What are the principles of BFRT, and its mechanism of action, as best as we currently understand it now in 2022?

I think we're dialing in our understanding of the mechanism of action of BFRT’s action mechanism a little bit better. Currently, we believe that the metabolic stress from vascular occlusion and mechanical tension from resistance training or other exercise lead to increases in muscle hypertrophy and strength. Metabolites at the cellular level, as well as hormonal differences, cell-to-cell signaling, cellular swelling and intracellular signaling pathways, are all involved. Metabolites, which are known mediators of muscle hypertrophy, are amplified by the relative ischemic and hypoxic conditions generated with BFRT.

One way to explain this is that the human body has two muscle fiber types: Type I slow-twitch and Type II fast-twitch. Slow-twitch fibers use oxygen for fuel, and that’s what your body prefers to use when possible. When you first start to lift a heavy load, sometimes it's not that harid because your body's trying to use slow-twitch to get that load moving. But eventually if the load is sufficient, you switch to an anaerobic metabolism, not using any oxygen, and you start having to use those fast-twitch fibers, which are these big motor threshold units – these big fiber types that can push some significant power. So, with blood flow restriction, we hack that system and we take the oxygen out of the equation. When you have a limb that has the tourniquet on, and we reduce the oxygen to a sufficient level, you can generate greater motor unit recruitment with low load resistance.

During the rest period we keep the tourniquet on and then the magic starts. If you're doing it right, even at a low load, your body just doesn't have enough oxygen to use those slow-twitch fibers. So, it has to switch to this anaerobic metabolism and it's a low load weight, but all of a sudden it feels very, very heavy because your body's having to recruit these big, fast-twitch fibers simply from an oxygen deficit.

And so, once you use those fast-twitch fibers, be it with a heavy load or the anoxic state induced with blood flow restriction, you get a real anabolic signal. So, for every glucose molecule that you use in that fast-twitch metabolism, you start to cleave off these muscle metabolites, things like lactate and hydrogen ions, and those are really powerful signals. They're fuel, but they're also a signal that kicks off this anabolic cascade. In a nutshell, we basically flip the switch no matter what the load is that we can recruit those fast-twitch fibers. If you can recruit fast-twitch fibers after injury and rehabilitation, that is a huge win.

The evolution that we are seeing now in 2022 extends beyond the basic understanding of recruiting this fast-twitch metabolism. Now we are understanding that just the hypoxic state alone seems to drive quite a bit of things like gene expression, and so even being in hypoxia without exercise, there's some positive changes that we can see. The 2019 Nobel Prize in Physiology was given to three gentlemen for work showing that hypoxia around cells can really drive these interesting changes. And one of their main discoveries was on hypoxia-inducible factor 1-alpha, or HIF1A. And so that low oxygen state makes HIF1A come out, which has really positive effects on potentially helping with bone, creating angiogenesis, [appearing to] help drive stem cell proliferation and things like that. So, we're starting to move more into seeing what this acute hypoxia can do.

Can you speak to the variety of applications for BFRT in the clinical setting and explain each of them for us?

It's really a spectrum. BFRT application has its origin in muscular growth with resistance training, but has now expanded into multiple additional forms, such as BFRT with low load resistance, aerobic exercise, passive BFRT and even neuromuscular stimulation.

Passive BFRT allows the tourniquet to really do more of the work. Picture a patient laying on the mat doing quad sets or other mat exercises, [which is] really almost no load at all. But the tourniquet in that passive state seems be able to mitigate atrophy.

And so, we've seen in studies where they've done disuse, where they have healthy individuals that are immobilized, that if you just keep them immobilized and do nothing for two weeks, they lose a lot of muscle and strength. After about 10 days, you've already lost about 30% of your quad strength and you'd lose more than the size of your heart in muscle mass. But if you put a tourniquet on, you can mitigate that loss. You still lose some, if you're doing it passively without exercise, but you seem to lose much less than if you do nothing at all. So clinically, we say in the early days, let's just get the tourniquet on these individuals.

A recent paper came out last year that explored why this might happen, and they found from muscle biopsies that there was one gene that was significantly downregulated: MuRF1. Whenever people are in a state of disuse, MuRF1 signals the body to sacrifice muscle tissue. In the study, the cohort involved in BFRT failed to have an increase in MuRF1 gene expression above baseline, whereas the control groups certainly did. And so, in those early days of BFRT, we might be slowing the catabolic cascade through MuRF1.

The next application of BFRT is with aerobic exercise, such as walking on a treadmill or riding a bike lightly with a tourniquet on. That seems to move the needle a little bit and result in an increase in some muscle strength and size. We've also seen that it creates some volume of oxygen, or VO2, adaptations, because when you do BFRT, you accomplish a complete block of venous return to the heart, which results in an increased heart rate to maintain cardiac output with the decreased stroke volume.

Aerobic BFRT is a little bit easier than doing resistance training BFRT with the 20 or 30% rep max, so you can progress naturally first from passive to aerobic BFRT, and that can condition the patients to the process. We have found that when a person is in a period of disuse and muscle atrophy starts, muscle protein synthesis will start to decrease as well, starting around Day Three. There are some beautiful, elaborate studies that have shown how this happens.

Fortunately, it's been shown in multiple trials that when you do BFRT resistance exercise at low loads, we can actually drive up muscle protein synthesis by at least 30% on average with a lasting effect.

These are the main ways we apply BFRT in the clinic. The most effective still seems to be BFRT with low load resistance training with the tourniquet on until people can tolerate increased loads. Ideally, we do BFRT early after injury or surgery to minimize atrophy and maintain strength and size, and then when appropriate, you can wean them off the BFRT and progress to a more traditional resistance training program.

Can you share with us some of your own personal experiences with BFRT, particularly how you might recommend practitioners get started implementing it in their practice and any specific tips or pearls for those wanting to start to offer this to their patients?

Our experience with BFRT has run the spectrum from professional soldiers and special forces operatives, to professional athletes in the NBA and NFL, as well as recreational athletes who are your next-door neighbors. 

Our early experience with BFRT was with some special forces soldiers who were limb salvage patients experiencing chronic weakness and atrophy. They had plateaued with traditional rehabilitation programs, then we applied the tourniquet for two weeks and every subject increased strength and power in their quadriceps. That was amazing, because several of those individuals were facing potential delayed amputations [from the inability] to get their strength back. I love caring for patients who are at their wits end willing to trust in you and try something new, and it works!

We did a story in the media with [NBA player] Dwight Howard, who had chronic osteoarthritis in his knee, and we did a story with [NFL player] Jadeveon Clowney who had some pretty significant cartilage procedures done. We also had the opportunity to care for [NFL quarterback] Alex Smith who was a limb salvage patient. Dwight changed the way he worked out and was able to get his quad size back and doubled the number of games he played with the [Houston] Rockets. Jadeveon was eight weeks nonweight bearing because of his cartilage procedures and benefitted from BFRT in the postoperative setting.

The postoperative patient can often be just the perfect blood flow restriction patient because as the therapist in rehab, you're just banging your head against the wall, watching all that muscle go away. But with BFRT, you can get a tourniquet on these individuals and really minimize the muscle atrophy. And so that's the most typical. And then with Alex [Smith], it was just neat to see this whole BFRT concept come back to the way we were applying it in the early days of the military. He was in a ring external fixator. The whole team was excited, and we got BFRT on him quickly and really maintained his quadriceps muscle the entire time that he was going through his salvage procedure. And he made it back as a starting quarterback in the NFL. I love that spectrum.

With respect to pearls for practitioners, I think it’s important to emphasize that doing BFRT is hard. I suggest practitioners try it out once just to experience what it feels like, [which is] an extremely hard workout. So, you need to make sure your patients understand that, but also understand that most patients get used to it and they attenuate to how hard it is, usually over the first few sessions. It’s important that the practitioner understands this and provides reassurance and coaches the patient through that. It's also [important] to remember that BFRT is not just for young athletes or military service members. We have ongoing trials that show really good promise in Parkinson's patients and diabetics. Some of these older patients are tolerating it well, [which also shows] promise. [These patients] probably have the most to gain from it.

Can you comment on potential safety concerns, contraindications, patient compliance issues and any other difficulties that challenge establishing a BFRT program?

While it’s exciting to see the clinical results from BFRT, some caution is warranted, especially given the risks associated with inappropriate application or technique of utilizing BFRT. Some temporary side effects such as short-term paresthesias, bruising and delayed-onset muscle soreness can all result after routine BFRT and should not be considered worrisome. However, serious adverse effects such as rhabdomyolysis, prolonged pain and syncopal events are not typical and can result from incorrect use, less-precise uncalibrated tourniquets or in individuals not healthy enough for an exercise program.  One of the most common concerns initially in BFRT use and research was the risk of blood clots. Fortunately, through our extensive investigation, multiple research studies into this topic and our partnership with the Institute of Surgical Research in San Antonio, no evidence has been found to support any increase risk of thromboembolic events with proper BFRT use. In fact, the opposite may even be true, with BFRT offering a protective effect against clotting events due to the stimulation of the fibrinolytic system.

What would you say is the most important takeaway with respect to BFRT?

I think we might have finally found the solution to one of the biggest problems we have postsurgery and/or postinjury when we're forced to use light loads in rehabilitation strengthening, which in the past really didn't do much for muscle strength or size. But if we simply add a tourniquet to the equation, we have changed that complete paradigm and we see significant changes in muscle strength and size, even at a low load.