Definition/Introduction

Liver failure is a medical emergency carrying a high mortality rate. It presents in an individual with normal liver function as acute liver failure(ALF), and in an individual with chronic liver disease either as ‘acute on chronic’ liver failure(AOCF) or decompensated end-stage liver disease. Though the etiology may be different, all the types of liver failure result in the accumulation of toxic metabolites in the body that causes end-organ dysfunction, eventually culminating in multi-organ failure and death.[1] Liver support devices/systems play a significant role in the management of ALF and AOCF, as they are likely reversible and these systems replicate the detoxifying function of the liver, until the endemic function of the liver recovers. Though liver transplantation is the only potent therapeutic option for end-stage liver disease, a matching liver transplant may not be immediately accessible. Also, by the time the donor graft becomes available, the patient may be having multi-organ failure rendering it unsuitable for transplantation. Liver support systems can be useful in such scenarios as they can stabilize the patient’s health until the time transplant becomes available or he/she is eligible for transplantation.[2] Liver support systems group into artificial systems and the bioartificial systems.[3] This review article focuses on the Molecular Adsorbent Recirculating System (MARS), an artificial system that has been comprehensively used since 1998 when it was made accessible for clinical usage.[4] 

Issues of Concern

MECHANISM 

Molecular adsorbent recirculating system (MARS) is an extracorporeal hepatic support system that integrates the mechanisms of dialysis, ultrafiltration, and adsorption.[5] It involves the elimination of toxins from the blood, albumin-bound as well as water-soluble toxins, thus cleansing the body of toxic catabolites accumulated from hepatic failure.[6]

MARS exploits the usage of three different circuits- a blood circuit that utilizes hemodialyzer (MARS FLUX dialyzer), an albumin circuit that contains an anionic exchange column, and an activated charcoal adsorber, and a dialysate circuit that utilizes conventional dialyzer. Of the two pumps that drive the system, one pump drives the blood circuit and is catered by the standard hemodialyzer (HD)/conventional veno-venous hemofiltration (CVVH) equipment. The closed-loop albumin circuit interconnects the blood and dialysate circuits and is controlled by the pump provided by the MARS monitor.[7][8][9]

Vascular access is obtained through a double lumen catheter either from the internal jugular vein, subclavian vein, or the femoral vein. Blood runs through the MARS FLUX dialyzer at a flow rate controlled between 150 TO 250 ml/min and its dialysis done against an albumin solution across an albumin permeated membrane. 600 ml of 10 to 20% albumin dialysate is used to fill the circuit and is run in a direction opposite to the blood flow across the hemodialyzer.[10][9]

Based on the concepts of protein affinity and the difference in the concentration gradient of the solutes between the two compartments of the MARS FLUX dialyzer, the highly permeable membrane facilitates the diffusion of protein-bound and water-soluble toxins into the albumin dialysate. Albumin in the dialysate solution has free binding sites, and its affinity towards hydrophobic toxins in the circulating blood pulls them across the membrane and is thus retained by the dialysate. The MARS flux membrane doesn’t allow proteins larger than 50 kDa (example: growth factors) to diffuse across the membrane.[7][11]

The albumin dialysate then circulates through an anionic exchanger and an activated carbon adsorber, which facilitates the removal of protein-bound toxins through the process of adsorption. Subsequently, the solution undergoes another cycle of detoxification where it is dialyzed against bicarbonate buffered dialysate in a diaFLUX dialyzer to clear it of water-soluble toxins and thereby, the purified albumin dialysate recirculates into the blood circuit for reuse.[10]

Unfractionated heparin is administered during the therapy at a dosage of 1500 to 4000 IU/hour for effective anticoagulation. The monitoring of heparin therapy is via activated clotting time (ACT), maintained between 160 and 200 seconds.[12][13] Therapy takes place in sessions, and typically, each session of MARS treatment takes around 6 TO 8 hours.[10]

Clinical Significance

MARS assists in attenuation of the clinical manifestations of liver failure through the removal of accumulated bilirubin, bile acids, ammonia, aromatic amino acids, pro-inflammatory cytokines, and nitric oxide, which carry implications in the pathophysiology of hepatic encephalopathy, hepatorenal syndrome, and hyperdynamic circulatory failure. By removal of the vasoactive agents (NO and inflammatory cytokines), MARS assists in increasing the systemic vascular resistance and mean arterial pressure, thus, stabilizing the circulation. Bilirubin and bile acids are hepatotoxic and have the potential to cause hepatocyte necrosis. Therefore, by removing them from the body, MARS serves to halt the process of liver damage temporarily. MARS has also been associated with improvement in liver function, as evidenced by an increase in the synthesis of factor VII, antithrombin III, and prothrombin.[14][4][8]

MARS has demonstrated an improvement in short term survival in patients with acute on chronic liver failure in a few studies. In a randomized controlled trial conducted by Mitzner et al., out of the 13 patients with type 1 hepatorenal syndrome, eight received treatment with MARS and five with hemodiafiltration (HDF). MARS correlates with a 68% survival impact compared to 0% survival in patients treated with HDF. There was a significant improvement in hemodynamic status, decreased bilirubin, improved biochemistry, and prothrombin time index. The RELIEF trial saw the participation of 189 patients with ACLF. Compared to the patients treated with standard therapy, a greater percentage of patients treated with MARS had a significant improvement in hepatic encephalopathy (38.2% vs. 62.5%, respectively). Hepatic encephalopathy improved from grade III-IV to grade 0-I, and the study was statistically significant (p=0.07). Several studies assessing the impact of MARS on ACLF patients were associated with a decrease in hepatic encephalopathy and improvement of Child-Pugh scores. At present, the FDA has approved the use of MARS for HE improvement in patients with chronic liver disease.[15][16][9][17][18] There is relatively less information on the benefit of MARS in acute liver failure. Even though there is uncertainty about the survival benefit in ALF, MARS has linked with the betterment of hepatic encephalopathy, hemodynamic status, and reduction of bilirubin.[9][7][2]

INDICATIONS [10][19][20][21][22][5][14]

Indications for MARS usage includes:

1.Acute Liver Failure (ALF)

MARS is used in ALF, provided there is a failure of disease resolution despite maximal medical treatment and that the etiology can be treated. ALF is potentially reversible, and by stabilizing the patient, MARS provides time for recovery and also serves as a ''bridge to transplantation'', if a liver transplant is needed.

Causes of ALF where MARS has been used include:

• Acute alcoholic hepatitis
• Fulminant viral hepatitis: hepatitis B, hepatitis C
• Drugs: acetaminophen, allopurinol,[23] chromium,[24] and copper[25]
• Natural toxins: Amanita phalloides

2. Acute on Chronic Liver Failure (rehabilitation/bridge to transplantation)

3. Decompensated End-Stage Liver Disease (bridge to transplantation)

4. Acute Decompensation of the liver causing: hepatic encephalopathy (grade ≥ 2), hepatorenal syndrome

5. Intractable pruritus despite maximal medical treatment. Causes include: primary biliary cirrhosis, primary sclerosis cholangitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic hepatitis

6. Post-transplantation liver failure

7. Liver failure following hepatectomy/severe mechanical trauma

8. Poisoning with albumin-bound drugs unrelated to liver failure: phenytoin,[26] theophylline,[27] and lamotrigine[28]

SAFETY & CONTRAINDICATIONS

MARS has a very good safety profile and is tolerated well by the patients. Except for the fact that MARS is expensive, patients have no specific complaints regarding the procedure. Thrombocytopenia has been documented during the therapy, but it is mild and poses no significant threat to the patient. The risks associated with MARS are the same as the ones with conventional hemodialysis and requires the use of anticoagulants to prevent coagulation activation during the procedure. In patients with end-stage liver disease, the risk of thrombosis and bleeding significantly increases, and hence, the use of anticoagulation is of utmost importance. For this, unfractionated heparin is the anticoagulant of choice, as evidenced by most clinical trials.[19][10][7]

MARS is relatively contraindicated if there is an increased risk of coagulopathy (example: disseminated intravascular coagulation) i.e., when platelets are below 50,000/microlitre of blood or when the INR is greater than 2.3. Uncontrolled sepsis or uncontrolled hemorrhage are also prohibitions to the use of MARS and are considered as relative contraindications.[20] 

MARS has been so successful in attenuating the symptomatology and biochemical parameters of liver failure that it is now in use for a wide range of indications. The usage of MARS has been increasing ever since its inception and has received considerations from different sub-specialties of medicine. There are no large clinical trials proving its efficacy as far as mortality benefit is concerned; however, there are numerous case reports, case series, and underpowered studies showing its effectiveness in the settings described above. However, it certainly a costly therapy requiring highly specific skill set and expertise to operate available only at certain centers which offer transplant. Larger randomized control trials with effective endpoints are necessary to justify its use at a bigger scale and expanding its indication. Until we have better data regarding its efficacy, this therapy will be a highly specialized therapy limited to certain small centers.[29][9][14]

Nursing, Allied Health, and Interprofessional Team Interventions

MARS is a complex medical therapy and requires effective communication and teamwork between the gastroenterologist, critical care specialist, transplant surgeon, nephrologist, and healthcare workers in the ICU to resuscitate the patient and improve patient outcomes.