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Acute liver failure is a very complex type of disease with a mortality of up to 90%, leading to numerous severe disturbances of the whole organism. Bleeding because of absent synthesis of various coagulation factors and disseminated intravascular coagulation, acute kidney failure, circulatory failure with vasopressor dependence, respiratory failure with adult respiratory distress syndrome, neurological failure up to coma because of hepatic encephalopathy, and a very high risk of infection and sepsis frequently result from the initial state of isolated liver failure. High urgency liver transplantation is a highly efficient therapy if performed in time. However, increasing the rate of spontaneous recovery of the patients' own liver, and reducing the need for liver transplantation is preferable and would further improve the outcome of acute liver failure. Extracorporeal liver support by multipass albumin dialysis or plasmapheresis and filtering systems may offer a possibility to fulfill these aims of therapy. A prospective study in 88 patients with acute liver failure has shown a nonsignificant trend in improvement of survival after acute liver failure by multipass albumin dialysis and filtering. Other retrospective studies have shown benefits in improving hepatic encephalopathy and brain oedema. Further, an increase in the rate of spontaneous recovery of liver function has been described. With regional citrate anticoagulation for multipass albumin dialysis and filtering, the need for systemic anticoagulation – a potentially very harmful measure in these patients – can be eliminated and the rate of filter clotting can extremely effectively be reduced.
Acute liver failure is one of the most severe and challenging diseases in intensive care. It is not only the liver with its excretory and synthetic components of function that is severely reduced or even absent, it is the effect of this lack of organ function on numerous biological functions and systems and the usually subsequent failure of other organs, i.e. acute kidney failure, circulatory failure, dramatic coagulation disorders with menacing spontaneous, life-threatening bleeding, neurological failure up to coma and cerebral herniation, and most severe disorders of the acid–base system just to mention the most prominent types of problems (1). The patient population may include children <1 year of age, pregnant females, young to middle-aged adults, as well as typical elderly intensive care patients. Because of the great number and variety of possible causes for acute liver failure, the patients may have been completely healthy before the start of their illness, or may suffer from other concomitant diseases, such as drug addiction, congestive heart failure, psychiatric disorders like depression or sepsis as a result of a completely different initial problem (1). The rate of spontaneous recovery from acute liver failure has been described to range within 5–80%, with not so clear factors predicting it (2). It has been shown that the probability of spontaneous recovery from acute liver failure is very low if a patient becomes dependant on mechanical ventilation, or if the patient develops hepatic encephalopathy of grade three or four (2). Liver transplantation is a very important therapeutic measure to substantially improve the survival rate even in cases of very severe forms of acute liver failure. However, long time prognosis of liver transplantation is limited by the requested immunosuppressive therapy, causing kidney function derangement and increasing the risk of malignancies. Therefore, the indication to liver transplantation has to be carefully evaluated. Extracorporeal liver support devices may offer a possibility to bridge patients until an organ is available, or even until the patient's own liver recovers. The question arises, whether currently available extracorporeal liver support devices have the potential of increasing the rate of spontaneous recovery of liver function from acute liver failure, and of improving the state of patients suffering from acute liver failure during their waiting time to liver transplantation.
Firstly, there were some case reports describing successful recovery from very severe forms of acute liver failure in patients not eligible for high urgency liver transplantation because of drug abuse or malignancies (3, 4). In these patients, either a haemodialysis- and plasmapheresis-based system (Prometheus®), or a multipass albumin dialysis system with a charcoal adsorber and an ion exchanger [molecular adsorbent recirculating system (MARS®)], have been used as extracorporeal liver support devices (3, 4). Both systems are based on the elimination of small molecules, such as ammonia, uremic toxins, phenols and mercaptanes, by haemodialysis, and elimination of albumin-bound substances, such as bilirubin, aromatic amino acids, false neurotransmitters, middle- and short-chain fatty acids and endogenous benzodiazepines, by adsorption to charcoal and ion exchange. In both cases, the patients' prognoses were very bad because of multi-organ failure developing in the course of acute liver failure (3, 4). In the first case, a young man with intoxication with cocaine and 3,4-methylenedioxymetamphetamine developed severe cerebral oedema and hyperammonemia leading to intermittent cerebral herniation. He was treated with Prometheus® twice over a total period of 6 days, which resulted in a decrease in intracranial pressure, recovery from brain oedema, and even recovery of his liver function without the need of transplantation (3). The second case of successful treatment of an almost hopeless case (APACHE II score of 38 with predicted mortality of 87%) of acute liver failure with severe neurological deterioration and brain oedema and multi-organ failure was a young man suffering from an insulinoma, who experienced haemorrhagical shock after surgical resection. He was treated with five cycles of MARS® that led to clinically relevant improvement of haemodynamic and respiratory function, neurological function, and a decrease in serum ammonia concentration, so that he could be discharged from the hospital in a very good health state (4).
Such case reports are encouraging enough to further investigate the effectiveness of extracorporeal liver support devices in the treatment of acute liver failure.
Only few data exist, where MARS® or Prometheus® have prospectively been evaluated in their effectiveness of improving the condition or even survival rates in patients with acute liver failure. A multicentre study of 88 patients with acute liver failure showed that MARS® treatment led to a trend in improvement of survival rates after 6 months in acute liver failure (82.9 vs. 75.5%), but this did not reach statistical significance (5). At least, in this study, there was no increase in bleeding rates or other adverse events associated with MARS® (5). One limitation of this study is the fact that the median waiting time for high urgency liver transplantation after listing was only 16.2 h, which may preclude a significant effect, because the number and time of MARS® therapies was low (5). Some retrospective studies have been published, generally demonstrating a good effect of MARS®. In 45 patients with acute live failure, 80% survived, and 50% even without high urgency liver transplantation (6). Hepatic encephalopathy grade 3 or 4 was present in 44% of acute liver failure patients and it improved to grade 1.1 on average (6). The patients in this study were treated with 8–22 h-cycles of MARS® as long as clinical recovery occurred, or high urgency liver transplantation was performed (6). Another retrospective study compared 113 patients with acute liver failure treated with MARS® with 46 previous patients without MARS® (7). Of the MARS-treated patients 94% survived, whereas in the conventionally treated group, 77% (NS) survived (7). In the latter study, the patients of the MARS® group received a mean number of 2.9 (range 1–12) MARS® cycles with a mean duration of 15.2±4.6 h (SD) (7). The rate of recovery of the native liver was higher in the MARS®-treated group (49 vs. 17%) (7). Similarly, good results could be shown in 10 patients with acute liver failure after Amanita phalloides intoxication, of which all survived, and only one liver transplantation was necessary (8). The rate of spontaneous recovery from acute liver failure can possibly be increased by MARS®, as it has been shown in another series of 18 patients already listed for high urgency liver transplantation, in whom nine patients recovered without transplantation (9). In a French cohort of other patients with acute liver failure, the spontaneous rate of recovery from acute liver failure was only 19.3% (9). Three patients who had no spontaneous recovery of liver function died (one before, two after liver transplantation) (9). Again, it has been shown, that patients only have a benefit if at least 15 h of MARS® therapy are administered (9).
Any type of extracorporeal liver support requires anticoagulation to inhibit clotting of filter membranes and extracorporeal tubes. In case of acute liver failure, anticoagulation is very peculiar because of an extreme derangement of the normal balance of pro- and anticoagulative factors that normally causes both, spontaneous, life-threatening bleeding, as well as disseminated intravascular coagulation with (1). The administration of heparin and prostacycline derivatives imposes a high bleeding risk, and on the other hand, may be ineffective in avoiding clotting of the extracorporeal circuit. A recent study has clearly demonstrated that regional anticoagulation of the extracorporeal MARS® circuit is safe and effective in patients with acute liver failure (10). With a reduced dose of trisodiumcitrate administered into the arterial blood line of the dialysis machine, the lifetime of a MARS cycle can usually be expanded to its maximum, and bleeding events can be attenuated by avoidance of high-dose systemic anticoagulation (10).
In conclusion, the treatment of patients with acute liver failure with multipass albumin dialysis or plasmapheresis and filtering systems is promising. Case reports showed surprisingly good results in extremely severe cases. Some retrospective studies showed an increase in the rate of spontaneous recovery of liver function and resolving of multi-organ failure in patients with acute liver failure. Further, a substantial improvement of hepatic encephalopathy and cerebral oedema has been observed. A prospective multicentre study did not reveal a statistically significant improvement of survival of these treatment options, although a strong trend towards a better survival could be demonstrated. The reason for the lack of statistical significance of the latter study could be a very short median waiting time for high urgency liver transplantation of only about 16 h.