Liver support systems

Liver support systems
Specialty	hepatology
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Liver support systems are therapeutic devices to assist in performing the functions of the liver in persons with liver damage.

The primary functions of the liver include removing toxic substances from the blood, manufacturing blood proteins, storing energy in the form of glycogen, and secreting bile. The hepatocytes that perform these tasks can be killed or impaired by disease, resulting in hepatic insufficiency. A sudden onset of life-threatening hepatic insufficiency is known as acute liver failure (ALF).

In hyperacute and acute liver failure the clinical picture develops rapidly with progressive encephalopathy and multiorgan dysfunction such as hyperdynamic circulation, coagulopathy, acute kidney injury and respiratory insufficiency, severe metabolic alterations and cerebral edema that can lead to brain death.^[1][2] In these cases the mortality without liver transplantation (LTx) ranges between 40-80%.^[3][4] LTx is the only effective treatment for these patients although it requires a precise indication and timing to achieve good results. Nevertheless, due to the scarcity of organs to carry out liver transplantations, it is estimated that one third of patients with ALF die while waiting to be transplanted.^[5] On the other hand, a patient with a chronic hepatic disease can suffer an acute decompensation of liver function following a precipitating event such as variceal bleeding, sepsis and excessive alcohol intake among others that can lead to a condition referred to as acute-on-chronic liver failure (ACLF). Both types of hepatic insufficiency, ALF and ACLF, can potentially be reversible and liver functionality can return to a level similar to that prior to the insult or precipitating event. LTx is the only treatment that has shown an improvement in the prognosis and survival with most severe cases of ALF. Nevertheless, cost and donor scarcity have prompted researchers to look for new supportive treatments that can act as “bridge” to the transplant procedure. By stabilizing the patient's clinical state, or by creating the right conditions that could allow the recovery of native liver functions, both detoxification and synthesis can improve, after an episode of ALF or ACLF.^[6] Basically, three different types of supportive therapies have been developed: bio-artificial, artificial and hybrid liver support systems (Table 2).

Table 2: Liver Support Systems

Bio-artificial	Artificial	Hybrids
ELAD[7] Extracorporeal liver assist device Molecular adsorbent recirculating system	Hepat-Assist[8]
BLSS[9] Bioartificial Liver Support System	Prometheus FPSA[10] Fractionated plasma separation and adsorption system	TECLA-HALSS[11] TECA-Hybrid Artificial Liver Support System
RFB[12] Radial Flow Bioreactor	SPAD[13] Single-pass albumin dialysis	MELS[14] Modular Extracorporeal Liver Support
AMC-BAL[15] Bioartificial Liver	SEPET[16] Selective plasma filtration therapy	-

Bio-artificial liver support systems are experimental extracorporeal devices that use living cell lines to provide detoxification and synthesis support to the failing liver. Bio-artificial liver (BAL) Hepatassist 2000 uses porcine hepatocytes¹¹ whereas ELAD system employs hepatocytes derived from human hepatoblastoma C3A cell lines.^9,[17][18] Both techniques can produce, in fulminant hepatic failure (FHF), an improvement of hepatic encephalopathy grade and biochemical parameters. Nevertheless, they are therapies with high complexity that require a complex logistic approach for implementation; a very high cost and possible inducement of important side effects such as immunological issues (porcine endogenous retrovirus transmission), infectious complications and tumor transmigration have been documented. Other biological hepatic systems are Bioartificial Liver Support (BLSS)¹² and Radial Flow Bioreactor (RFB).¹⁵ Detoxification capacity of these systems is poor and therefore they must be used combined with other systems to mitigate this deficiency. Today its use is limited to centers with high experience in their application.^[19]

Artificial liver support systems are aimed to temporally replace native liver detoxification functions and they use albumin as scavenger molecule to clear the toxins involved in the physiopathology of the failing liver. Most of the toxins that accumulate in the plasma of patients with liver insufficiency are protein bound, and therefore conventional renal dialysis techniques, such as hemofiltration, hemodialysis or hemodiafiltration are not able to adequately eliminate them. Between the different albumin dialysis modalities, single pass albumin dialysis (SPAD) has shown some positive results at a very high cost;^[20] it has been proposed that lowering the concentration of albumin in the dialysate does not seem to affect the detoxification capability of the procedure.^[21] Nevertheless, the most widely used systems today are based on hemodialysis and adsorption. These systems use conventional dialysis methods with an albumin containing dialysate that is later regenerated by means of adsorption columns, filled with activated charcoal and ion exchange resins. At present, there are two artificial extracorporeal liver support systems: the Molecular Adsorbents Recirculating System (MARS)¹⁰ from Gambro and Fractionated Plasma Separation and Adsorption (FPSA), commercialised as Prometheus (PROM) from Fresenius Medical Care.¹³ Of the two therapies, MARS is the most frequently studied, and clinically used system to date.

The MARS System

MARS was developed by a group of researchers at the University of Rostock (Germany), in 1993¹⁰ and later commercialized for its clinical use in 1999.^[22] The system is able to replace the detoxification function of the liver while minimizing the inconvenience and drawbacks of previously used devices.^[23][24][25]

In vivo preliminary investigations indicated the ability of the system to effectively remove bilirubin, biliary salts, free fatty acids and tryptophan while important physiological proteins such as albumin, alpha-1-glicoproteine, alpha 1 antitrypsin, alpha-2-macroglobulin, transferrin, globulin tyrosine, and hormonal systems are unaffected.^[26] Also, MARS therapy in conjunction with CRRT/HDF can help clear cytokines acting as inflammatory and immunological mediators in hepatocellular damage, and therefore can create the right environment to favour hepatocellular regeneration and recovery of native liver function.

MARS System Components

MARS is an extracorporeal hemodialysis system composed of three different circuits: blood, albumin and low-flux dialysis. The blood circuit uses a double lumen catheter and a conventional hemodialysis device to pump the patient's blood into the MARS FLUX, a biocompatible polysulfone high-flux dialyser. With a membrane surface area of 2.1 m², 100 nm of thickness and a cut-off of 50 KDa, the MARSFLUX is essential to retaining the albumin in the dialysate. Blood is dialysed against a human serum albumin (HSA) dialysate solution that allows blood detoxification of both water-soluble and protein-bound toxins, by means of the presence of albumin in the dialysate (albumin dialysis). The albumin dialysate is then regenerated in a close loop in the MARS circuit by passing through the fibres of the low-flux diaFLUX filter, to clear water-soluble toxins and provide electrolyte/acid-base balance, by a standard dialysis fluid. Next, the albumin dialysate passes through two different adsorption columns; protein-bound substances are removed by the diaMARS AC250, containing activated charcoal and anionic substances are removed by the diaMARS IE250, filled with cholestyramine, an anion-exchange resin. The albumin solution is then ready to initiate another detoxifying cycle of the patient's blood that can be sustained until both adsorption columns are saturated, eliminating the need to continuously infuse albumin into the system during treatment (Fig. 1).

Results published in the literature with the MARS system

A systematic review of the literature from 1999 to June 2011 was performed in the following databases:

1. Specialized in systematic reviews: Cochrane Library Plus and NHS Centre database for Reviews and Dissemination (HTA, DARE and NHSEED).
2. General databases: Medline, Pubmed and Embase.
3. On-going clinical trials and research project databases: Clinical Trials Registry (National Institutes of Health, EE.UU.) and Health Services Research Projects in Progress.
4. General web searching engines: Scholar Google.

LiverNet

The LiverNet is a database dedicated to the liver diseases treated with the support of extracorporeal therapies. To date, the most currently used system is the Molecular Adsorbent Recirculating System (MARS), which is based on the selective removal of albumin bound molecules and toxins from the blood in patients with acute and acute-on-chronic liver failure. The purpose is to register prospectively all patients treated worldwide with the MARS system in order to:

1. Improve our understanding of the clinical course, pathophysiology and treatment of these diseases
2. Evaluate the clinical impact of MARS therapy on the course of the disease in different specific indication
3. Increase the knowledge in this extremely innovative area, a basis for an improvement of liver support devices and the treatment of these patients in the next future

The liverNet is an eCRF database (www.livernet.net) using a SAS platform that allows major advantages for the centres including the automatic calculations of most liver rand ICU scoring systems, instant queries online, instant export of all patients included in the database of each centre to an Excel file for direct statistical analysis and finally instant online statistical analysis of selective data decided by the scientific committee. Therefore, the LiverNet is an important tool to progress in the knowledge of liver support therapies.

Effects of MARS treatment on Hepatic Encephalopathy (HE)

Hepatic encephalopathy (HE) represents one of the more serious extrahepatic complications associated with liver dysfunction.^[27][28] Neuro-psychiatric manifestations of HE affect consciousness and behaviour.

Evidence suggests that HE develops as some neurotoxins and neuro active substances, produced after hepatocellular breakdown, accumulates in the brain as a consequence of a portosystemic shunt and the limited detoxification capability of the liver. Substances involved are ammonia, manganese, aromatic aminoacids, mercaptans, phenols, medium chain fatty acids, bilirubin, endogenous benzodiazepines, etc.
The relationship between ammonia neurotoxicity and HE was first described in animal studies by Pavlov et al.^[29]
Subsequently, several studies in either animals or humans have confirmed that, a ratio in ammonia concentration higher than 2 mM between the brain and blood stream, causes HE, and even a comatose state when the value is greater than 5 mM. Some investigators have also reported a decrease in serum ammonia following a MARS treatment (Table 3).

Table 3. Clinical studies showing some improvement in the treatment of HE following a MARS treatment

References	Nº patients	Age (years) [aver. ±SD]	Treatment Hours/patient	Ammonia Pre-MARS (μg/dl)	Ammonia Post-MARS (μg/dl)	p
Awad et al.[30] (1999)	9	38±5	73.2	130	64	<0.05
Novelli et al.[31] (2002)	10	42±12	51.2	247	126	<0.003
Schmidt et al.[32] (2001)	8	43±5	10.0	150	121	<0.05
Sorkyne et al.[33] (2001)	8	47±16	28.1	280	65	<0.005

Manganese and copper serum levels are increased in patients with either acute or acute on chronic liver failure. Nevertheless, only in those patients with chronic hepatic dysfunction, a bilateral magnetic resonance alteration on Globos Pallidus is observed,^[34] probably because this type of patients selectively shows higher cerebral membrane permeability. Imbalance between aromatic and branched chain aminoacids (Fischer index), traditionally involved in HE genesis,^[35][36][37] can be normalized following a MARS treatment. The effects are noticeable even after 3 hours of treatment and this reduction in the Fisher index is accompanied with an improvement in the HE.^[38]

Novelli G et al.^[39] published their three years experience on MARS analyzing the impact of the treatment in the cerebral level for 63 patients reporting an improvement in Glasgow Coma Score (GCS) for all observed in all patients. In the last 22 patients, cerebral perfusion pressure was monitored by Doppler (mean flow velocity in middle cerebral artery), establishing a clear relationship between a clinical improvement (especially neurological) and an improvement in arterial cerebral perfusion. This study confirms other results showing similar increments in cerebral perfusion in patients treated with MARS.^[32]

More recently, several studies have shown a significant improvement of HE in patients treated with MARS. In the studies by Heemann et al.^[40] and Sen et al.^[41] an improvement in HE was considered when encephalopathy grade was reduced by one or more grades vs. basal values; for Hassenein et al., in their randomized controlled trial, improvement was considered when a decrease of two grades was observed.^[42] In the latter, 70 patients with acute on chronic liver failure and encephalopathy grade III and IV were included. Likewise, Kramer et al.^[43] estimated an HE improvement when an improvement in peak N70 latency in electroencephalograms was observed. Sen et al.44 observed a significant reduction in Child-Pugh Score (p<0,01) at 7 days following a MARS treatment, without any significant change in the controls. Nevertheless, when they looked at the Model for End-Stage Liver Disease Score (MELD), a significant reduction in both groups, MARS and controls, was recorded (p<0,01 y p<0,05, respectively). Likewise, in several case series, an improvement in HE grade with MARS therapy is also reported.^{[44][45][46][47][48][49][50][51][52]}

Effects of MARS Treatment on Unstable Hemodynamics

Hemodynamic instability is often associated with acute liver insufficiency, as a consequence of endogenous accumulation of vasoactive agents in the blood. This is characterized by a systemic vasodilatation, a decrease of systemic vascular resistance, arterial hypotension, and an increase of cardiac output that gives rise to a hyperdynamic circulation.
During MARS therapy, systemic vascular resistance index and mean arterial pressure have been shown to increase and show improvement.^{[44][46][48][53][54]}
Schmidt et al.^[55] reported the treatment of 8 patients, diagnosed with acute hepatic failure, that were treated with MARS for 6 hours, and were compared with a control group of 5 patients to whom ice pads were applied to match the heat loss produced in the treatment group during the extracorporeal therapy. They analyzed hemodynamic parameters in both groups hourly. In the MARS group, a statistically significant increase of 46% on systemic vascular resistance was observed (1215 ± 437 to 1778 ± 710 dinas x s x cm⁻⁵ x m⁻²) compared with a 6% increase in the controls. Mean arterial pressure also increased (69 ± 5 to 83 ± 11 mmHg, p< 0.0001) in the MARS group, whereas no difference was observed in the controls. Cardiac output and heart rate also decreased in the MARS group as a consequence of an improvement in the hyperdynamic circulation. Therefore, it was shown that a statistically significant improvement was obtained with MARS when compared with the SMT.

Catalina et al.^[56] have also evaluated systemic and hepatic hemodynamic changes produced by MARS therapy. In 4 patients with acute decompensation of chronic liver disease, they observed after MARS therapy, an attenuation of hyperdynamic circulation and a reduction in the portal pressure gradient was measured. Results are summarized in table 4.

Table 4: Hemodinamic parameters during MARS treatment

PARAMETER	BASE LINE	AFTER 1st TREAT.	AFTER 2nd TREAT.
MAP(mmHg)	77.8 ± 11.7	82.7 ± 11.7	84.2 ± 8
WHVP(mmHg)	40.7 ± 5.6	34 ± 9.6	37.3 ± 5.5
FHVP(mmHg)	17.7 ± 7.4	16.7 ± 7.5	17 ± 3.6
HVPG(mmHg)	23 ± 7.0	17.3 ± 9.9	20.3 ± 5.5
PAP(mmHg)	23.7 ± 7.3	22 ± 4.8	15.7 ± 4.1
PCP(mmHg)	17.2 ± 8.3	14.5 ± 2.9	9.7 ± 7.0
rPAP (mmHg)	11.2 ± 4.6	10 ± 4.2	7.3 ± 7.6
CO(l/min)	11.2 ± 1.6	10 ± 2.8	9.4 ± 2.1
SVRI (dinas x seg/cm5)	478.5 ± 105	514 ± 104.7	622 ± 198

Abbreviations: MAP= mean arterial pressure; WHVP= wedged hepatic venous pressure;FHVP= free hepatic venous pressure; HVPG= hepatic venous pressure gradient; PAP= pulmonary arterial pressure; PCP= pulmonar capillary pressure; rPAP= right pulmonary arterial pressure; CO= cardiac output; SVRI= systemic vascular resistance index.

There are other studies also worth mentioning with similar results: Heemann et al.^[40] and Parés et al.^[57] among others. Dethloff T et al.^[58] concluded that there is a statistically significant improvement favourable to MARS in comparison with Prometheus system (Table 5).

Table 5. Changes in hemodynamic parameters with MARS therapy

MARS System	MAP	SVRI	CO	BR
Mitzner et al.[59] (2000)	↑NS	-	-	-
Heemann et al.[40] (2002)	↑S	-	-	-
Schmidt et al.[55] (2003)	↑S	↑S	↓S	↓S
Laleman et al.[54] (2006)	↑S	↑S	↔	↔
Dethloff et al.[58] (2008)	↑NS	↔	↔	↔

Abbreviations: MAP: Mean arterial pressure; SVRI: Systemic vascular resistance index; CO: Cardiac output; BR: Beat rate; S: Statistically significant, p< 0.05; NS: not statistically significant. ↑: Increase; ↓:Decrease; ↔: No changes.

Effects of MARS Treatment on Renal Function

Hepatorenal syndrome is one of the more serious complications in patients with an acute decompensation of cirrhosis and increased portal hypertension. It is characterized by hemodynamic changes in splanchnic, systemic and renal circulation. Splanchnic vasodilatation triggers the production of endogenous vasoactive substances that produce renal vasoconstriction and low glomerular filtration rate, leading to oliguria with a concomitant reduction in creatinine clearance. Renal insufficiency is always progressive with a very poor prognosis,^[59][60] with survival at 1 and 2 months of 20 and 10% respectively.

Pierre Versin^[61] is one of the pioneers in the study of hepatorenal syndrome in patients with liver impairment. Great efforts have been made trying to improve the prognosis of this type of patient; however, few have solved the problem. Orthotopic liver transplantation is the only treatment that has shown to improve acute and chronic complications derived from severe liver insufficiency. Today it is possible to combine albumin dialysis with continuous veno-venous hemodialfiltration, which provides a greater expectation for these patients^[62] by optimization of their clinical status.

MARS treatment lowers serum urea and creatinine levels improving their clearance,^{[54][55][56][58]} and even favors resolution of hepatorenal syndrome.^{[40][47][48][53][63]} Results are confirmed in a randomized controlled trial published by Mitzner et al.^[59] in which 13 patients diagnosed with hepatorenal syndrome type I were treated with MARS therapy. Mean survival was 25,2±34,6 days in the MARS group compared to 4,6±1,8 days observed in the controls in whom hemodiafiltration and standard care (SMT) was applied. This resulted in a statistically significance difference in survival at 7 and 30 days (p<0.05). Authors concluded that MARS therapy, applied to liver failure patients (Child-Pugh C and UNOS 2A scores) who develop hepatorenal syndrome type I, prolonged survival compared to patients treated with SMT.

Although mechanisms explaining previous findings are not yet fully understood, it has been reported that there was a decrease in plasma rennin concentrations in patients diagnosed with acute on chronic liver failure with renal impairment that were treated with MARS. Likewise, other studies have suggested some efficacy for MARS in the treatment of hepatorenal syndrome.^[64][65][66]
However, other references have been published that do not show efficacy in the treatment of these types of patients with MARS therapy. Khuroo et al.^[67] published a metaanalysis based in 4 small RCT's and 2 non RCT's in patients diagnosed with ACLF, concluding that MARS therapy would not bring any significant increment on survival compared with SMT. Another observational study in 6 patients with cirrhosis, refractory ascitis and hepatorenal syndrome type I, not responding to vasoconstrictor therapy, showed no impact on hemodynamics following MARS therapy; however authors concluded that MARS therapy could effectively serve as bridge to liver transplantation.^[49][68]

Effects of MARS Treatment on Biochemical Parameters

Total bilirubin was the only parameter analyzed in all trials that was always reduced in the groups of patients treated with MARS; Banayosy et al.^[69] measured bilirubin levels 14 days after since MARS therapy was terminated and observed a consistent, significant decrease not only for bilirubin but also for creatinine and urea (Table 6).

Table 6: Biochemical parameters analysis with MARS therapy

MARS study	Controls (n)	MARS Group (n)	Pathology	MARS Intervention	Bilirubin	Creatinine	Albumin	Urea	ALT	AST	Ammonia	BUN
Mitzner et al. (2000)[59]	8	5	ACLF (OH)	6 h x 3 d	↓S	↓S	↑NS	-	-	-	-	-
Heemann et al. (2002)[40]	12	12	ACLF	6 h x 3 d	↓*	↓S	-	-	-	-	-	-
Sen et al. (2004)[41]	9	9	ACLF+HE (OH)	8 h x 7 d 4 sessions	↓S	↓S	↔	-	-	-	↔	-
Laleman et al. (2006)[54]	6	6	SHR	6-8 h x 10 d	↓S	↔	↔	↔			↔
Hassanein et al. (2007)[42]	31	39	ACLF+HE (III / IV)	6 h x 5 d	↓S	↓S	-	-	-	-	↓S	↓S
Schmidt et al. (2003)[55]	5	8	ALF	6 h	↓S	↓S	↔	↓S	↓S	-	↔
El Banayosy et al. (2004)[69]	13	14	ALF	8 h x 3 d	↓S	↓S	-	-	↔	↔	-	↓S
Dethloff et al. (2008)[58]	8:8 Prometheus	8	ACLF	-	↓S	↓S	-	-	-	-	-	-
Montejo et al. (2009)[70]	26	19	IHA/GD/ACLF	8 h x 3 d	↓S	↓S	↔	↓S	↓S	↓S	-	-

Abbreviations; ALF= acute liver failure; ACLF= acute on chronic liver failure; GD= graft dysfunction; HE= hepatic encephalopathy; AST: aspartate amino transferase; BUN: blood urea nitrogen; NS: not significant; S: statistically significant (p<0,05); ↓decrease; ↑ increase; ↔ no change; ALT: alanine amino transferase; h: hours; d: days Primary goal in the Heemann trial was to achieve a bilirubin level beloiw 15 mg/dl during three consecutive days, which was observed in 42% of the patients treated with MARS® compared to 17% in the control group.

Impact of MARS therapy on plasma biliary acids levels was evaluated in 3 studies. In the study from Stadbauer et al.,^[71] that was specifically addressing the topic, it is reported that MARS and Prometheus systems lower to the same extent biliary acids plasma concentration. Heemann et al.^[40] and Laleman et al.^[54] have also published a significant improvement for these organic ions.

Effects of MARS Treatment on Pruritus

Pruritus is one of the most common clinical manifestations in cholestasis liver diseases and one of the most distressing symptoms in patients with chronic liver disease caused by viral hepatitis C. Many hypothesis have been formulated to explain physio pathogenesis of such manifestation, including incremental plasma concentration of biliary acids, abnormalities in the bile ducts,^[72] increased central neurotransmitters coupling opioid receptors,^[73][74] etc..... Despite the number of historical drugs used, individually or combined (exchange resins, hidrophilic biliary acids, antihistamines, antibiotics, anticonvulsants, opioid antagonists), there are reported cases of intractable or refractory pruritus with a dramatic reduction in patients’ quality of life (i.e. sleep disorders, depression, suicide attempts...).^[75][76] Intractable pruritus can be an indication for liver transplantation.

The MARS indication for intractable pruritus is therapeutically an option that has shown to be beneficial for patients in desperate cases, although at high cost.^{[77][78][79][80]} In several studies, it was confirmed that after MARS treatments, patients remain free from pruritus for a period of time ranging from 6 to 9 months.^[80] Nevertheless, some authors have concluded that besides the good results found in the literature, application of MARS therapy in refractory pruritus requires larger evidence.^[78]

Effects of MARS Treatment on Drugs and Poisons clearance

Pharmacokinetics and pharmacodynamics for a majority of drugs can be significantly be modified with liver failure, affecting the therapeutic approach and potential toxicity of the drugs. In these type of patients, Child-Pugh score represents a poor prognostic factor to assess the metabolic capacity of the failing liver.

• Metabolic performance of the liver depends on several factors:
• Hepatic flow rate
• Cytochrome P-450 enzimatic activity
• Albumin affinity for the drug
• Extrahepatic clearance for the drug

In patients with hepatic failure, drugs that are only metabolized in the liver, accumulate in the plasma right after they are administered, and therefore it is needed to modify drug dosing in both, concentration and time intervals, to lower the risk of toxicity. It is also necessary to adjust the dosing for those drugs that are exclusively metabolized by the liver, and have low affinity for proteins and high distribution volume, such as fluoroquinolones (Levofloxacin and Ciprofloxacin).^{[81][82][83][84]}

Extracorporeal detoxification with albumin dialysis increases the clearance of drugs that are bound to plasmatic proteins (Table 7).

Table 7: Drugs Highly Bound to Proteins

NSAIDs	Antibiotics	Anti-H2	Statins	Antipsychotics
Diclofenac	Cephazoline	Omeprazole	Clofibrate	Chlorpromazine
Ibuprofen	Cefoperazone	Antifungals	Lovastatin	Haloperidol
Indomethacine	Ceftriaxone	Amphotericine B	Simvastatine	Chemotherapy Drugs
Ketoprofen	Cloxacilin	Itraconazole	Fluvastatine	Chlorambucil
Naproxen	Oxacilin	Ketoconazole	Hypotensors	Etoposide
Phenylbutazone	Clindamycin	Barbiturates	Hydralacine	Melphalan
Piroxicam	Erythromycin	Thiopental	Irbesartan	D-penicillamine
Anaesthetics	Teicoplanin	Benzodiazepines	Losartan	Tamoxifen
Bupivacaine	Rifampicin	Clonazepam	Misoprostol	Opioids
Calcium Anthagonists	Rifabutin	Diazepam	Prazosin	Fentanyl
Nimodipine	Antidepresants	Flunitrazepam	Valsartan	Methadone
Nifedipine	Amitriptyline	Flurazepam	ACE's	Antipsychotics
Nitrendipine	Desipramine	Lorazepam	Fosinopropil	Clozapine
Antiarrhythmics	Imipramine	Midazolam	Quinapril	Fluoxetine
Amiodarone	Nortriptyline	Nitrazepam	Immunosuppressors	Risperidone
Quinidine	Anticoagulants	Oxacepam	Ciclosporin	Sertraline
Propafenone	Warfarin	Temazepam	Tacrolimus	Zolpidem
Lidocaine	Antiemetics	Beta Blockers	Methylprednisolone	Others
Digoxin	Ondansetron	Carvedilol	Prednisone	Celecoxib
Verapamil	Antiepilectics	Propanolol	Budesonide	Diphenhydramine
Oral Antidiabetics	Carbamazepine	Diuretics	-	Ethinylestradiol
Glibenclamide	Valproic acid	Furosemide	-	Mefloquine
-	-	Spironolactone	-	Paclitaxel
-	-	Torsemide	-	-

Effects of MARS on Survival

In the meta-analysis published by Khuroo et al.^[67] which included 4 randomized trials^{[40][55][59][69]} an improvement in survival for the patients with liver failure treated with MARS, compared with SMT, was not observed.

However, neither in the extracorporeal liver support systems review by the Cochrane^[85] (published in 2004), nor the meta-analysis by Kjaergard et al.^[86] was a significance difference in survival found for patients diagnosed with ALF treated with extracorporeal liver support systems. Nevertheless, these reviews included all kind of liver support systems and used a heterogeneous type of publication ( abstracts, clinical trials, cohort, etc.).

There is literature showing favorable results in survival for patients diagnosed with ALF, and treated with MARS., In a randomized controlled trial, Salibà et al.^[87] studied the impact on survival of MARS therapy for patients with ALF, waiting on the liver transplant list. Forty-nine patients received SMT and 53 were treated with MARS. They observed that patients that received 3 or more MARS sessions showed a statistically significance increase in transplant-free survival compared with the others patients of the study. Notably, 75% of the patients underwent liver transplantation in the first 24 hours after inclusion in the waiting list, and besides the short exposure to MARS therapy, some patients showed a better survival trend compared to controls, when they were treated with MARS prior to the transplant.

In a case-controlled study by Montejo et al.^[70] it was reported that MARS treatment do not decrease mortality directly; however, the treatment contributed to significantly improve survival in patients that were transplanted. In studies by Mitzner et al.^[59] and Heemann et al.^[40] they were able to show a significance statistical difference in 30-day survival for patients in the MARS group. However, El Banayosy et al.^[69] and Hassanein et al.^[42] noticed a non significant improvement in survival, probably because of the short number of patients included in the trials. In the majority of available MARS studies published with patients diagnosed with ALF, either transplanted or not, survival was greater in the MARS group with some variations according to the type of trial, ranging from 20-30%,^[88][89] and 60-80%.^{[49][90][91][92]} Data is summarized in Tables 8, 9 and 10.

Table 8: Studies of MARS Therapy

MARS Study	Pathology	Nº Patients	Type of Study	Level of Evidence	Study Groups		Analysed Variables
					MARS	Controls
Mitzner et al..[59] (2000)	ACLF	13	RCT (LN)	III	18	5 HD	1, 3, 4
Heemann et al..[40] (2002)	ACLF	24	RCT (LN)	III	12	12 SMT	1, 2, 3, 4, 5
Sen et al..[41] (2004)	ACLF	18	RCT (LN)	III	9	9 SMT	1, 3, 4, 5
Hassanein et al..[42] (2007)	ACLF	70	RCT (HN)	II	39	31 SMT	1, 2, 3, 5
Schmidt et al..[55] (2003)	ALF	13	RCT (LN)	III	8	5 SMT	1, 3, 4
El Banayosy et al.[69] (2004)	ALF	27	RCT (LN)	III	14	13 HD	1, 3
Montejo et al.[70] (2009)	ACLF / ALF	45	Case-control	-	19	26 SMT	1, 2, 3, 4, 5
MARS-Prometheus Studies
Evenepoel et al.[93] (2006)	ACLF	18	Case serie	VIII	Comparative series		1, 2, 3
Faenza et al.[94] (2008)	ACLF	57	Case serie	VIII	Comparative series		1, 2, 5
Krisper et al.[95] (2005)	ACLF	10	RCT (LN)	III	Crossover		1, 2, 3
Laleman et al.[54] (2006)	ACLF	18	RCT (LN)	III	6	6	2, 3, 4
Stadlbauer et al.[96] (2006)	ACLF	8	RCT (LN)	III	Crossover		1, 2, 3
Dethloff et al.[58] (2008)	ESLD	24	RCT (LN)	III	8	8	1, 2, 3, 4

Abbreviations; ACLF: Acute on chronic liver failure; ALF: Acute liver failure; ESLD: End-stage liver disease; RCT: Randomized controlled trial; RCT(LN): RCT, low number of patients; RCT (HN): RCT, high number of patients; HD: Hemodialysis; SMT: Standard medical treatment; 1: Survival/mortality; 2: Security; 3: Biochemical parameters; 4: hemodynamic parameters; 5: Clinical parameters.

Table 9: Survival with MARS Therapy

Study	Pathology	Controlled Study	Follow-up	Survival (%)
Faenza et al.[94] (2008)	ACLF	No	Bridging to LTx	7/10 (70)
			3 months	2/6 (33)
Krisper et al.[95](2005)	ACLF	Yes (crossover)	30 days	4/9 (44)
Stadlbauer et al.[96] (2006)	ACLF	Yes (crossover)	30 days	4/8 (50)
Laleman et al.[54]'(2006)	ACLF	Yes	7 days	6/6 (100)
Dethloff et al..'[58]'(2008)	ESLD	Yes	6 months	5/8 (63)

Abbreviations; ALF: Acute liver failure; ACLF: Acute on chronic liver failure; ESLD: End-stage liver disease; Not statistically significance.

Table 10: Mortality in Selected Studies

Study	N	Mortality MARS (%)	Mortality Controls	Time	Odds Ratio (OR)
Acute on Chronic Liver Failure
Mitzner et al. [59]	13	63	100	7 days	0.63
Heemann et al. [40]	24	50	67	6 months	0.75
Sen et al..[41]	18	56	56	3 months	1
Hassanein et al. [42]	70	49	55	NR	0.89
Dethloff et al. [58]	24	25	50	6 months	0.50
Acute Liver Failure
Schmidt et al. [55]	13	38	40	NR	0.94
El Banayosy et al.[69]	27	50	69	NR	0.72

Abbreviations; NR: Not reported.

For patients diagnosed with acute on chronic liver failure and treated with MARS therapy, clinical trial results showed a not statistically significant reduction in mortality (odds ratio [OR] =0,78; confident interval [CI] =95%: 0,58 – 1,03; p= 0,1059, Figure 3)

A non-statistically significant reduction of mortality was shown in patients with ALF treated with MARS (OR = 0,75 [CI= 95%, 0,42 – 1,35]; p= 0,3427). (Figure 4)

Combined results yielded a non-significant reduction on mortality in patients treated with MARS therapy. However, the low number of patients included in each of the studies may be responsible for not being able to achieve enough statistical power to show differences between both treatment groups. Moreover, heterogeneity for the number of MARS sessions and severity of liver disease of the patients included, make it very difficult for the evaluation of MARS impact on survival.

Recently, a meta-analysis on survival in patients treated with an extra-hepatic therapy has been published.^[97] Searching strategies yielded 74 clinical trials: 17 randomized controlled trials, 5 case control and 52 cohort studies. Eight studies were included in the meta-analysis: three addressing acute liver failure, one with MARS therapy^[69] and five addressing acute on chronic, being four MARS related.^{[40][41][42][59]} Authors concluded that extra-hepatic detoxifying systems improve survival for acute liver insufficiency, whereas results for acute decompensation of chronic liver diseases suggested a non significant survival benefit. Also, due to an increased demand for liver transplantation together with an augmented risk of liver failure following large resections, development of detoxifying extrahepatic systems are necessary.

Safety Aspects

Safety, defined as presence of adverse events, is evaluated in few trials. Adverse events in patients receiving MARS therapy are similar to those in the controls with the exception of thrombocytopenia and hemorrhage that seems to occur more frequently with the MARS system.^[98]

Heemann et al.^[40] reported two adverse events most probably MARS related: fever and sepsis, presumably originated at the catheter.

In the study by Hassanein et al.,^[42] two patients in the MARS group abandoned the study owing to hemodynamic instability, three patients required larger than average platelets transfusion and three more patients presented gastrointestinal bleeding.

Laleman et al.^[54] detected one patient with thrombocytopenia in both the MARS and Prometheus treatment groups, and an additional patient with clotting of the dialysis circuit and hypotension, only in the Prometheus group.

Kramer et al. (Biologic-DT)^[43] wrote about 3 cases with disseminated intravascular coagulation in the interventional group, two of them with fatal outcomes.

Mitzner et al.^[59] described, among patients treated with MARS, a thrombocytopenia case and a second patient with chronic hepatitis B, who underwent TIPS placement on day 44 after randomization and died on day 105 of multiorgan failure, as a consequence of complications related to the TIPS procedure.

Montejo et al.^[70] showed that MARS is an easy technique, without serious adverse events related to the procedure, and also easy to implement in ICU settings that are used to renal extracorporeal therapies.

The MARS International Registry, with data from more than 500 patients (although sponsored by the manufacturer), shows that the adverse effects observed are similar to the control group. However, in these severely ill patients it is difficult to distinguish between complications of the disease itself and side effects attributable to the technique.

Health Economics

Only three Studies addressing cost-effectivenenss of MARS therapy have been found. Hassanein et al.^[99] analysed costs of randomized patients with ACLF receiving MARS therapy or standard medical care. They used the study published in 2001 by Kim et al.^[100] describing the impact of complications in hospitalization costs in patients diagnosed with alcoholic liver failure. Cost of 11 patients treated with standard medical care (SMT) were compared to those that received MARS, in addition to SMT (12 patients). In the MARS group, there was less in-hospital mortality and complications related to the disease, with a remarkable reduction in cost which compensated the MARS related expenditure (Table 11).

Table 11. Analysis of Complications According to the Modality of treatment.

	MARS GROUP n=12	CONTROL GROUP n=11
In-hospital mortality	1/12	6/11
Worsening of hepatic encephalopathy (grade 4)	0/12	3/11
Worsening of renal function (Hepatorenal Syndrome)	1/12	7/11
Ascites	0/12	1/11
Variceal bleeding	0/12	1/11
Severe hypotension	2/12	3/11
Electrolyte disorders	4/12	10/11
Coagulopathy	4/12	3/11

There were 5 survivors in the control group, with a cost per patient of $35.904, whereas in the MARS group, 11 patients out of 12 survived with a cost per patient of $32.036 which represents a $4000 savings per patient in favors of the MARS group. Hessel et al.^[101] published a 3-year follow-up of a cohort of 79 patients with ACLF, of whom 33 received MARS treatments and 46 received SMT. Survival was 67% for the MARS group and 63% for the controls, that was reduced to 58 and 35% respectively at one year follow-up, and then 52 and 17% at three years.

Hospitalization costs for the MARS treated group were greater than that for the controls (€31.539 vs. €7.543) and similarly direct cost at 3-year follow-up (€8.493 vs. €5.194). Nevertheless, after adjusting mortality rate, the annual cost per patient was €12.092 for controls and €5.827 for MARS group; also in the latter, they found an incremental cost-effectiveness ratio of 31.448 € per life-year gained (LYG) and an incremental costs per QALY gained of 47171 €.

Two years later, same authors published the results of 149 patients diagnosed with ACLF.^[102] There were 67 patients (44,9%) treated with MARS and 82 patients (55,1%) were allocated to receive SMT. Mean survival time was 692 days in the MARS group (33% at 3 years) and 453 days in the controls (15% at 3 years); the results were significant (p=0,022). Differences in average cost was €19.853 (95% IC: 13.308-25.429): 35.639 € for MARS patients and 15.804 € for the control group. Incremental cost per LYG was 29.985 € (95% IC: 9.441-321.761) and €43.040 (95% IC: 13.551-461.856) per quality-adjusted life years (QALY).

Liver support systems, such as MARS, are very important to stabilize patients with acute or acute on chronic liver failure and avoid organ dysfunction, as well as a bridge-to-transplant. Although initial in-hospital costs are high, they are worth for the favorable outcome.

MARS Therapy Indications

Acute on Chronic Liver Failure

Etiology:

• Chronic viral hepatitis^[103]
• Alcoholic liver disease^[104][105]
• Autoimmune disease^[106]
• Metabolic disease such as hemochromatosis
• Idiopathic Cirrhosis

Goals of MARS Therapy

• Re-compensation of previous chronic state.
• Prolong survival time and bridge to urgent or elective transplant
• Pre-transplant optimization of the patient

MARS Therapy Indication

• Bilirubin > 15 mg/dl (255 μmol/l), not responding to standard medical care alter 3 days
• Renal dysfunction or hepatorenal syndrome.
• Hepatic encephalopathy ≥ II

Treatment Schedule:

• 3 to 5 eight-hour treatment sessions in consecutives days
• Continuous treatment with hemodynamic inestability (in any case, treatment kit must be replaced every 24 hours)

Acute Liver failure

Etiology:

• Viral infection^{[31][55][107]}
• Poisoning (paracetamol overdose, mushrooms)^{[90][108][109][110][111]}
• Multiorgan dysfunction (severe sepsis)
• Vascular diseases (Budd Chiari syndrome)
• Hypoxic hepatitis^[112]
• Liver failure during pregnancy or Reye syndrome
• Unknown etiology

Goals of MARS Therapy

• Native liver recovery.
• Bridging to liver transplant
• Pre-transplant optimization of the patient.

MARS Therapy Indication

• King's College or Clichy criteria for liver transplantation
• Hepatic encephalopathy ≥ II
• Increased intracraneal pressure
• Acute hypoxic hepatitis with bilirubin > 8 mg/dl (100 μmol/l)
• Renal dysfunction or hepatorenal syndrome
• Progressive intrahepatic cholestasis
• Fulminant Wilson disease
• Acute liver dysfunction following paracetamol overdose

Treatment Schedule:

• 3 to 5 eight-hour treatment sessions in consecutives days
• Hypoxic hepatitis. 3 eight-hour treatment sessions in consecutives days
• Paracetamol overdose: 3 to 5 twenty four-hour treatment sessions
• Mushroom poisoning: 3 to 5 twenty four-hour treatment sessions
• Fulminant Wilson: minimum 5 twenty four-hour treatment sessions owing to copper saturation of the treatment kit
• Drug overdose: 3 to 5 eight-hour treatment sessions in consecutives days

MARS in Graft Dysfucntion After Liver Transplant^[113][114]

Etiology:

• Graft damage during preparation and transportation
• Infection
• Hepatotoxic drugs
• Graft rejection
• Technical complications (vascular, biliary)
• Recurrence of primary disease

Goals of MARS Therapy

• Recovery and prevention of re-transplantation
• • Prolong survival time and stabilize the patient to receive a re-transplant if the above goal is not achieved

MARS Therapy Indication

• Primary graft dysfunction
• Hepatic encephalopathy ≥ II
• Increased intracranial pressure
• Renal dysfunction or hepatorenal syndrome.
• Progressive intrahepatic cholestasis

Treatment Schedule:

• 3 to 5 eight-hour treatment sessions in consecutives days
• Continuous treatment with hemodynamic inestability (in any case, treatment kit must be replaced every 24 hours)

MARS in liver Failure after Liver Surgery

^[115]

Etiology:

• Liver Resection in hepatocellular carcinoma
• Transarterial Chemoembolization (TACE)
• Partial resection in living donor transplantation
• Other surgical intervenctions

Goals of MARS Therapy

• Recovery until hepatic regeneration

MARS Therapy Indication

• Hepatic encephalopathy ≥ II
• Renal dysfunction or hepatorenal syndrome.
• Progressive intrahepatic cholestasis

Treatment Schedule:

• 3 to 5 eight-hour treatment sessions in consecutives days
• Continuous treatment with hemodynamic inestability (in any case, treatment kit must be replaced every 24 hours)

MARS for intractable pruritus in Cholestasis^{[63][63][103][106][116]}

Etiology:

• Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)
• Benign intrahepatic cholestasis (BIC)
• Biliary Atresia

Goals of MARS Therapy

• Attenuate pruritus symptoms and improve patients’ quality of life

MARS Therapy Indication

• Pruritus not responding to SMT

Treatment Schedule:

• 3 to 5 eight-hour treatment sessions in consecutives days
• Repeat treatment when symptoms reoccur

MARS Therapy Contraindications

Same contraindications as with any other extracorporeal treatment may be applied to MARS therapy.

• Unstable hemodynamics with mean arterial pressure (MAP)< 55 mmHg despite vasoconstrictors administration
• Uncontrolled hemorrhage
• Severe coagulopathy
• Severe thrombocytopenia

Treatment Parameters

Blood Flow

The trend is to use high flow rates, although it is determined by the technical specifications of the combined machine and catheters’ size

Intermittent treatments:

• Without renal dysfunction, it is recommended a blood and albumin flow rates ranging from 150 to 250 ml/min

Continuous treatments:

• With or without renal impairment it is recommended to use flow rates from 100 to 150 ml/min.

Dyalisate Flow Rate

Intermittent treatments:

• Without renal impairment: 1800 a 3000 ml/hour
• With renal impairment: 3000 a 6000 ml/hour

Continuous treatments:

• Recommended flow rate: 1000 to 2000 ml/hour.

Replacement Flow Rate

• According to medical criteria and same as in CVVHD

Heparin Anticoagulation

Similarly to CVVHD, it depends of previous patient's coagulation status. In many cases it will not be needed, unless the patient presents a PTT inferior to 160 seconds. In patients with normal values, a bolus of 5000 to 10000 IU of heparin could be administered at the commencement of the treatment, followed by a continuous perfusion, to keep PTT in ratios from 1,5 to 2,5 or 160 to 180 seconds.

Monitoring

A biochemical analysis is recommended (liver and kidney profile, ionic, glucose) together with a hemogram at the end of first session and before starting the following one.

Coagulation analysis must be also performed before starting the session to adjusting heparin dose.

In case that medication susceptible to be eliminated by MARS is being administered, it is also recommended to monitor their levels in blood

End of the Session

• Once the treatment is finalized, blood should be returned following the unit procedure,

and both catheter's lumens heparinized

• For the next session a new kit must be used
• For continuous treatments, kit must be changed by a new one every 24 hours
• Treatment must be stopped before schedule owing to the particular circumstances listed below:

1. MAP inferior to 40 mmHg at least for 10 minutes
2. Air embolism of the extracorporeal circuit
3. Transmembrane pressure (TMP) greater than 600 mmHg.
4. Blood leak detection in the albumin circuit
5. Disseminated intravascular coagulation (DIC)
6. Severe active hemorrhage

FDA Clearance (US only)

Federal Drug Administration (FDA) cleared, in a document dated on May 27, 2005, MARS therapy for the treatment of drug overdose and poisoning. The only requirement is that the drug or poison must be susceptible to be dialysed and removed by activated charcoal or anionic exchange resins.

More recently, on December 17, 2012, MARS therapy has been cleared by the FDA for the treatment of hepatic encephalopathy due to a decompensation of a chronic liver disease Clinical trials conducted with MARS treatment in HE patients having a decompensation of chronic liver disease demonstrated a transient effect from MARS treatments to significantly decrease their hepatic encephalopathy scores by at least 2 grades compared to standard medical therapy (SMT).

The MARS is not indicated as a bridge to liver transplant. Safety and efficacy has not been demonstrated in controlled, randomized clinical trials.

The effectiveness of the MARS device in patients that are sedated could not be established in clinical studies and therefore cannot be predicted in sedated patients

References

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