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19th ISAD

The International Liver Support Meeting Rostock

Liver failure and extracorporeal liver support systems: a place for haemoadsorbtion (CytoSorb) to remove cytokines and reduce hyperammoniemia?

Acute liver failure (ALF) and acute on chronic liver failure (ACLF)  are two forms of hepatic decompensation intensivists might have to face with increasing frequency in the modern ICU.  ALF is a rare (< 10 cases per million population) and  life-threatening clinical syndrome (90% mortality rate in the pretransplant era) characterized by rapid-onset, severe liver injury and  associated with hepatocellular necrosis and severe hepatic impairment. It occurs over a timespan of 24 weeks since the first presentation and it is heralded by coagulopathy and any grade of hepatic encephalopathy (HE). 

Multiorgan system failure due to the systemic inflammatory response (SIRS) can be its extreme presentation,  making mandatory a  multimodal approach in the ICU to care for hepatic and extrahepatic organ dysfunction(s). In ALF, cerebral edema and intracranial hypertension (ICH) continue to be major causes of morbidity and mortality along with multiorgan failure.  Development of HE and cerebral edema are mainly (but not only) associated with ammonia, inflammatory cytokines, aromatic amino acids (AAAs) , Nitric Oxide(NO),  endogenous benzodiazepines (EBZD). Short and medium term survival rates have  markedly increased in the last 20 years: liver transplantation (LT )(mainly)  and changing etiologies (in part) are responsible for a one year survival rate close to 60 – 70%,  ALF accounting  worldwide for 5%-7% of LT indication.

Better understanding of ALF pathophysiology and effective means of optimizing liver regeneration or bridging to transplantation (mainly artificial hepatic support waiting for LT) may result in further improvements in survival rate. Control of ICH, mild therapeutic hypothermia and ammonia lowering therapies (hemofiltration or, very recently, the use of sorbents) are the mainstays of treatment.  In ESLD patients, ACLF is an acute decompensation of chronic conditions, possibly evolving toward multiple organ dysfunction/ failure (acute kidney injury (AKI), HE, cardiovascular failure, infections. 

According to the CLIF SOFA score, the higher the number of failing organs, the higher the mortality if a LT does not become available. In both ALF and ACLF  ammonia, inflammatory cytokines, damage-associated molecular patterns (DAMPs), AAAs, EBZD, NO  accumulate and impact heavily on brain, circulation (altered vascular tone, increased capillary permeability)  and kidney function, among the others. LT is the only definitive option for ALF and ACLF: the shortage of organs, or a bordeline indication to LT might indicate an extracorporeal artificial liver support  to facilitate spontaneous recovery or  to buy time while waiting for the graft (the latter option for both ALF and ACLS). Artificial extracorporeal liver support  systems (ECLS) are based on the principles of adsorption and filtration and are aimed at removing circulating toxins by using membranes with different pore sizes and adsorbent columns. 

Due to the ability of Albumin of binding toxins, albumin based dialysis has been set upand used  since long .  Dialysis-related techniques include the Molecular Adsorbent Recirculating System (MARS) , single-pass albumin dialysis (SPAD and Fractionated plasma separation and adsorption (Prometheus).Unfortunately, no difference in survival benefit was demonstrated between the albumin based extracorporeal liver supports  and standard treatment  groups in  studies performed both in ALF (FULMAR, 2013) and ACLF (RELIEF, 2013). Recently, a prospective randomized controlled trial in ALF utilizing high-volume plasma exchange (HVP) was able to demonstrate a survival benefit of HVP compared to standard treatment, with significant improvement in INR, bilirubin, and ammonia and significantly reduced circulating levels of proinflammatory cytokines and  DAMP: survival benefit might then be mechanistically  attributed to the decreased SIRS. Further randomized studies are required to assess extracorporeal supports efficacy in ALF, addressing, as suggested by some Authorities, also non survival end points (LT bridging as an example). However the almost always cumbersome and costly application of the available ECLS techniques limits its wide use. Very preliminary and limited experiences are now reported both in ALF and ACLS using haemoadsorbtion techniques (CytoSorb, USA )in parallel to continuous renal replacement therapy: the rational of the use of sorbent relies upon the ability to remove inflammation- triggering factors (mainly cytokines , widely demonstrated in septic shock)  and liver toxins (mainly  bilirubin and ammonia) in the context of the systemic inflammatory condition demonstrated both in ALF and ACLS. Very recents case reports and small non randomized series  of the ability of CytoSorb to remove bilirubin in hyperbilirubinemia conditions are available both in vitro and in vivo: main consequence could be to avoid , if confirmed,  the often complicated application of albumin dialysis or plasma separation techniques in the seting of hyperbilirubinemic liver failure. 

Even more interesting are the initial  results on  hyperammoniemia, since long known to play a relevant role in the development of hepatic encephalopathy, neurotoxicity  and brain edema (the most feared complication of ALF):  a significant role in enhancing ammonia induced neurotoxicity is  played by  inflammatory cytokines. Very recent reports are now able to demonstrate a possible significant role of haemoadsorbtion (CytoSorb ) in controlling / reducing hyperammoniemia and its consequences on central nervous system:  while continuous renal replacement therapy (CRRT) with haemofiltration (HF) is demonstrated to reduce hyperammonemia by 25% in moderately high hyperammoniemia (average 150 μmol/L),very preliminary results coming from some groups and from our own group demonstrate  very  interesting results: in our experience (preliminary ad anedoctal, but interesting) we recorded an  even larger ammonia reduction (ammonia from 470 to 117  mmol/L) with full and rapid recovery from severe hepatic encephalopathy documented by clinical, laboratory and EEG support  in a case of very severe early graft dysfunction after LT). 

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