SCCM Resource Library-Extracorporeal Life Support: What’s Here, What You Need to Know, and What’s Coming

Video Transcription

revisited. This is my typical disclaimer. I am the principal investigator for a DOD-funded grant  called PURIFY, and we'll be discussing this briefly at the end of my talk. So you've heard a  lot about vasopelagia, which essentially means vasodilatory shock or uncontrolled vasodilation,  and throughout this session you've heard about a variety of different therapeutic targets to  reverse this condition, both cellular in nature and intracellular in nature. Extracorporeal blood  purification is what I'm going to focus on for the next 15 to 20 minutes. Extracorporeal therapies  in general, or taking blood outside the body, doing something to it, and then putting it back,  is a technique that's utilized for a variety of different conditions in ICUs around the globe.  The most commonly utilized therapy, extracorporeal therapy, is kidney replacement therapy, followed  by extracorporeal membrane oxygenation to support the lung, and a technique called MARS to support  extracorporeal blood purification for sepsis, and I'm going to focus on sepsis in general,  as it is the most common cause of vasodilatory shock. This is a concept that's been around for  quite some time, and this is a nice review published in Blood Purification a few years ago that provides an overview of the variety of techniques available. They categorize these  techniques into four major categories, those that target pathogens, others that target endotoxin,  ones that target activated neutrophils or leukocytes, and then others that reduce or target cytokines. Cytokine removal is a concept that's been around for quite some time, removal  of pro and anti-inflammatory mediators to have a net gain of beneficial effects from a hemodynamic  and physiological standpoint, and a variety of different therapeutics target cytokines. As you  can see, the most commonly studied or written about therapeutic for the purpose of cytokine  removal is hemofiltration or continuous venous hemofiltration, which has been around for quite  some time. In this study, published by Ronco and colleagues, they compared different doses  of hemofiltration, anywhere from 20 to 45 cc per kick per hour, and randomized these patients  comparing these doses to control. And what they were able to demonstrate was that there was a  mortality benefit when you're comparing higher doses to lower doses. What we've determined since  then is that a number of studies have been published that demonstrate that normal dose or typical dose hemofiltration somewhere on the order of 25 cc per kick per hour to 45  or 40 cc per kick per hour does not really make a dent and has not been shown to improve outcomes.  And so hemofiltration at normal doses doesn't seem to have any benefit physiologically and or  in terms of outcomes and mortality. How about high volume hemofiltration? This is something that I  have personal experience with and have conducted a randomized control trial in the burn population.  Here we have a systematic review and meta-analysis of all the studies that published and you can see that in totality when you group all the patients together, treated  versus control, you see evidence that favors treatment potentially. The problem with this is  that all these different studies had different definitions of what high volume hemofiltration was  anywhere from 35 cc per kick per hour to higher than 100 cc per kick per hour. So that's a lot of volume and technically this is really challenging sometimes to deliver that kind of  dose especially in CBVH mode. How about cytosol? This is a technology that's been around for a  couple of decades now. It's manufactured by Cytosorbent Corporation and here's a randomized  control trial that evaluates this technology. This is a bead-based technology that is a bunch of  beads that are packed into a column whereby blood flows through it and a variety of different size  proteins are able to be removed including cytokines and pro- and anti-inflammatory cytokines.  In this study, a randomized control trial randomized 100 patients to treatment versus control  and what they demonstrated was that it didn't do much when you compare treatment versus control  in terms of overall IL-6 levels over 70s. And so they concluded that in a patient population with  septic shock and multi-organ failure, hemo adsorption, it does remove IL-6 as it passes  through the column. However, systemic levels are not lowered over a period of time when compared  to controls. Secondary outcomes were no different as well. How about endotoxin removal? This is a  technology that is based on a polymyxin B coated membrane and as blood passes through and touches this membrane that's bound by polymyxin B, endotoxin is removed.  This is manufactured by Spectral Medical. This was a trial that I'm sure many of you may have participated in or at least some of your centers. It's called the Euphrates  trial that looked at the efficacy of polymyxin B hemoperfusion on 20-80 in a patient population  with septic shock and they randomized over 200 patients in each group to receive polymyxin B  versus sham in a patient population with septic shock. And what they demonstrated was that  in all participants and in a cohort of patients with multiple organ dysfunction  as defined by a score, a mod score greater than nine, there didn't seem to be a difference.  However, when you look at a subgroup analysis, and that Euphrates study looked at all comers  with high levels of endotoxin activity. When you look at just the subgroup within a specific range  of activity, 0.6 to 0.9, there seems to be a signal favoring benefit in the treatment arm. And so perhaps this is a subpopulation that should be targeted in future trials.  So the story is not done with polymyxin B hemoperfusion, more to follow.  How about cytokine plus endotoxin removal? Baxter has acquired this technology, Oxiris, which  has the combination of endotoxin removal and cytokine removal via these two layers  that for the cytokine removal, they utilize AN69 technology. This is an observational study looking at this therapeutic in patients who were treated. And you can see the demographic  of the population was treated. And what they concluded was that in those treated with this  technology, hemodynamics improved as represented by norepinephrine levels and lactates cleared,  as well as mean arterial pressures improving. However, there was no control group. And so it's hard to speak on efficacy, but clearly it seemed to be safe.  How about removal of activated neutrophils? The concept that was put forward by the University  of Michigan and Dr. Humes and his colleagues, where they found and observed that in a hypocalcemic environment induced by citrate, neutrophils seem to bind hemofilters. And so they  acted on this observation and created a technology specifically for this.  They took this technology and evaluated it in a randomized control study here by the  Selective Cytophoretic Device Investigator Group. And they randomized patients to treatment control.  And what they found was that overall, it didn't seem to make a difference. However, when they looked at a subgroup of patients that achieved the recommended ionized calcium  range, there was a signal towards benefit. So there's more to come on that.  How about removal of everything in the form of, or using the technique that many of us are  familiar with, plasmid exchange? So there have been a number of small studies that have been  published. And this meta-analysis from 2014 attempts to look at pool analysis. And you can  see that they separated out between studies in children and studies in adults. And you can see  that there's not a difference seen in the few studies that looked at randomized children. And they stated that and found that in adults, the two studies that looked at adults, there  seems to be a difference. And so they conclude that plasmid exchange overall was not associated  with a reduction in all cause mortality, but there may be a potential signal in adults. And that further rigorous, larger randomized trials are needed.  A few have been done. The most recent was performed by this exchange study group.  It was published in Intensive Care Medicine last year. They randomized about 20 patients  to receive plasmid exchange versus standard of care. And they looked at physiologic parameters as their primary endpoint and norepinephrine dose specifically, and showed that  norepinephrine dose decreased significantly in the plasmid exchange group.  They did not power this for mortality, and they concluded that a larger study was needed.  For the first time in any of the reviews that discuss extracorporeal blood purification  for sepsis, there is mention of pathogen removal. And this is from the study that I reviewed here.  This may have resulted from, it specifically resulted from DARPA-funded program called  Dialysis-Like Therapeutics, where they called performers to take their technologies and try to remove circulating pathogens from the blood as their objective, their main objective.  And so from that program, it yielded a couple of different technologies, one manufactured by Xterra and another manufactured by Boa Medical.  The Xterra technology is called Serif 100. And this is a sorbent-based hemoperfusion technology  where beads that are coated with heparin sulfate are proposed to bind pathogens as blood  flows through this hemofilter. Heparin sulfate, as you may know, comprises of  a number of about 70% of the glycocalycs that are natural occurring in the endothelium, vascular endothelium. And so that, the normal function of heparin sulfate is to  bind pathogens as they circulate throughout the bloodstream. And this is considered a biomimetic device that attracts pathogens using this protein, naturally occurring protein.  And in vitro, they've demonstrated significant reduction in pathogen levels  for a variety of different bacterial pathogens as well as viral.  The Garnet is manufactured by Boa Biomedical, and it is a hollow fiber hemofiltration device that takes a normal hemofilter, encodes it with a proprietary protein called FNBL,  so mannose-binding lectin. Mannose-binding lectin is a broad-spectrum opsonin that's able to bind  pathogen molecular patterns. And as you may know, opsonins are naturally occurring proteins that  enhances phagocytosis by marking antigens for removal. And so this mannose-binding lectin, a naturally occurring opsonin, through this technology, they're able to  manufacture this proprietary protein, combining it with an FC portion of an IgG and creating this  new protein called FCL. And in vitro, they were able to demonstrate removal of a variety of  bacterial pathogens, as you hear. And so this is really broad-spectrum removal of pathogens,  both these technologies. And what's intriguing is that potentially broad-spectrum removal  or source control in the bloodstream could potentially nip the cytokine storm in the bud  and prevent it from happening in the first place. So think about this as a non-pharmacologic,  pathogen-agnostic, source-control device that can be used as an adjunct to standard therapies.  And it is really the focus of the PURIFY program to evaluate not only those DARPA derivatives,  DARPA-funded derivatives, but other potential blood purification technologies  in a platform trial design. We are already on the way to enrolling in a feasibility study  to evaluate Serif100. A first-in-human study for the Garnet has been accomplished and has concluded recently, and it will move very shortly into a feasibility study. And then  soon we'll conduct a pivotal trial looking at a variety of different technologies, many that  I've mentioned here today, to see which one of these technologies impact physiology in the setting of septic shock, but also improve outcome. That is all. Thank you very much  for your attention and looking forward to the Q&A session.

Video Summary

In this video, the speaker discusses the use of extracorporeal blood purification techniques in the treatment of vasodilatory shock caused by sepsis. The speaker explains that extracorporeal therapies involve taking blood out of the body, treating it in some way, and then returning it to the patient. The most commonly used extracorporeal therapy is kidney replacement therapy, followed by extracorporeal membrane oxygenation and a technique called MARS for sepsis. The speaker then goes on to discuss various techniques for extracorporeal blood purification, including hemofiltration, hemo adsorption, endotoxin removal, cytokine removal, removal of activated neutrophils, and plasmid exchange. The speaker mentions several studies that have been conducted to evaluate the effectiveness of these techniques, highlighting the potential benefits and limitations of each. Finally, the speaker introduces the concept of pathogen removal as a potential source control method and discusses ongoing research in this area. The speaker concludes by mentioning the "PURIFY" program, which aims to evaluate different blood purification technologies in a platform trial design to improve outcomes in septic shock.

Asset Subtitle

Cardiovascular, Procedures, 2022

Asset Caption

This session will combine the most popular learning methods for extracorporeal support, combining didactic information on the most up-to-date research and clinical outcomes, case-based presentations that will be used to incorporate the didactic portion, and audience participation by Q&A with the expert faculty panel. Topics covered are: 1. New technology, what's here, why it's important, what's coming 2. Expanding populations, criteria and outcomes (extracorporeal CPR, COVID-19, transplant, cardiac) 3. What's new in anticoagulation? Maybe the answer is to do nothing! 4. How we handle the lung during venovenous extracorporeal membrane oxygenation (ECMO), the heart during venoarterial ECMO, sedation, when and how to unload the left ventricle, whether I need to change from venovenous to another mode for hypoxia (and why) This sessions will focus on adult and pediatric patients but not much on neonatal ECMO. Didactic talks will be incorporated into case-based presentations. Time for Q&A with the speakers will be a major focus.

Meta Tag

Content Type Presentation

Knowledge Area Cardiovascular

Knowledge Area Procedures

Knowledge Level Intermediate

Knowledge Level Advanced

Learning Pathway Skills and Procedures

Membership Level Select

Tag Extracorporeal Life Support

Tag Extracorporeal Membrane Oxygenation ECMO

Year 2022

Keywords

extracorporeal blood purification techniques

sepsis

hemofiltration

cytokine removal

PURIFY program

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