SCCM Pod-455 Introduction to Molecular Adsorbent Recirculating System Albumin Dialysis

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This podcast will describe the principle of albumin dialysis of the molecular adsorbent recirculating system (MARS). Host Pamela M. Peeke, MD, MPH, FACP, FACSM, is joined by Ram M. Subramanian, MD, MBA, FCCM, to discuss the logistics of starting a MARS program to outline indications for MARS. Dr. Subramanian is a hepatologist at Emory University in Atlanta, Georgia. This podcast is sponsored by Baxter.

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Transcript:

This podcast is sponsored by Baxter Healthcare Corporation. When you choose Baxter for your CRRT program, you’re not only choosing true patient-focused treatment with industry-leading CRRT technology, you’re also selecting a partner dedicated to optimizing your clinical success in treating patients with acute kidney injury. Our commitment to you starts with a program individualized to your facility’s needs and provides complete support every step of the way. For more information, visit us at www.renalacute.com. Baxter Healthcare Corporation has provided funding for this podcast, but all content was developed independently by the presenter. Therefore, the views expressed on the podcast are those of the speaker and should not be attributed to Baxter Healthcare Corporation. For prescription use only for the safe and proper use of this product, please refer to the owner’s manual. 

MARS is indicated for the treatment of drug overdose and poisonings. The only requirement is that the drug or chemical be dialyzable in unbound form and bound by charcoal and/or ion exchange resins. MARS is not indicated for the treatment of chronic liver disease conditions or as a bridge to liver transplant. Safety and efficacy have not been demonstrated for these indications in controlled randomized clinical trials. The effectiveness of the MARS device in patients who are sedated could not be established in clinical studies and therefore cannot be predicted in sedated patients. 

Pamela M. Peeke MD MPH, FACP, FACSM: Hello, and welcome to the Society of Critical Care Medicine’s iCritical Care podcast. I’m your host, Dr. Pam Peeke. Today we’re going to be talking about an introduction to molecular adsorbent recirculating system albumin dialysis, and I’m joined by Ram M. Subramanian, MD, MBA, FCCM. Dr. Subramanian is a professor of medicine and surgery and medical director of liver transplantation and liver critical care services at Emory University. Welcome, Dr. Subramanian. 

Dr. Subramanian: Thank you for having me. 

Dr. Peeke: Excellent. Before we start, do you have any disclosures to report? 

Dr. Subramanian: I am a consultant for Baxter Incorporated, which makes the MARS device.

Dr. Peeke: Any other disclosures relative to this podcast?

Dr. Subramanian: I have no other disclosure relevant to this.

Dr. Peeke: Excellent. The learning objectives include describing the principle of albumin dialysis related to the molecular adsorbent recirculating system, known as MARS. We want to outline the current indication for MARS, highlight application of MARS in critical toxicology, and describe logistics related to starting a MARS program. Why is this podcast needed? It’s needed to educate ICU and other clinicians on MARS as a therapy. The knowledge gaps that this podcast will address include allowing clinicians to understand how MARS works and engage in understanding which patients are ideal for this therapy. To put this in context, the extracorporeal techniques most frequently employed for the removal of toxins—that includes drug overdoses and intoxication—are hemodialysis, continuous hemofiltration techniques, hemoperfusion, and the molecular adsorbent recirculating system known as MARS. Dr. Subramanian, how did MARS come about? We have all of these other options. What was the genesis of MARS? 

Dr. Subramanian: MARS was actually discovered by two German nephrologists—just to date the device, this was back when we had East Germany and West Germany. So these are two nephrologists in East Germany who came up with it. The rationale was to create a system that would change the dialysate to an albumin dialysate instead of an aqueous dialysate that is used in traditional hemodialysis and therefore to be able to extract a whole other class of toxins from the patient’s plasma that are specifically albumin bound. That was the original genesis of, and the rationale behind, this device.

Dr. Peeke: Excellent. And coming forward now, how long has MARS been utilized in contemporary critical care? 

Dr. Subramanian: It has not been used often, especially in North America. There are very few centers that are using this with any degree of expertise or knowledge. It’s an area that is attracting more and more attention in the field of critical care toxicology and the other area, and this—just for full disclosure—is an off-label indication. There is growing interest in the field of critical care hepatology with regard to the use of the MARS device. We can talk about that more. 

Dr. Peeke: Excellent. So basically the actual therapy itself, the MARS, has a fairly ancient history here in terms of evolution and origin and has not been typically used in North America but now is beginning to emerge as another tool in our toolbox for the treatment of drug overdose and intoxication. Describe to us the principle of albumin dialysis related to MARS. 

Dr. Subramanian: A useful construct to understand MARS is to compare and contrast it with regular hemodialysis or CRRT. A couple of major differences. Number one, as I mentioned before, the dialysate has changed from an aqueous dialysate to a 16% albumin solution. That’s the first difference. The second difference is that if you change the dialysis membrane pore size and increase it to 50 kilodaltons, that facilitates the extraction of a whole other class of toxins that are what I described as medium-molecular-weight substances that would not come off with regular CRRT, which has a smaller dialysis membrane size. So by changing the membrane pore size and by changing the dialysate to an albumin dialysate, you suddenly create a system where you can extract a whole other class of toxins that are specifically albumin bound that will not come off with CRRT but suddenly can now come off with the MARS machine. 

Dr. Peeke: Give us examples of that.

Dr. Subramanian: When you think about—and we can get more into this when we talk about critical care toxicology—one example is calcium channel blocker toxicity, which is well treated with the MARS device. That is one example in the critical care toxicology field where you can suddenly start extracting drugs, such as calcium channel blockers that are heavily protein bound and, using the properties of the MARS device, you can now extract this efficiently, using the MARS device, which regular CRRT will not do. From an off-label standpoint—and I briefly alluded to the fact that there is growing interest in critical care hepatology—an example of a molecule that may be clinically important is endogenous benzodiazepines, which represent another example of a molecule that is heavily protein bound that can come off with a MARS circuit that will not come off with a CRRT machine.

So the clinical relevance of that—and this is based on RCT-level data—is that the MARS device has been shown to be very effective in the reversal of refractory hepatic encephalopathy in cirrhosis. The mechanistic rationale for that may be the extraction of endogenous benzodiazepines, just to give you a couple of molecules that are clinically relevant, if you will, in the context of critical care toxicology and critical care hepatology.

Dr. Peeke: There are quite a few indications with substances, with drugs, for which extracorporeal removal is indicated, barbiturates and lithium and metformin, salicylates, valproic acid, toxic alcohols, it goes on, and you’re saying that MARS is able to take it to the next level. 

Dr. Subramanian: That is correct. Specifically, I would draw attention to the critical care providers about if you see a toxin that has the property of being highly protein bound, as an example, I’d mentioned calcium channel blocker toxicity, amlodipine is a calcium channel blocker that is 98% protein bound. That’s a perfect target or a perfect example of a molecule or a drug that can be extracted very effectively with the MARS system because of the high protein-bound nature of the toxin.

Dr. Peeke: Excellent. Absolutely. So what you’re saying is, if you were talking to a critical care peer and they asked you to highlight the best applications for MARS in critical care toxicology, what you’re saying is that protein-bound substances, as you’ve mentioned, would definitely be part of the significant application. Anything else?

Dr. Subramanian: I think that is the major big-ticket item to focus on. I’ll give you other examples of some of these drugs. Phenytoin is 90% protein bound. That’s a great example. There have been case reports written about the successful treatment of phenytoin toxicity. Lamotrigine is another example, which is less protein bound, it’s 65%. But the general consensus is, if you have a drug or a molecule that is greater than 50% protein bound and especially at higher levels, then you should definitely consider this strategy in the treatment of that specific toxidrome.

Dr. Peeke: Absolutely. In drug overdoses, per se, are there a top three to five that really seem to be most ideal for MARS in drug overdoses? 

Dr. Subramanian: I think the data are still emerging. As we discover its utility, I think it’s just a matter of time before poison control centers and critical care providers start identifying and looking at the albumin or the protein-bound nature of these substances. Things that have already been written about are calcium channel blocker toxicity, diltiazem, and amlodipine are perfect examples. As I’ve mentioned, phenytoin has also been mentioned and written about. I think, as there’s more awareness of this technology, you’ll see a greater uptick in its application and its utilization. The other thing I’d like to mention is there is an epidemic, if you will, of herbal hepatotoxicity, which is a whole class of drugs or toxins that are an unregulated market. As we think about herbal toxicity, including hepatotoxicity, I think there may be an increasing application of the MARS device in that specific context, especially if you start identifying molecules that are highly protein bound. 

Dr. Peeke: When you’re talking about herbal toxicity, what are examples? 

Dr. Subramanian: It’s hard to tease this out because sometimes it’s unclear which is the active ingredient in some of these herbal meds, but cases that we have treated here are kava kava toxicity, we’ve treated chaparral toxicity, we’ve treated even cases of green tea overdose. We’ve treated examples including high androgen-containing or testosterone-containing compounds, which don’t exactly fall in the herbal category but they can be mixed in with it. I share this with the audience because I think that is a toxicology domain that is emerging, if you will, as we see more of it in ICUs and healthcare systems, and that may be an interesting opportunity to apply this device to. 

Dr. Peeke: Very interesting. Correct me if I’m wrong: So many people out there in the populace who do overdose oftentimes do it with more than one substance. This complicates things, doesn’t it? 

Dr. Subramanian: It does. Then it becomes very challenging to identify the true inciting agent, as you mentioned, especially if you have a coingestion. As healthcare providers, we sometimes forget to ask whether there is a consumption of an herbal agent because we are looking at the conventional medication list. I think it behooves the provider to be asking about potential herbal toxicity, especially when you have cryptogenic toxidrome. 

Dr. Peeke: I think that this is such an important point because people are now basically self-medicating. They may be on Rx medications and then add herbals and there are interactions, which can be problematic, and they can also basically creatively come up with their own idea about what will be good for them. If one is good, three is better, a concept that we see in our patients so often. This really is important. Most people out there, not our peers, we’re talking about our patients, consider herbal to be, and I quote, natural, therefore safe and you could take as much of it as you want. So I think, to your point, it is imperative to ask the question, because we don’t know.

Dr. Subramanian: Just to add on to this, the other application that we have used at our center is the treatment of severe jaundice. To add to the list, bilirubin is another example of a molecule that is well extracted by the MARS device, which will not happen with a regular CRRT or intermittent hemodialysis system. In the context of drug toxicity, and especially drug hepatotoxicity, we’ve had very good success with reversing severe hyperbilirubinemia. We’re talking about bilirubin of 50-60 that patients can languish with and that could eventually progress to fibrosis and chronic liver disease. We’ve had very good success in reversing severe hyperbilirubinemia associated with drug toxicity, which is more of an example of a focused toxicology hit on the liver. I just wanted to add that to the conversation. 

Dr. Peeke: That’s very important. I want everyone out there to know that Dr. Subramanian is author of an article, “Current Evidence for Extracorporeal Liver Support Systems and Acute Liver Failure and Acute-on-Chronic Liver Failure.” I believe you’re drawing from that article when you’re talking about jaundice. Were there any other high points from that specific piece of literature?

Dr. Subramanian: Yes. As I alluded to before, the one specific indication—again, just to underline the fact, this is off-label use—but the one scenario where MARS works really well is reversal of refractory hepatic encephalopathy in cirrhosis. I think that’s an important take-home point for the listener. At this moment in time, we have somebody who’s in severe hepatic encephalopathy and we are trying to prevent intubation and that patient has been refractory to all aggressive pharmacological therapy, including lactulose, rifaximin, zinc, metronidazole. When you hit that stage, we’ve had very good success with the timely initiation of MARS to reverse refractory hepatic encephalopathy. Again, off-label indication, but it has been shown in an RCT from many years ago that actually it does have efficacy in that context and that has been our experience as well.

Dr. Peeke: That’s fantastic. Describe the logistics that are related to starting a MARS program at your institution. 

Dr. Subramanian: This has been an interesting journey. We’ve been using MARS at Emory for over 10 years now. As I reflect back on the experience, a couple of things to share with the audience, number one, it’s a team sport. You need the involvement of an intensivist—and these need to be champions—an intensivist, a hepatologist, and a nephrologist. I think those are the three important players, if you will, as you start thinking about starting a program, because they have to put their collective wisdom together to initiate a program. The second feature, as I reflect back on our experiences, and I’ve had the good fortune of being part of the process, we have created a dedicated ICU for administering this technology. We have dedicated nursing colleagues who have developed a passion for this technology, and we have a call pool to initiate the MARS system. So if we decide to trigger MARS on a patient with some urgency, we are able to mobilize that specific cohort of nursing super-users in MARS who are able to trigger timely therapy in a very effective and efficient manner. So I share that with the audience to say that, in addition to the physician champions, you need your nursing colleagues to be passionate about initiating and continuing this therapy as well.

Dr. Peeke: I absolutely love this integrative approach. Thank you for identifying the team members and the significance and importance of everyone working together to be able to execute an optimal MARS program. Do you have any other thoughts as we wrap up this introduction to molecular adsorbent recirculating system albumin dialysis, or MARS?

Dr. Subramanian: I look forward to a growing interest in this technology. As people discover its utility, especially in critical care toxicology related to highly protein-bound drugs, I think it’s exciting technology moving forward. I look forward to its application in the future. 

Dr. Peeke: Are you available if somebody out there is wanting to ask you a question since you have a program already up and running?

Dr. Subramanian: Oh, most definitely. I would be glad to be of service to anyone interested in starting such a program. 

Dr. Peeke: Excellent. Thank you so very, very much. This concludes another edition of the iCritical Care podcast. Dr. Subramanian, thank you so much for your knowledge and your wisdom with regard to this issue. For the iCritical Care podcast, I’m Dr. Pam Peeke. 

This podcast is sponsored by Baxter Healthcare Corporation. When you choose Baxter for your CRRT program, you’re not only choosing true patient-focused treatment with industry-leading CRRT technology, you’re also selecting a partner dedicated to optimizing your clinical success in treating patients with acute kidney injury. Our commitment to you starts with a program individualized to your facility’s needs and provides complete support every step of the way. For more information, visit us at www.renalacute.com. Baxter Healthcare Corporation has provided funding for this podcast, but all content was developed independently by the presenter. Therefore, the views expressed on the podcast are those of the speaker and should not be attributed to Baxter Healthcare Corporation. For prescription use only for the safe and proper use of this product, please refer to the owner’s manual. 

MARS is indicated for the treatment of drug overdose and poisonings. The only requirement is that the drug or chemical will be dialyzable in unbound form and bound by charcoal and/or ion exchange resins. MARS is not indicated for the treatment of chronic liver disease conditions or as a bridge to liver transplant. Safety and efficacy have not been demonstrated for these indications in controlled randomized clinical trials. The effectiveness of the MARS device in patients who are sedated could not be established in clinical studies and therefore can not be predicted in sedated patients. 

Pamela M. Peeke, MD, MPH, FSCP, FACSM is a nationally renowned physician, scientist, expert, and thought leader in the field of medicine. Dr. Peeke is a Pew Foundation Scholar in nutrition and metabolism, assistant professor of medicine at the University of Maryland, holds dual master’s degrees in public health and policy and is a fellow of both the American College of Physicians and the American College of Sports Medicine. Dr. Peeke has been named one of America’s top physicians by the Consumers Research Council of America. She is a regular in-studio medical commentator for the national networks and an acclaimed TEDx presenter and national keynote speaker. Dr. Peeke is a three-time New York Times best-selling author and is a science and health advisor for Apple.

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