Nuelle-Cook-Edit (Completed 12/13/20)
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Dr. Clayton Nuelle:To the Arthroscopy Association of North America's Arthroscopy Journal podcast. The views expressed in this podcast do not necessarily represent the views of the Arthroscopy Association of North America for the Arthroscopy Journal.
Dr. Clayton Nuelle:
Welcome everyone, I'm Dr. Clayton Nuelle with TSAOG Orthopaedics in San Antonio. Today, I have the privilege of speaking with Dr. James Cook. Dr. Cook is the William and Kathryn Allen Distinguished Chair and the Chief of Orthopaedic Research at the University of Missouri. He was the senior author on a paper entitled Use of a Hyperosmolar Saline Solution to Mitigate Pro-inflammatory and Degradative Responses of Articular Cartilage and Meniscus for Application to Arthroscopic Surgery, which was published in the December of 2020 edition of the Arthroscopy Journal.
Dr. Clayton Nuelle:
Jimmy, thank you for joining me today. Dr. James Cook:
Oh, my pleasure. Thanks, Clay. Dr. Clayton Nuelle:
So let's start out with the background of the study and the impetus of the study and why you guys went about bringing this study about, and then kind of the basics of the setup itself.
Dr. James Cook:
Yeah, this has actually been a research focus for us for almost seven years now, and it's one of my favorites because it actually came from a resident. And so when we're talking to the residents, I always say, "What questions you have? What can you answer for a patient or an attending today?" And actually, this is the one that came from one of our residents a few years back, Nick Capito, and the question he asked me was, "Why in the world do we use saline or LRS for our scope irrigation fluids when they're so different from synovial fluid? And isn't there something better for that?"
Dr. James Cook:
And so I think that's a great question, right? So we kind of started talking through the variable, things that we could control and maybe make a difference with, and so we decided to start with osmolarity. And so synovial fluid is about four to 500 milliosmoles per liter, while these isotonic solutions that we use are around 300 or so. And then there's some good evidence in the literature that a hyperosmolar solution, so up in the range of about 600, have beneficial effects on chondrocytes and the joint environment.
Dr. James Cook:
Nuelle-Cook-Edit (Completed 12/13/20)
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Dr. James Cook:And those two articles really set it up and they showed us that it was safe and chondro-protective, and then there were some potential clinical benefits with respect to less periarticular fluid retention. And some of those associated complications that we see with that fluid around the joint, especially in the shoulder arena, and then even some potential benefits for postoperative pain.
Dr. James Cook:
And then so where we got started with the arthroscopy one is another resident then came to us, he's also doing a PhD at Mizzou, the first author on this paper, the son of [inaudible 00:02:55], and he said, "Let's do this for knee. This seems like it's working for shoulder and there's really probably so many more knee scopes, and so let's take this kind of basic science translational clinical research to the knee." Dr. James Cook:
So that's the first paper that we're talking about today and it's actually part of a series we can talk a little bit more about, and we were super, of course, excited to get it published in Arthroscopy.
Dr. Clayton Nuelle:
Yeah, that's awesome. I remember you guys doing all that work and I remember Nick being super excited about that and taking it all the way. It's always impressive when you can take it from the lab and bench work and then translate that into something clinically, like a randomized controlled trial and then show statistical and clinically significant differences.
Dr. Clayton Nuelle:
So just with the nuts and bolts of this paper, and then yeah, definitely would love to talk about the continuing line of study in this study. So you guys utilized both cartilage explants and meniscus pathology, and the explants were from tissue that was already being harvested, either from a patient having to get getting a total knee arthroplasty or an osteochondral allograft.
Dr. Clayton Nuelle:
So just from a logistics standpoint, kind of take us through that, and in particular, that tissue, do you think is that ... I know you guys kind of looked at a wide range of tissues, but that tissue obviously is probably not healthy tissue from the get go. So how did you mitigate that when you looked at that and knowing that some of that tissue is probably not the healthiest tissue just at baseline?
Dr. James Cook:
Yeah. And so I think you really hit the key point, at least for us, why this is in vitro study, the starting point, like you talked about, why that really is clinically relevant. And I would say just as you pointed out, so we looked at both articular cartilage and meniscus explants, so the actual tissue, and you know, Clay, one of my big mantras is the joint is an organ and so we want to look at those multiple tissues to really get a handle on is this really clinically relevant.
Dr. James Cook:
Nuelle-Cook-Edit (Completed 12/13/20)
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in the study. It was a range which is great, right? Because I think we have to have real life and it's not every patient is a single impact that we would do in the lab or some other type of insult to the cartilage. Dr. James Cook:So these were real life samples and most of them were in the grade one to three ICRS scoring system for articular cartilage pathology. And so I think that again made it both pretty standardized, but where we're looking at more of the whole joint and then a more real life application to it.
Dr. James Cook:
So I think that study design has some good relevance, but then it also allowed us, which the other thing I think is good, is it ... So many of these studies have looked at yeah, this does something, these
hyperosmolar solutions do something, but haven't really boiled it down to mechanisms. And that's, again, what I think we wanted to distinguish for us. So we were able to look at what could be the mechanisms of decreased pain or chondroprotection in these samples since we had actual tissue samples.
Dr. Clayton Nuelle:
Yeah, that's great information. So how applicable do you think this might be to say maybe like ... Because the average aged patient I think from this tissue is 66.9 years old. So how applicable might this be to say a young patient, a 20 year old patient, that has an ACL tear, and then we know gets some of those pro-inflammatory mediators that happened within the joint in the first 48 hours or so too. So do you think that the applicability of this would be similar to that or maybe slightly different? Or how would that apply?
Dr. James Cook:
Yeah, great question. I would say a little bit different. I would say to us this was more the worst case scenario, but still within the realm of applying to scope patients, not total knee or not big open
procedures. Because even though it was from those patients, really the reason for that, right, is that we were resecting tissues we could use so that we could ethically use it because they would be otherwise discarded.
Dr. James Cook:
But then when we went into that, we went away from the major lesions and looked at the more healthy cartilage that would be a little bit more like our ACL patients, our meniscectomy patients, though, so I do think you definitely need to look at that, like you're pointing out and that is definitely one limitation. But I do think if you look at that as a worst case scenario type, we can apply it to those patients, and at least because we did look at it mechanistically as well, we can say those same mechanisms will be in place because we know that for the ACL versus even the total knee patients, those mechanisms of
inflammation and degradation are the same, right? It's just severity and duration, and then some of the other things that are brought into play along with that severity and duration. So yeah, so long-winded way to say I think it is applicable as a worst case scenario for our typical knee scope patient.
Dr. Clayton Nuelle:
Nuelle-Cook-Edit (Completed 12/13/20)
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Dr. James Cook: Yep. Dr. Clayton Nuelle:Does duration of exposure matter or play a role? Dr. James Cook:
I think it does. So great question again too, and we kind of said, a little bit, hopefully, maybe worst case scenario though certainly we'll have some of those more complex cases, meniscal transplants and things like that that could push the three hour mark for that, and I think that was about our average for the shoulder surgery cases that we talked about. So we said, again, kind of, what's going to be the longest you would be putting fluid through a joint during an average procedure? I think it was ... I think you're going to see less affects if this is a 15 minute diagnostic scope versus that meniscal transplant that we just talked about. So we did just want to go a little bit more to the extremes of that as well, too. So yeah, definitely take that into consideration as well.
Dr. Clayton Nuelle:
Yeah, that makes sense. Yeah. I think like you mentioned, maybe the meniscus transplant or some of our multi-leg knee reconstructions or something.
Dr. James Cook: Right.
Dr. Clayton Nuelle:
They may go that long, but the kind of the standard ACL surgery or standard knee scope certainly, they'd be a little bit on the shorter end of that. So you mentioned that this is kind of one in a line of studies and things coming down the line. Can you kind of take us through where the research is going with this and where things are headed?
Dr. James Cook:
Yeah. Two things. So we've actually completed now and are just submitting to Arthroscopy, so we're going back to you all, thank you so much for accepting this one and publishing it. We love to get in your journal because that's really the target audience for sure, right? And so we're just submitting them and we did a prospective randomized double-blind clinical trial for knee scopes, so a similar kind of deal to our shoulder scopes.
Dr. James Cook:
And we did see in that a little bit unveil the curtain before the reviewers have a chance at it is we did see less scope irrigation fluid used in the hyperosmolar solution versus the standard saline or lactated ringers, shorter surgeries. So what we were just talking about a little bit, maybe even the fluid
Nuelle-Cook-Edit (Completed 12/13/20)
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Dr. James Cook:And then we think the basic science of we're going to have to see on longer term outcomes to say is it making a real difference in what happens in that joint? I mean, potentially you could see things like slower development of osteoarthritis, different changes that are not quite as degenerative if we're protecting that cartilage and meniscus like we hope. That part is still a hypothesis to be tested, but I think there's a mechanistic way to do that.
Dr. James Cook:
And then the other thing is that we've said, "Wow, it does seem like from this article that we just published and our previous basic science work, that it is both anti-inflammatory and anti-degradative mechanisms." And so we've actually then looked at another kind of souped up solution, if you will, and we've added then some FDA approved and clinically applicable anti-inflammatory agents to the solution to kind of make a Mizzou specific solution that we're now then testing further from there. So those are kind of the next stages for us.
Dr. Clayton Nuelle:
Wow, that's awesome. That's some really exciting research. I think that'll be really interesting, and the fact that you guys are able to get some randomized control trials done is really nice too. We just did a podcast recently talking about how difficult it is to do a well done randomized control trial. So taking it from the bench to the lab is great, and I certainly appreciate your mantra of the joint is an organ. I think about that almost on a daily basis actually, every single time I see a knee swell up or a knee ... An ACL come in, I think about that pretty much every single time. So I certainly ... That has been impressed well upon me.
Dr. Clayton Nuelle:
So what does everybody that does arthroscopic knee surgery at Mizzou do and has this changed clinical practice for people? Is this something that people are now doing using a hyperosmolar saline solution and every knee scope or only long, long arthroscopic knee surgeries? Or is it changing clinical practice for people yet or is it not quite there yet?
Dr. James Cook:
Yeah, I would say a slow wave appeasing clinical practice, so the participants in this study are really doing that for both shoulder and knee now. And I think the cool thing is it's really pretty easy to do, so super easy to make up. I mean, you literally take the hyperosmolar hypertonic saline solution, the 23.4% solution, take 120 mils of it, add it to your three liter bag of isotonic saline or lactated ringers, and here, at least at Mizzou, that costs you 17 bucks per bag to do it.
Dr. James Cook:
And so really both logistically and cost effective wise, I think it's appropriate that way. And then again, the good thing is that right, it's safe. So we definitely didn't have any problems with it, whether that be on a very basic science level, when we looked at chondrocyte viability, we looked at matrix water content, all of those things, and then of course on the patient side. And so yeah, people are starting to invoke it a little bit more and I think we're making converts as we go.
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Well, that would definitely be $17 well spent if it's chondroprotective in any way, or certainly mitigates the pro inflammatory response. So that definitely would be well worth it.Dr. James Cook:
Yeah, we've been really happy with it and I think things here at Mizzou were pretty practical, I think, and pragmatic about it, so that's made it easy to do that. And I think we're really shifting over to that, and maybe even then with the enhanced solution, maybe that's even more effective and more beneficial to our patients long-term as well.
Dr. Clayton Nuelle:
Absolutely. That's terrific. Jimmy, thank you very much for sharing your immense knowledge and wisdom and for joining me today.
Dr. James Cook:
Thank you so much. It's been my pleasure. Dr. Clayton Nuelle:
