The use of a single pass albumin dialysis for the management of liver failure- a case series

Intoduction. A single pass albumin dialysis (SPAD) is a form of
 extracorporeal liver support system for the removal of albumin-bound toxins
 and water-soluble substances that accumulate in liver failure (LF). Case
 report. We present a retrospective case series of three patients
 hospitalized for LF and treated using the SPAD in the Clinical Center of
 Vojvodina, between 2018 and 2019. Of whom, two patients presenting with
 acute liver failure and one with acute-on-chronic liver failure. A total of
 6 SPAD sessions were performed in each patient, resulting in decreased serum
 bilirubin and bile acid levels, and hepatic encephalopathy grade. On
 discharge from the hospital, liver function has been shown to improve in all
 the patients. Conclusion. SPAD removes the hepatotoxic substances without
 improvement of synthetic liver function, providing a supportive treatment
 for LF patients that do not respond to standard of care offering longer time
 for bridging to organ transplantation or spontaneous recovery of the liver
 function.


Introduction
There is a growing incidence of liver diseases in the world, accounting for approximately two million deaths per year. Liver failure (LF) is characterized by the lack of metabolic and regulatory functions, resulting in life-threatening complications which can include bleeding, impaired renal function, hepatic encephalopathy (HE) or brain edema, cardiovascular disorders and immune dysfunction, which eventually may lead to multiple organ failure and death 1,2 . It is important to identify patients who are not likely to progress after receiving standard medical therapy (SMT) and accordingly prepare them for the possibility of liver transplantation. In order to function as bridge therapy until the recovery to liver function or organ transplantation, extracorporeal liver support systems are used.
Extracorporeal albumin dialysis (ECAD) is a mechanical, completely artificial support system which presents detoxification systems of many potential liver toxins that are using albumin as transport protein, such as hydrophobic bile acids, bilirubin, and serum nitric oxide even though it has not been shown to have effect on synthetic liver function 3 . Several ECAD systems are in use, but the best-known and the most commonly used are the Molecular adsorbent recirculating system (MARS), the Fractionated plasma separation and adsorption technique (Prometheus system) and the Single pass albumin dialysis (SPAD).

Case Report series
After being admitted to hospial, patients who were treated with SMT received parenteral fluids (0.9% of sodium chloride solution and 10% of glucose solution) for volume resuscitation and maintaince of normoglycaemic state, in addition to proton pump inhibitor (pantoprazole 40 mg per 12 hours) in stress ulcer prophylaxis, fresh frozen plasma (10 mL per kilogram of body weight) supplemented with 10 mg of vitamin K prior to the placement of central venous lines, l-ornithine-l-aspartat was used for treating HE patients.   Table 1 and 2.

Second case:
A 49-year-old female patient who was admitted to hospital with fever, jaundice, and abdominal pain. Physical examination revealed patient to be oriented, without fever, with ABP of 109/53mmHg, HR 82/min, RR 18/min, painful sensation in the abdomen, GCS 15 and APACHE II 2. Diagnosis of acute LF caused by the hepatitis B virus was made. Additionally, SMT was initiated together with the nucleoside analogue reverse transcriptase inhibitor, Lamivudin, with a daily dose of 100mg. Despite the applied SMT, on the fifth day of hospitalization HE has developed (stage II) with a worsening of coagulation disorder and increase in bilirubin and bile acid levels. The patient was transferred to the intensive care unit (ICU) and SPAD procedures were initiated.
Preparation for the liver transplantation was carried out, but on the 10 th day of hospitalization HE progressed to stage IV, GCS was 8 and the Model for End-stage Liver disease (MELD) score of 37 points was calculated. Mechanical ventilation was initiated, with the continuation of daily SPAD procedures. Given the performed endocranial CT scan, the signs of a diffuse cerebral edema without altered density in supratentorial and infratentorial region have been shown (Figure 3). After 6 SPAD sessions, the treatment was discontinued due to the clinical improvement, but jaundice and elevated bilirubin values persisted. The patient was extubated on the 15 th day of hospitalization. On the 20 th day, she was referred to the Clinic for Infectious Diseases and after 72 days of hospitalization discharged with improved laboratory test results.
Third case: A 59-year-old female patient, who was hospitalized due to the nausea, vomiting, frequent diarrhea and jaundice that occurred seven days before admission to the Clinic for Infectious Diseases. She has been treated for migraine with analgetics (ibuprofen, diclofenac) and Avamigran (ergotamine, mecloxamine, camilofin, caffeine, propifenazone) for years. Also, she has been acquainted with the elevated aminotransferase levels for ten years, but not treated for that condition. Physical examination revealed a communicative but disoriented patient, without fiber, with ABP of 130/80mmHg, HR 100/min, RR 20/min, yellowish discoloration of the skin and sclera, painful sensation in the abdomen, GCS 15 and APACHE II 4. Diagnosis of an acute hepatitis A virus was confirmed by detection of IgM anti-HAV antibodies and a positive epidemiological data (patient's husband was also diagnosed with acute hepatitis A and had positive IgM anti-HAV antibodies).
The patient was treated with SMT but on the third day of hospitalization HE progressed to the stage III. Subsequently, she was transferred to ICU where SPAD sessions were started.
After 6 sessions the HE withdrew and she was transferred back to the Clinic for Infectious Diseases. Eventually, she was discharged after 37 days with improved hepatogram and normalization of the coagulation parameters.

Discussion
The use of the ECAD can contribute to an effective removal of albumin-bound toxins, but these procedures cannot substitute the synthetic liver function 2 . Given the fact that the greatest clinical experience in the field of ECAD refers to MARS, SPAD has the equal effectiveness in reducing the level of bilirubin as MARS, as well as the same safety profile, while MARS has shown the advantage in reducing the bile acid, creatinine, and urea 4 . Taking into account that the level of bilirubin represents the surrogate marker for proteinbound toxins and correlates positively with the patients' mortality, the greatest significance of the SPAD is in their removal 4-8 . The cause of ALF in one of our cases was the use of anabolic steroids that include a 17alpha alkyl group that have been linked to the development of jaundice. The literature describes four cases of successful MARS treatment of anabolic steroid-induced liver failure, but according to our knowledge, this has been the first case the SPAD was used for this indication 10 . The decrease in the bilirubin level has been verified, which correlates to the literature data regarding SPAD [4][5]8,11 . Also, the meta-analysis, which has included ten randomized clinical trials (RCT), has shown that the use of the ECAD as opposed to the isolated application of SMT has achieved significant net decrease in a total serum bilirubin level of 8.0 mg/dl 7  determined that the application of ECAD has not led to a significant net decrease in the mean platelet count in patients treated by ECAD compared with patients treated with SMT, while other meta-analysis has shown that the use of ECAD was associated with increased risk of thrombocytopenia 7,12 .
All the patients have been discharged from the hospital with liver function improved. The latest meta-analysis of Alshamsi et al. that included patients with ALF and AoCLF showed that ECAD tend to reduce mortality in these patients 12 .

Conclusion
To the best of our knowledge, this type of case series has not been presented in this region before. In conclusion, as one of the ECAD techniques, SPAD has the capacity to remove the hepatotoxic substances without improvement of synthetic liver function, providing a supportive treatment for patients with LF who do not respond to standard of care that can be used either as a bridge to transplant or for spontaneous recovery of the liver function.
However, further prospective studies and meta-analisys are needed for evaluation of the efficacy and safety of the SPAD and other ECAD techniques used as "salvage" therapy in LF patients.