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The use of the molecular adsorbent recirculating system (MARS)[TM] Albumin dialysis for the treatment of liver failure: a nursing perpective.

The liver is the largest internal organ and performs more than 500 different functions that are meant to maintain metabolic homeostasis. When function is disrupted, so is homeostasis and multi-organ failure may occur. The pathophysiology of the multi-organ failure that occurs is complex (Sen, Jalan, & Williams, 2003) and it is still unclear what functions during failure must be replaced or supplied until spontaneous regeneration or a transplant occurs (Gaspari et al., 2006).

There are many causes of liver disease including viral hepatitis, toxic ingestions, infections, cancer, Budd-Chiari Syndrome, hemochromatosis, and Wilson's disease. Liver disease affects more than three million Canadians (Canadian Liver Foundation, 2008). This article includes an overview of liver failure and a description of the role of albumin dialysis in liver failure, the potential adverse effects of this therapy, and the impact of liver dialysis on the nursing care of this patient population.

Liver failure

Liver failure occurs when there is loss of 80% to 90% of function, and is classified as acute liver failure (ALF), chronic liver failure, or acute-on-chronic liver failure (AoCLF) (Whiteman & McCormick, 2005). Acute and AoCLF are potentially reversible because the liver has the ability to regenerate (Starr & Hand, 2002).

ALF is a syndrome of rapid onset (days) among individuals with no preexisting liver disease (Sen et al., 2003) and is usually due to infections, toxic ingestion (e.g., drug overdose such as acetominophen, or poisoning with hallucinogenic mushrooms such as amanita), or acute fatty liver during pregnancy. With chronic liver disease, the liver cells are destroyed over long periods of time (years) due to a variety of etiologies, viral infections being the most common. Over time, the liver develops fibrosis (cirrhosis) and there is formation of nodules inside the liver, which alter its structure (Starr & Hand, 2002). Once this occurs, this is considered the late stages of chronic liver disease and, if the individual presents with signs and symptoms of liver failure, it is likely that the liver is incapable of regeneration and, therefore, transplantation is the only option.

AoCLF occurs in patients with chronic liver disease who decompensate following an acute process such as an infection or gastrointestinal bleed. With supportive therapy, these patients may return to their previous status and not require a liver transplant (Whiteman & McCormick, 2005).

The "toxin hypothesis" (Sen et al., 2003) describes the effects of liver failure on other organs. It states that toxins such as nitric oxide, aromatic amino acids, ammonia and proinflammatory cytokines are responsible for the multi-organ dysfunction that accompanies liver failure. When liver cell death occurs, there is loss of the synthetic and excretory functions of the liver (Lai, Haydon, Mutimer, & Murphy, 2005). Table One includes some of the functions of the liver and consequences of failure.

Standard medical treatments for liver failure such as oral lactulose, pericentesis, and albumin infusions have focused on treating symptoms and providing support. Standard treatments are not as effective as once thought. Volk and Marrero (2006) state that there is very little evidence for the use of lactulose and low-protein diets weaken the patient and adversely affect prognosis. As well, there is a debate among specialists regarding treatment of hepatic encephalopathy; more aggressive treatments such as ICP monitoring, hypertonic saline, sedation and hypothermia are being done but, so far, there is little evidence to support their use (Wright & Jalan, 2007). The use of standard therapies has improved survival, but survival rates for ALF have plateaued in recent years (Riordan & Williams, 2008). Standard therapies address symptoms, but lack the ability to remove the protein-bound toxins that are the source of the multi-organ failure. Support continues until the acute incident has resolved and adequate hepatic function recurs, or until a donor liver becomes available for those patients whose liver functions do not recover adequately. However, there is a shortage of organs. Many patients die waiting for a transplant. In Ontario, there are 317 people waiting for a liver transplant (Trillium Gift of Life Network, 2008). The shortage of organs and the inability of standard therapies to remove protein-bound toxins make albumin dialysis an attractive proposition. The use of albumin dialysis is a potential treatment to augment standard medical treatments and may perform one or both of the following functions:

1. support the patient as a bridge to transplantation, or

2. support the patient until adequate liver function has resumed following the acute injury.

Role of albumin dialysis: Indications and mechanism of action

Albumin dialysis is used to cleanse the blood of albumin-bound toxins when the liver is not functioning. It is a relatively new treatment modality. It has three main mechanisms of action, which are described below. There are two forms of extracorporeal liver assist devices: bioartificial systems that use primary hepatocytes (e.g., porcine), and artificial systems, which are purely mechanical systems and include albumin dialysis systems (McKenzie, Lillegard, & Nyberg, 2008). Bioartificial systems are expensive and complex and are not available in Canada.

There are two main albumin dialysis systems available for clinical use: the Prometheus[TM] (Fresenius Medical Care) and the Molecular Adsorbent Recirculating System (MARS)[TM] (Gambro, Lund Sweden). Prometheus has not been used in Canada and our experience has been limited to MARS. Therefore, the author will focus on the MARS. MARS was introduced clinically in 1993 (Stange, Ramlow, Mitzner, Schmidt, & Klinkmann, 1993) in Europe and was initially introduced to Canada in 2006. Since 2006, a total of seven patients (nine treatments in total) have received MARS therapy at the London Health Sciences Centre (LHSC). Patients may receive MARS therapy after standard therapy has not produced optimal results.

The MARS is an albumin-based therapy whereby albumin dialysis is the process of cleansing the blood of protein-bound toxins by exposing the blood to an albumin dialysate and, thus, extracting the toxins from blood protein carriers. Albumin is the most abundant human protein in the blood and is the most important carrier molecule, transporting fatty acids, nitric oxide, bilirubin, hormones, vitamin D and metals. As well, albumin is an important carrier of serum toxins that accumulate in liver failure and, ultimately, are responsible for multi-organ dysfunction. These toxins, along with oxidative stress lead to liver and end organ (brain, kidney, etc.) dysfunction (Helm, 2003).

Indications

More than 20,000 MARS treatments have been performed in more than 5,000 patients worldwide (Mitzner, 2007). In 2007, Karvellas and Wendon wrote that there are a limited number of studies of MARS and most are retrospective, uncontrolled, and with a limited number of treatment sessions. This statement is supported by a Cochrane Review (Liu, Gluud, Als-Nielsen, & Gluud, 2008), which identified 55 studies for possible inclusion in the review, but was only able to evaluate four randomized control trials involving MARS/albumin dialysis that met their inclusion criteria. The data regarding MARS use in ALF are sparse (Fealy, Baldwin, & Boyle, 2005), and limited data about the use of MARS following post-donation graft failure or liver resection exist. Most studies have been in the AoCLF group with alcoholic liver disease being the most prevalent patient population studied (Sen et al., 2003). Mitzner (2007) suggests that ALF and AoCLF patient populations have different mechanisms for liver failure and, therefore, have different indications for liver support therapy. With so few studies, it is difficult to develop any evidence-based criteria for clinical practice, particularly guidelines on when to initiate therapy and duration of therapy (Karvellas & Wendon, 2007). The authors of a 2008 Cochrane Review (Liu et al., 2008) evaluated 14 randomized control trials involving MARS/albumin dialysis and the following conclusions were identified:

a) artificial systems may reduce mortality in acute-on-chronic liver failure, but not in acute liver failure,

b) based on the strength of evidence, more trials are needed before any system can be recommended for routine use. Based on the limited trials, the therapy looks promising,

c) adverse effects could not be determined, and

d) there was a positive effect on hepatic encephalopathy, but none demonstrated as a bridge to transplant.

The most common use of MARS occurs in AoCLF patients when the patient decompensates either due to alcohol use, bleeding, or an infection. When the patient decompensates to the point where standard medical treatment is no longer sufficient and a liver transplant is urgently needed, MARS can be considered for use to support the patient until an organ becomes available. One potential benefit of MARS therapy is an improvement in level of consciousness during hepatic encephalopathy (often severe enough to necessitate intubation for airway protection). Hemodynamic improvements such as increased systemic vascular resistance and increased mean arterial pressure may occur, but whether these result in improvement in patient outcome is a matter of controversy (Faenza et al., 2008).

MARS treatments can be provided as a single treatment or a course of several treatments. Mitzner (2007) suggests that in ALF, support should start as soon as the diagnosis is made, as need for treatment is greater. Also, continuous treatments with few breaks are better in terms of improving clearance of toxins. However, with AoCLF, time to treatment is difficult to determine and it may be comparably effective to have intermittent treatments lasting only six to eight hours instead of continuous therapy.

Mechanism of action

There are three theories that describe the MARS mechanism of action:

1. Using albumin, MARS can cleanse the blood of albumin-bound toxins and the liver can recover, or the patient can stabilize long enough to receive a transplant.

2. The MARS stops the intrahepatic inflammatory process that leads to hepatocyte death; this may lead to improved liver function and patient stabilization.

3. Klammt et al. (2008) hypothesize that the MARS not only cleanses the blood of toxins, but also improves the albumin binding capacity, which allows the albumin to carry more toxins to be removed.

Description of MARS

The MARS can be set up with either a hemodialysis machine or with the Prisma[TM] (Gambro, Lund, Sweden). At LHSC, the MARS is set up alongside a Prisma machine. There may be only one treatment, which can last up to 32 hours, or several treatments lasting for shorter lengths (e.g., eight hours of treatment daily x five days).

There are two separate circuits involved with MARS therapy: a blood circuit and an albumin circuit (Figure One).

The blood leaves the patient via a venovenous dialysis line and flows though the MARSFLUX filter[TM] (polysulfone with a pore size of 50kDa) countercurrent to a 25% albumin supply. (NOTE: The albumin may be of a different concentration in other countries.) The pore size of 50kDa allows toxins to pass through, but larger molecules such as growth factor and albumin cannot. Albumin-bound toxins move between the plasma, albumin molecules bound to the albumin dialysate side of the MARSFLUX and the circulating albumin solution (Fealy et al., 2005). Once the albumin passes the blood, it is loaded with toxins and needs to be cleansed in the albumin circuit. The blood is anticoagulated, if necessary, with heparin or citrate using standard CRRT protocols. The blood pump runs at a maximum of 180 mls/min, as that is the maximum blood pump speed on the Prisma. Other centres using hemodialysis machines with the MARS may be able to run the blood faster. With faster blood speeds, more clearance can be obtained.

In the albumin circuit, the albumin first passes through a dialysis filter where it runs counter-current to a common dialysate such as Hemosol BO[TM] (Gambro, Dasco, Italy); water, if desired, and water-bound toxins are removed and a replacement solution is added. Next, the albumin passes through a charcoal filter, which removes low molecular weight non-ionic toxins such as fatty acids. Lastly, it passes though an anion exchange resin where ion resins like bilirubin are removed. The albumin is now cleansed of toxins (regenerated) and ready for recirculation in the MARSFLUX filter. The albumin circuit runs at the same speed as the blood circuit (max. of 180 mls/min if used in conjunction with Prisma).

Adverse effects

Adverse effects that may be encountered specific to the MARS therapy include:

Bleeding: the blood circuit may need to be anticoagulated depending on the patient's coagulation status. Patients in liver failure already have coagulation dysfunction (Mitzner, 2007), which may be exacerbated by the MARS. MARS should not be attempted in patients whose platelets are less than 50 x 109 L due to an increased risk of bleeding. Patients in ALF are more tolerant of a higher INR than are AoCLF patients (Mitzner) and, thus, are at less risk of an adverse bleeding event. Cautious anticoagulation with heparin or citrate is effective (Mitzner).At LHSC, heparin is used and titrated by nomogram ranging from zero units to 800 units/hr. In their Cochrane Review, Liu et al. (2008) found that bleeding is the most serious adverse effect, with 3 out of 27 patients suffering a serious bleeding episode.

Infection: may occur at the dialysis line site or in the extracorporeal circuit.

Electrolyte imbalances: dialysate and replacement solutions must include electrolytes; standard CRRT electrolyte protocol can be used.

[FIGURE 1 OMITTED]

Hypothermia: the extracorporeal circuit cools the blood. Thus, the blood and the dialysate solution are warmed to avoid hypothermia. Despite these measures, patients may also require active heating measures.

Medication elimination: medication dosages, particularly those medications that are protein bound, must be carefully monitored and modified, as the MARS may remove them from the blood.

Nursing implications

There are nursing implications for the critical care program, as well as the bedside nurse, that need to be carefully considered before implementing a MARS program.

Program implications:

1. Education: The best model of care involves having only a core team of nurses educated on performing the therapy, as there will not be a large number of patients who require it and, therefore, maintenance of competence becomes an issue. Nurses who are already expert at CRRT are certainly more adept at learning and running MARS, as they have an understanding of dialysis principles and troubleshooting extracorporeal lines. As this skill is high-risk yet low-demand, a good basic knowledge of the therapy is crucial for success. A 16-hour education program provides that basic knowledge. At LHSC, there are 20 educated staff members. However, due to the small number of patients who have been treated, only six nurses are currently comfortable with the therapy.

2. Staffing: At LHSC, staffing has been an issue when only one MARS nurse was scheduled on a shift. In such cases, the MARS nurse champion was involved to help with coverage. MARS patients at LHSC are only in the ICU and are always 1:1 patients. Even though the patient is nursed 1:1, it takes two nurses to set up the machine, which impacts staffing.

3. Cost: The therapy itself is very expensive with the circuits alone costing approximately $4,000. Also, educating the nursing staff is a large expense.

Practice considerations:

1. All MARS patients at LHSC are placed on continuous EEG monitoring before treatment begins because non-clinical seizures may occur in liver failure patients and monitoring should be done to detect them.

2. There is frequent blood work such as monitoring PTT, ammonia and, possibly, drug levels, which impacts nursing workload.

3. There must be a nurse champion on the team. At LHSC, this champion is a Critical Care Nursing Educator who works closely with both the nursing and physician teams to modify procedures as necessary.

4. Although it is not considered "life support" like a ventilator, there is often urgency to getting the treatment started in situations where there is cerebral edema causing potential neurological compromise/injury, or after a drug overdose where clearing the toxins can not only save liver and other organ function, but also avoid transplantation if instituted early enough.

5. Setting up the machines can take several hours, even for experienced MARS nurses. Steps in the process, before the machines are even set up include: obtaining orders, albumin, MARS circuits and supplies needed for accessing the dialysate line. The actual setting up of the machine, even with experienced nurses at their quickest will take 1.5 to 2 hours. During the albumin priming process, the nurse cannot leave the machine to attend to other duties, as several bottles of albumin need to be hung with the machine stopped in between. Having two nurses set up the machine is ideal, as mistakes in set-up must be avoided due to the cost of one filter set (several thousand dollars) and the time involved. As these patients are very ill, they have many other treatments needed, so two nurses may be needed (one to continue set-up and one to provide other necessary nursing care).

6. Once the machine is set up, very little is done to maintain it (changing bags, emptying effluent, etc.). There are very few alarms that require a nurse's attention once it is set up.

7. Tests that involve leaving the unit (e.g., CT scan) must be done before treatment is started. Treatment times may range from eight to 24 hours. The treatment, once started, cannot be interrupted and restarted without losing the whole set-up. As well, invasive procedures (such as line insertions) should be done before the treatment is started due to the risk of bleeding with treatment.

8. The nurse champion must be involved with every case to provide assistance with set-up, maintenance and troubleshooting. As the educated staff nurses would rarely set up a MARS, an expert nurse is needed to provide support. At LHSC, the nurse champions are the critical care clinical educators. They received extra education and attended every set-up of the machine to become experts. As well, at the beginning of the program particularly, the nurse champion needs a resource to go to if troubleshooting becomes difficult. The company representatives provided this support. At LHSC, the nurse champions were comfortable after about four treatments.

Conclusion

Albumin dialysis is being used around the world (e.g., Germany, Spain, Italy, Israel and Australia) to support liver failure patients to permit regeneration of liver tissue, or as a bridge to transplantation. Nurses with CRRT experience are well suited to caring for patients on the MARS. More evidence is required to determine the specific role(s) of MARS therapy in the critically ill patient.

References

Bhatia, V., Singh, R., & Acharya, S.K. (2006). Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut, 55, 98-104.

Butterworth, R. (2003). Hepatic encephalopathy. Alcohol Research and Health, 27, 240-246.

Canadian Liver Foundation. (2008). Discover the world of hepatology. Retrieved October 26, 2008, from http://www.liver.ca/DWOH

Faenza, S., Baraldi, O., Bernardi, M., Bolondi, L., Coli, L., Cucchetti, A., et al. (2008). MARS and Prometheus: Our clinical experience in acute chronic liver failure. Transplantation Proceedings, 40, 1169-1171.

Fealy, N., Baldwin, I., & Boyle, M. (2005). The molecular adsorbent recirculating system: A therapy for the treatment of liver failure; Review and case study. Australian Critical Care, 18, 96-102.

Gaspari, R., Avolio, A.W., Zileri Dal Verme, S., Agnes, S., Procetti, R., Castagneto, M., et al. (2006). Molecular adsorbent recirculating system in liver transplantation: Safety and efficacy. Transplantation Proceedings 38, 3544-3551.

Helm, T. (2003). 5th International symposium on albumin dialysis. Insert in: Intensive Care Medicine, 29(11), 1-6.

Karvellas, C., & Wendon, J. (2007). MARS in acute-on-chronic liver failure. Indian Journal of Gastroenterology, 26, 109.

Klammt, S., Mitzner, S., Stange, J., Loock, J., Heeman, U., Emmrich, J., et al (2008). Improvement of impaired albumin binding capacity in acute-on-chronic liver failure by albumin dialysis. Liver transplantation, 14, 1333-1339.

Lai, W.K., Haydon, G., Mutimer, D., & Murphy, N. (2005). The effect of molecular adsorbent recirculating system on pathophysiological parameters in patients with acute liver failure. Intensive Care Medicine, 31, 1544-1549.

Liu, J.P., Gluud, L.L, Als-Nielsen, B., & Gluud, C. (2008). Artificial and bioartificial support systems for liver failure. The Cochrane Database of Systematic Reviews, 3, 1-41.

McKenzie, T., Lillegard, J., & Nyberg, S. (2008). Artificial and bioartifical liver support. Seminars in Liver Disease, 28, 210-217.

Mitzner, S. (2007). Albumin dialysis: An update. Current Opinions in Nephrology and Hypertension, 16, 589-595.

Pugliese, F., Ruberto, S.M., Perrella, A., Cappannoli, K., Bruno, S., Martelli, P., et al. (2007). Modifications of intracranial pressure after molecular adsorbent recirculating system treatment in patients with acute liver failure: Case reports. Transplantation Proceedings, 39, 2042-2044.

Riordan, S., & Williams, R. (2008). Perspectives on liver failure: Past and future. Seminars in Liver Disease, 28, 137-141.

Sen, S., Jalan, R., & Williams, R. (2003). Liver failure: Basis of benefit of therapy with the molecular adsorbents recirculating system. International Journal of Biochemistry and Cell Biology, 35, 1306-1311.

Shakil, A.O., Mazariegos, G.U., & Kramer, D.J. (1999). Fulminant hepatic failure. Surgical Clinics of North America, 79, 77-108.

Starr, S., & Hand, H. (2002). Nursing care of chronic and acute liver failure. Nursing Standard, 16(40), 47-54.

Stange, J., Ramlow, W., Mitzner, S., Schmidt, R., & Klinkmann, H. (1993). Dialysis against a recycled albumin solution enables the removal of albumin-bound toxins. Artificial Organs, 17, 809-813.

Trillium Gift of Life Network. (2008). Waiting list year to date. Retrieved October 26, 2008, from http://www.giftoflife.on.ca/page.cfm?id=58F02D0F- 39DB-4BFE-A653-10EF328C266

Vaquero, J., Chung, C., Cahill, M.E., & Blei, A.T. (2003). Pathogenesis of hepatic encephalopathy in acute liver failure. Seminars in Liver Disease, 23, 259-269.

Volk, M.L., & Marrero, J.A. (2006). Advances in critical care hepatology. Minerva Anestesiologica, 72, 269-281.

Whiteman, K., & McCormick, C. (2005). When your patient is in liver failure. Nursing 2005, 35(4), 58-63.

Williams, R. (2006). The elusive goal of liver support: Quest for the Holy Grail. Clinical Medicine, 6, 482-487.

Wright, G., & Jalan, R. (2007). Management of hepatic encephalopathy in patients with cirrhosis. Best Practice and Research Clinical Gastroenterology, 21(11), 95-110.

By Rachelle McCready, RN, BScN, CNCC(C)

Rachelle McCready, RN, BScN, CNCC(C), Critical Care Clinical Educator, London Health Sciences Centre, University Hospital, London, Ontario. E-mail: Rachelle.McCready@lhsc.on.ca
Table One: Liver functions and consequences of failure

Liver function                      Consequences of failure

Metabolism, synthesis and storage   * malnourishment
of carbohydrates, fats and          * low serum albumin leading to:
proteins (including albumin)        low plasma oncotic pressure,
                                    ascites, and cerebral edema.
                                    Cerebral edema
                                    rarely occurs with chronic
                                    failure, but may occur in 38% to
                                    81% of acute failure patients
                                    (Shakil, Mazariegos & Kramer,
                                    1999)

Detoxification of drugs, toxins     * hepatic encephalopathy
such as aromatic amino acids,
bile acids, bilirubin,
prostacyclins, tryptophan, etc.
(Williams, 2006)

Manufacture of most clotting        * coagulopathy
factors

Production of heat                  * hypothermia
(liver is highly metabolic)

Filters blood to remove toxins      * portal hypertension leading to
and nutrients                       esophageal varices and bleeding
* hepatic artery: 1/4 of blood
supply to the liver; carries
oxygenated blood
* portal vein: 3/a of the blood
to the liver; carries blood rich
in nutrients from the GI tract

Converts ammonia to urea            * build-up of ammonia; ammonia
                                    crosses blood brain barrier
                                    leading to encephalopathy and
                                    cerebral edema. Ammonia levels on
                                    hospital admission are an
                                    independent predictor of outcome
                                    (Bhatia, Singh, & Acharya, 2006)
                                    * increased ICP from cerebral
                                    edema is a leading cause of death
                                    in patients with ALF (Vaquero,
                                    Chung, Cahill, & Blei, 2003).
                                    Ammonia leads to an increase in
                                    intracellular glutamine, which
                                    acts as an intracellular osmolyte
                                    causing astrocyte swelling
                                    (Pugliese et al., 2007)

Removal of bacteria or foreign      * infection-spontaneous bacterial
materials                           peritonitis may develop due to
                                    translocation of intestinal
                                    flora. This complication develops
                                    in 8% to 30% of hospitalized
                                    cirrhotic patients with ascites
                                    (Wright & Jalan, 2007)

Manufacture of bile                 * increased serum bilirubin

Removal of endogenous               * hemodynamic instability
vasoactive substances               (hyperdynamic hyperension)--
                                    occurs due to raised levels of
                                    nitric oxide and prostaglandins
                                    causing vasodilation (Starr &
                                    Hand, 2002). As well, it occurs
                                    due to triggering of the stress
                                    response and compromise of the
                                    adrenal axis (Wright & Jalan,
                                    2007)
                                    * decreased cerebral perfusion
                                    may cause cerebral anoxia, which
                                    increases the potential for
                                    seizures (Vaquero et al., 2003)

Production of substances            * hepatic encephalopathy is the
necessary for normal neurological   most challenging symptom to
functioning (Butterworth, 2003)     manage (Volk & Marrero, 2006)
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