for the opportunity to present. And as he mentioned, my topic for this session was a little bit on blood flow restriction therapy. And I think all of us, certainly the clinicians, the therapists, and any of us who are around sports medicine probably can't go too far without hearing about the potential role for BFRT. So I thought this was a helpful exercise, even for me to look back at the literature and see where are we with BFRT? What do we know and what do we don't know? So I'll step back and point out that the reason it has so much excitement for all of the clinicians and those around sports in the room is that it may have beneficial adaptations for skeletal muscle. And a little bit of where this started to give a lot of credit, I think whenever we think something is entirely new in orthopedics, it isn't. If you look back in the literature, Dr. Sato out of Japan described so-called katsu resistance training, which involved effectively using a tourniquet, creating an ischemic environment that would not necessarily occlude, but certainly impair inflow. And as a result demonstrated that with lower intensity training, we could achieve the benefits of higher intensity type training and repetition. Well, a lot of credit to Johnny Owens, a therapist who I think all of us know, but has done a lot of work in this area. And the inception of that was out of the military population. As you can see, those who are, who suffer significant limb threatening injuries or limb salvage injuries, oftentimes our conventional modalities of rehabilitation in running and strengthening are not an option for them. So BFRT proposed effectively a way of being able to incorporate new rehabilitation strategies for that unusually severe condition. Where that has resulted in a lot of excitement, however, is as we've learned from that military population, there's been parallel interest in its role for the healthy athlete and even augmenting recovery or expediting recovery. And all of those areas I think are the questions for symposiums like this one. So what's the typical approach in 2021? It's usually a pneumatic cuff as opposed to a traditional tourniquet. The idea is that it's applied to the proximal upper or lower extremity, and you select a pressure, the so-called limb occlusion pressure that's used. As we'll go through this talk, we'll learn that in fact, there's a lot of inconsistency with what is the right LLP. And there's a lot that we don't know. Resistance exercises are typically done at lower intensity. Most protocols talk about somewhere between 20 to 30% of a one rep maximum. Typically, the cuff's inflated for that particular set, and then it's deflated between those sets, and of course, post-exercise. So what is the limb occlusion pressure? And the key idea here is that it's the minimum pressure required to stop or impede arterial inflow, but of course, not to entirely occlude and block venous outflow. Fatella wrote an initial study that looked at neuromuscular activation and fatigue, and of course, showed that based on the LLP, it was more effective with 80% than 40 to 60%. And in general, with a little higher limb occlusion pressures, like 80%, the results seem to be a little bit more favorable. That being said, there's a lot of variability in the literature, and we'll go through that shortly. Please remember that the goal of this technology is restriction and not formal occlusion, given all the risks and complications that one would assume with occlusion, including rhabdomyolysis, deep venous thrombosis, et cetera. I think this is a really important point, and what makes a lot of what we do hard, as Jason just talked about with regard to biologic augmentation, there's so much variability in what we deliver, but sometimes gets labeled as BFRT. So let's talk about limb occlusion pressure alone. If you look at what varies for a limb occlusion pressure, there's sort of broad baskets of categories that can affect that. There's those on just the equipment side. Depending on the type of cuff you use, the shape of it, the width of it, whether or not it has a circumferential or peripheral bladder, and the technique and the location where you apply it to the limb can totally change the rendered limb occlusion pressure. Correspondingly, there's characteristics of the patient, including the size and shape of the patient themselves, the temperature of the limb, and their blood pressure. All of those factors, as you can imagine, lead to a lot of heterogeneity. So when we're making conclusions, it's hard to generalize when, in fact, what we're reporting can be so different. There's 15 papers that have published on BFRT, at least with regard to the upper extremity. Jesse et al. recently summarized those and pointed out this very issue, was that the cuff pressures that were used across all those studies varied widely. Some used it as a percentage of their personalized limb occlusion pressure. Others just used a fixed pressure. And some set it as some relative measurement from the systolic blood pressure. So all of those factors we need to take into account when we're considering the literature. What's the basic science behind this? And I don't want to belabor all of the molecular pathways because that's certainly above my pay grade, but there are basic scientists in the area of muscle atrophy and hypertrophy who study this certainly in great length. The idea behind it is simply this. I think we're all aware that skeletal muscle hypertrophy is gain in muscle mass, but it's not through replication and mitosis. It's an increase in the fiber size at the sarcomere type of level. What happens is, or the theory behind this, is that there's mechanoreceptors that are sensing the constriction or the effect around the muscle. That leads to these typical signaling pathways, namely the IGF-1 or insulin growth factor-like pathway that then stimulates the onset of hypertrophy or, in turn, inhibits the pathways for atrophy through molecules like myostatin. Typically, the ideal stress, as we've talked about, lives somewhere in the submaximal range of a one repetition maximum. And the idea is that perhaps this low oxygen tension or ischemic environment tends to favor the recruitment of your more low oxidative fast-twitch muscle fibers. And again, that affects the differential of how that muscle is performing. A huge factor or question in this is whether BFRT is just a local effect. So if you put it on the upper arm, is it just helping downstream from that extremity? Or is there a systemic increase in cytokines that can help in other locations? And there's a number of papers, including on the program at this meeting, that are assessing that effect as to whether BFRT on, for example, the proximal thigh might have some favorable effect on healing a bone like the clavicle. Are there systemic effects to BFRT? This is a nice study from Adam Anz that was truly just published in the past month or two, where he took 14 healthy recruits, performed blood draws on them before and after performing exercise. They did a simple CBC count, but also did flow cytometry to look at potential up-regulation of type of stem cells, hematopoietic stem cells. And they did find that with BFRT, there was an increase in the peripheral progenitor cells and platelet counts. So what does that mean? Potentially, can BFRT act a little bit like our GM-CSF, or marrow-stimulating factors, a natural way to autogenously up-regulate the healing potential of platelets and stem cells? We don't quite know, but at least this lends some thought to the fact that that ischemic environment may in fact create some systemic effect. Austin Ramey, who's a former fellow of mine now practicing in Iowa, and I did a study a year ago to try to study this in an animal model. And the idea behind that was, we knew that it's very difficult to get repetitive blood draws in patients. It's also very difficult to, for example, biopsy the muscle. And so we wanted to understand the mechanism as to how BFRT might work. This was just published in the last few months where we looked at two different models, the so-called repetitive restrictive cycle technique versus just standard BFRT. And we used submaximal contractions in a rat model. The specific purpose of this was to see with this ischemic therapy, could we see changes at the histologic level in the muscle? And could we see changes at the systemic level in terms of circulating cytokines that we could assess at multiple time points through tail vein aspiration? So believe it or not, a lot of credit to Austin, who's an MD-PhD. We had to standardize the exercise technique. So here it is creating this repetitive muscle stimulation at a specific current to always have the same load. This effectively digital tourniquet that was used on the limb of that animal, and then a number of different repetitive models for us to look both at histology and biomechanics. I won't belabor that point here other than to show that those protocols were standardized both for the repetitive restriction technique versus the standard BFRT. And again, what we wanted to look at was the local effects and the systemic effects and really see if in fact we were seeing the presence of so-called satellite cells, which are the stem cells that mobilize in muscle to promote healing or even to promote augmentation. The summary of those findings, I'll click through quickly here, but the long story short of it is we didn't see a lot of change. We didn't see any local response with regard to muscle mass or the maximal force that could be generated, so-called specific force. We didn't see any systemic response with regard to muscle hypertrophy or specific force. And then when we looked at histology to stain for these muscle satellite cells using PAC-7, we didn't see significant differences in the presence or mobilization of them as well. We saw the same baseline numbers in both groups. When we looked at cross-sectional area for each muscle fiber, we didn't see any significant difference there. When we looked at some of the important cytokines that we've talked about for the muscle hypertrophy pathway like IGF-1, no significant differences. But we did see some subtle increases in growth hormone concentrations after a month of treatment. So maybe some potential systemic effect down that pathway, we know growth hormone then in turn works via the IGF-1 pathway. Could it potentially inhibit proteins that we know are involved in muscle atrophy like myostatin? So we looked for that as well. We didn't see any significant difference there. So I think in summary, the purpose of this was to point out that at least at the basic science level in a small animal model, we were not able to identify significant differences in either local or systemic cytokines or effect on the muscle size or function, which again points out that while we see this clinical effect in patients, we're not yet fully understanding what the fundamental mechanistic pathways are for this to be effective. So of course, that's a call out for more research to understand this so that we can tap into that and augment the efficacy of BFRT. I don't think you wanna throw away the baby with the bathwater though. If you just use our rat study, you would say, well, forget BFRT, it doesn't work. And we know that's not true. Where does the basis for this come from clinically? Really, when I looked in the literature, the earliest studies for BFRT was not in the orthopedic world at all, but really in the cardiovascular world. This is Abe's study, which really looked at using Katsu-type walking training for cardiac rehab. And so elderly patients aged 60 to 78 did six weeks of training, sort of treadmill walking for cardiac rehab with or without BFRT. And what they found was that the patients that had used BFRT had significantly increased skeletal muscle mass and skeletal muscle density. That led to a number of other studies more in the orthopedic world, or Olympus Vasti, who all of us know in Shoulder Elbow, published last year, looking at the role for BFRT in healthy subjects using an upper extremity protocol. And again, in healthy populations that had randomized to or not BFRT, they found significant increases in strength as measured by dynamometry. And in fact, even saw some systemic effects through increased grip strength in the contralateral arm. Pat McCullough, actually this month, in this month's AJSM from the Society's Journal, published on 32 healthy adults that he randomized with low intensity cross training with or without BFRT, and actually saw a significant treatment effect that with the addition of BFR, they included and randomized in these groups and looked at pre-training and post-training assessments. The assessments were quite rigorous, looking both at isometric testing, DEXA scan, EMG testing, and looking at the systemic and local effect. And again, found significant increases in the lean muscle mass, but also strength in external rotation, scaption, and even with training volume, a bit of a training volume effect. So again, pointing out that there is a clinical effect here, but the basic science mechanisms we need to understand. I think one of the most exciting areas for us to consider is what about after surgery, right? All of us do these surgeries and we see the profound effect of even a simple knee scope. Tenet published on using it in 17 post-operative arthroscopic knee surgery patients and reported increased cross-sectional areas of the quadriceps musculature. DeFilippo and Ladlow also used BFRT and saw increases in muscle mass. And Dr. Noyes even published on this this year in 2021, when he looked at a heterogeneous mixture of open and arthroscopic patients that had severe muscle deficits, oftentimes multiple revision surgery patients, and found a treatment effect in terms of peak quadriceps and hamstring strength with BFRT. So one area of significant focus is after ACL surgery, where we know that one of the rate limiters for return to sport isn't in fact just the ligament and tendon healing to bone, but it's the muscle atrophy and quad atrophy that persists often several months after six or nine months. Takarada and Oda out of Japan both studied this and saw some treatment effects in terms of reducing atrophy, and that's led to a number of other studies looking into this. This is how it manifests clinically. You can see this is a study done with my colleagues, Ryan Palmieri-Smith at Voitus, who's actually here with us in the audience, and others looking at the effect. This is the same patient after a simple BTB-ACL. Just 24 hours out from surgery, we can see that the significant inhibition in quad function that occurs. You're really at the neuromuscular level, almost at a spinal cord reflex level, but we know this quad atrophy persists. So we wanted to study this in our population. This was recently published in AGSM by Ryan and her team where we looked at 20 to 30% of a one rep maximum and wanted to see if we added in BFRT at that three month plus time point, would it make any difference? So this is a little bit of a complicated study design, but what you can see here is we took these 36 patients and we divided them into eccentric or concentric postoperative rehabilitation protocols, but then these groups were subsequently divided. Half of them got BFRT and half didn't. Our IRB didn't really allow us to incorporate the BFRT any earlier than 10 weeks postoperatively because of the risk of DVT, at least from their perspective. So we implemented that as augmentation after that approximately three month time point. We then studied them looking at, again, a BioDex based assessment, again, using 80% limb occlusion pressure. And the best repetition was recorded as a percentage of one rep maximum and saved as that individualized 100% maximal intensity for each subject. Again, we looked at all of these different other factors as well using ultrasound. We looked at the rectus femoris volume. We looked at central activation ratio and we looked at the change of baseline with regard to their muscle mass. And interestingly, even though we saw some treatment effects we actually did not see any statistically significant differences. So this at least points out that maybe BFRT is very valuable but it may be less valuable as you get to that postoperative time point where you can already implement more traditional exercises. And maybe its most critical role is in that early postoperative period where you can't. So why no improvements in our study? Well, hard to know. Maybe it's because the mechanical tension is already high and so as I just pointed out, the benefits of additional metabolic stress are minimized when you're able to already allow that athlete to return to running or high load exercises. So again, more studies are necessary at those early time points. Additional variables to consider, what was the frequency? Should we do low intensity or high intensity? And did we use the right limb occlusion pressure? So the conclusion, at least for us, was BFRT did make a difference alongside with high intensity exercise at the later time points of ACL reconstruction but that doesn't take away from its value in the early time points with low intensity load. What can we take away in 2021 as we're learning more? I thought this was a nice paper that Rob LaProd and colleagues, actually Chris Larson's group, put out in 2018 looking at pearls and pitfalls. And I think this is an important table to keep with you in the clinic because if you use BFRT but you use it a little indiscriminately, you can run into trouble. And that's where we can get into case scenarios that have been published, including cases of rhabdomyolysis, deep venous thrombosis, or even at times some catastrophic muscle fatigue and pain that can delay rehab. So I won't belabor this list here but it's one worth looking up. And again, no two protocols are the same. We published this in AJSM. These are two sample ischemic therapy protocols that have had good traction in terms of outcomes in the literature, one published by Hylden and the other by Cook. And I would recommend you reference those so that it's not just being used by your physical therapy group, but not being used in a validated way, at least based on the literature. Have complications been reported with BFRT? It's always important for us to be responsible in looking at those. Cluly published this in AJSM in 2020 where they looked at 19 studies and over 300 patients. And fortunately, there really weren't too many catastrophic adverse side effects. There were three reported case events, including an upper extremity DVT and some rhabdomyolysis, but again, a deeper dive is necessary to know whether these were too high limb occlusion pressures or these were used a little bit in an indiscriminate way. So thanks for the opportunity to present this work and I want to acknowledge the grant agencies that funded that work. Thank you.

blood flow restriction therapy

sports medicine

rehabilitation

skeletal muscle

tourniquets