 1.42±0.21 Eu/ml) in the device group at 16hrs. The changes in ICP index (1.7±0.07 vs 1.4±1.58), INR (16.6±6.6 vs 6.8±0.5), ischaemia-modified albumin ratio (0.45±0.166 vs 0.35±0.108), ammonia (177±131 vs 153±84 μM) and mean arterial pressure (71±7.6 vs 87±6.0 mm Hg) showed marked improvement in the UCL-ARSeNEL group.
Conclusion The results of the study confirm that UCL-ARSeNEL is safe and effectively improves survival in ALF pigs by addressing the key pathophysiological derangements such as albumin dysfunction and endotoxinaemia; which impact upon end-organ function. The results justify a clinical trial, which is being planned.
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