Introduction
Rehabilitation using blood flow restriction (BFR) has garnished considerable attention in the field of sports medicine in recent years due to its potential widespread application and benefits. Exercise training with BFR, also known as Kaatsu, was first established in Japan and initially used as a performance tool rather than for rehabilitation. BFR uses an external pressure device to decrease the arterial blood inflow and restrict venous outflow during muscle loading (1). Generally, the compressive device is placed on the limb proximal to the targeted muscles and inflated to a specified fraction of the pressure required to stop blood flow within the limb (1,2). When performed with low-load (LL) muscle exercise, BFR has been shown to promote muscular hypertrophy and improvements in strength (1,2).
BFR's rapid growth in popularity and widespread use among physical therapy and sports medicine clinics warrants a review of the physiology of BFR, protocols for use, and precautions to consider.
Physiologic Effects and Response
The physiologic mechanism behind the increased muscular strength and hypertrophy seen with BFR exercise and rehabilitation is not completely understood at this time. The BFR procedure has traditionally been understood to cause partial restriction of arterial inflow and full restriction of venous outflow within contracting muscles during exercise (2). It is well understood that during exercise, blood flow increases. While application of BFR during exercise partially occludes arterial blood flow, the muscles of the affected limb are still receiving more blood than an unoccluded limb at rest (3). The resulting venous pooling results and hypoxia from a relative decrease in blood flow triggers a cascade of events with endocrine and muscle metabolic responses at local and systemic levels.
The hypoxic environment is thought to contribute to muscle growth by stimulating muscle protein synthesis, altering gene regulation of muscle satellite cells, increasing muscle fiber recruitment, and improving muscular endurance (4). These changes are at least partially facilitated by the acidic environment that develops secondary to hypoxia. Hypoxia and the accumulation of metabolites are hypothesized to promote muscle fiber recruitment and the release of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), which have been associated with muscle hypertrophy (5–7). This hormone hypothesis has not been universally accepted, as some research has found that exercise-induced increases in GH have limited impact on muscular hypertrophy (8).
The accumulation of metabolites leads to muscle hypertrophy partially through the production of reactive oxygen species (ROS), which induce alterations in cellular protein metabolism and increase satellite cell growth (6). One particular ROS, nitric oxide, has been linked to muscle hypertrophy via activation of the mammalian target of rapamycin (mTOR) pathway and has been found to increase with BFR (6).
This metabolic cascade also initiates the exercise pressor reflex, a series of cardiovascular changes triggered by the contraction of muscle that increases systemic vascular resistance and heart rate during exercise and activates the sympathetic nervous system (9). These peripheral responses are not different from that of high-load (HL) exercise alone. However, when muscles are loaded during BFR, the recruitment of muscle fibers occurs at lower exercise intensities (10).
Immediately following BFR resistance exercise, increased muscular blood flow, known as reactive hyperemia, is well documented (11,12). It had been theorized that reactive hyperemia contributed to adaptive muscle hypertrophy (11–13). Reactive hyperemia was thought to lead to improved nutrient delivery, which could explain the increase in muscle protein synthesis seen after BFR. Gundermann and colleagues (14) demonstrated that reactive hyperemia, increased protein synthesis, and activation of mTOR occur after LL BFR resistance exercise. However, in a comparison group performing LL exercise combined with a postexercise sodium nitroprusside infusion to simulate reactive hyperemia, there was no corresponding increase in protein synthesis or activation of the mTOR pathway. Similarly, Hill and colleagues (15) demonstrated that there was no significant difference in postexercise muscle thickness and blood flow between LL-BFR and LL exercise without BFR. Thus, the performance benefits from LL-BFR are likely not from reactive hyperemia and can more likely be attributed to hypoxia-associated metabolic stress.
Although metabolic stress is frequently cited as a primary mechanism in BFR-associated muscular hypertrophy, mechanical tension from muscle loading itself also plays a role.
Mechanical tension refers to the strain and stretch placed on muscle fibers with activation. Mechanical tension with BFR produces muscle hypertrophy through similar mechanisms as metabolic stress, including muscle fiber recruitment, ROS production, mechanotransduction, and muscle damage (6). In healthy muscle under normoxic conditions, initial muscle fiber recruitment at low loads is primarily slow-twitch fibers. However, at low exercise intensities with BFR, there also is recruitment of fast-twitch muscle fibers (16). This is likely due to an inadequate oxygen supply to fully support the aerobic metabolism of slow-twitch fibers, as well as metabolite accumulation. Stimulation of group III and IV afferents and inhibition of alpha-motor units may result in increased muscle fiber recruitment to compensate and maintain adequate muscle force (17). While this may explain the increased motor-unit recruitment and activation of fast-twitch muscle fibers described with LL-BFR exercise, it is important to note that LL-BFR may not recruit as many fast twitch fibers as traditional high-intensity exercise alone (16,18).
Loenneke et al. (10) suggest cellular swelling as another possible mechanism underlying muscle adaptations seen with BFR. The cellular swelling is postulated to be due to the creation of a pressure gradient from the accumulation of metabolites during BFR, which leads to a fluid shift from plasma to the intracellular space of muscle fibers (6). The cellular swelling from the fluid shift is believed to activate an intrinsic volume sensor, which in turn activates the mTOR and mitogen-activated protein kinase (MAPK) pathways. Activation of these pathways then leads to an increase in protein synthesis and decrease in proteolysis, thus leading to muscular hypertrophy. The exact mechanism of this cellular swelling and the amount of contribution of this pathway to muscle hypertrophy with BFR is still unknown and an area of ongoing research.
Rehabilitation and training with BFR also leads to change within the cardiovascular system. The externally applied compression against the arterial wall during resistance exercises stimulates increases in heart rate and systolic and diastolic blood pressures when compared with the same exercises performed without BFR (1). This response varies based on the specific application, exercise, and percentage of arterial occlusion. In the absence of other stimuli, BFR increases systemic vascular resistance, which simultaneously decreases cardiac output. These central cardiovascular responses are often less pronounced when compared with traditional HL resistance training (HL-RT) (10).
Muscle damage during LL-BFR has been proposed as a potential mechanism that induces hypertrophy (6). Studies looking for the presence of muscle damage have found conflicting results. A randomized trial evaluating muscle damage and recovery in HL-RT compared with LL-BFR suggested no clinically significant difference in changes to indirect markers for muscle damage and changes in muscle architecture between the two groups, although LL-BFR did result in increased muscle edema (19). Similar conclusions have been found in other studies looking at muscle hypertrophy with LL-BFR with no increase in markers of cellular damage throughout the training period (20). However, other small studies have demonstrated severe postexercise muscle pain and elevated serum creatine kinase after LL-BFR performed until muscle failure (21). Current available evidence suggests that LL-BFR, when performed submaximally (without exerting to muscle failure), results in little to no clinically significant muscle damage (22). This has been demonstrated when evaluating indicators of exercise-induced muscle damage, i.e., swelling of the exercised limb, decreased range of motion, decreased force production, and muscle soreness, as well as laboratory markers of muscle damage and cellular stress such as creatinine kinase and myoglobin levels (23). It is less likely for muscle damage to occur when BFR is performed as part of a carefully structured rehabilitation regimen. However, BFR can be associated with muscle damage in both animal models and humans, particularly when performed in conjunction with a high-intensity resistance training regimen or if applied when exercises are completed to muscle failure (24).
The physiologic changes induced by BFR with exercise and rehabilitation are complex. Multiple mechanisms have been identified to explain its role in promoting muscular hypertrophy and strength. These mechanisms include hypoxic events, mechanical stress, mechanical tension, as well as endocrine and cardiovascular changes. Recent research suggests that these mechanisms may be additive in nature (6). Further research will be helpful to clarify their relative contributions.
Protocol Choice
There are numerous variations of BFR application and techniques described in the literature. In 2019, Patterson et al. (1) published a position statement summarizing current guidance for training and treatment with BFR. Consideration of the individual patient, occlusion pressure, cuff width, and cuff size is paramount for proper BFR usage.
In a study surveying BFR practitioners, there was no standard method for determining the cuff pressure applied (25). A total of 43.4% of the 250 practitioners surveyed selected the pressure based on preassigned pressures from previous literature. Only 11.5% selected the pressure based on a percentage of the individual's limb occlusion pressure. The most dependable way to apply BFR is to use a percentage of the arterial occlusion pressure (AOP) as this corrects for individual differences among patients (1). This will reduce the risk of adverse outcomes, such as induction of complete ischemia.
The patient’s AOP is initially determined by measuring the cuff pressure at which blood flow is no longer detected (26). The cuff pressure required to reach AOP will vary based on the individual's physical characteristics. Underlying hypertension or abnormally large limb circumference can affect the pressure required to obtain the desired effect. Once the AOP for the specific limb is determined, a pressure below the AOP, typically 40% to 80% of the AOP, is selected for use during the BFR-assisted training (1). It has been demonstrated that under LL-BFR application, an AOP of 40% is effective and higher pressures may not provide additional improvements in muscle size and strength (13). Based on data showing a lack of additional improvement with higher pressures, Counts et al. (13) recommend application of BFR with 40% of AOP. Other guidelines have recommended a target AOP of 40% to 80% (1).
The interplay between cuff width and occlusion pressure is important as they directly affect one another. In the survey of BFR practitioners mentioned above, only 57.4% adjusted the width of the cuff based on the limb that it was applied to (25). Cuff width affects the amount of blood flow restriction that occurs (27). A wider cuff width will restrict a greater amount of blood flow in comparison to a smaller width cuff when both are inflated to the same pressure (28). Excess blood flow restriction can induce an exaggerated cardiovascular response and cause a greater increase in blood pressure and heart rate, which may not be desirable (29). Individual limb size, particularly limb circumference, also can influence the choice in cuff size. Thus, care should be taken in adjusting the cuff width and cuff pressure to match the needs of the individual patient and goals of BFR intervention. Special attention to this should be made in patients with underlying cardiovascular disease, as they may be more sensitive to corresponding changes in heart rate and blood pressure.
Cuff material also should be considered when using BFR. The most common cuff materials are elastic and nylon. It is unclear whether differences between cuffs are attributable to cuff width or cuff material variability (27). Loenneke et al. (12) found no difference in AOP between 5-cm cuffs made of nylon and elastic. However, there are few studies that examine the variability of cuff material in isolation. It appears that differences in cuff material can be compensated for by adjusting the applied pressure relative to the total AOP for a specific cuff (1).
Selection of Training Load with BFR
Increasing muscle strength and size with traditional resistance training requires loading muscle groups to approximately 70% of their one repetition maximum (1-RM) (30). However, depending on a patient's physical limitations, injury history, or current pain threshold, not all patients are able to safely tolerate this level of load. It is in patients with these limitations that BFR may have a significant impact.
A landmark study by Takarada et al. (5) in 2000 concluded that moderate vascular occlusion during resistance exercise assists with muscular hypertrophy, even at low levels of resistance activity. The level of vascular occlusion that led to the greatest levels of hypertrophy was a mean occlusion pressure midway between patient's systolic and diastolic blood pressure. Marked hypertrophy occurred with only 40% to 50% of participants' 1-RM. This is below the previously mentioned threshold of 70% to 80% 1-RM level. The authors postulated that this may be secondary to vascular occlusion promoting a hypoxic environment as discussed earlier in this article.
Multiple studies have analyzed what level of BFR-associated resistance training is ideal or necessary for muscle hypertrophy, strength improvement, and improved function. The LL-BFR resistance training (classified as 30% 1-RM exercises, often with an increased number of repetitions) has been compared with HL traditional resistance training in patients with lower limb injuries. After just 3 wk of dedicated treatment with LL-BFR, patients showed improvements in muscle hypertrophy, strength, and functional capacity when compared with controls using a standard 70% 1-RM load (31). This finding has been reproduced by other authors (32,33). A recent meta-analysis comparing rehabilitative training with LL-BFR to standard HL training demonstrated a greater increase in muscular strength with LL-BFR when compared with repetition matched LL training alone, but less strength gained than with HL training (7). Thus, LL-BFR is effective in promoting increases in muscular strength and hypertrophy which can help patients with limitations that preclude the performance of HL-RT.
Low-load BFR also may increase muscular hypertrophy and strength at sites distant from the location of actual blood flow occlusion. In a recent study by Bowman et al. (4), participants performed LL-RT with BFR for 6 wk and demonstrated increases in muscle strength and limb circumference. However, these increases were noted proximal to cuff placement, distal to the cuff, and in the contralateral limb. The exact mechanism of this change has not been determined. It is thought that BFR may have a systemic, crossover effect to contralateral limbs and help with overall strength, balance, and function. Although no definitive mechanism is present to explain this, it may be due to the increased levels of GH and IGF-1 described earlier.
The other key variable that impacts BFR's efficacy is the level of pressure applied to partially occlude blood flow and promote moderate hypoxemia. The pressure must be low enough to be safe for the patient and yet sufficient for LL BFR to be effective. As discussed above, a range of pressures from 40% to 60% AOP have been recommended, and higher pressure gradients do not seem to improve outcomes while performing LL-BFR (4,13,34).
Alternative Training and Rehabilitation Techniques Using BFR
Passive BFR (P-BFR) refers to the application of compressive cuffs to the affected extremity without undertaking exercise. This may be helpful for patients who cannot physically perform exercise, such as bed-rest patients, intensive care unit (ICU) patients, and postoperative patients where immobilization is required. Although research is limited, P-BFR in ICU patients was associated with decreased rates of muscular atrophy (35). P-BFR also has been studied in orthopedic patients and was associated with decreased rates of disuse atrophy after anterior cruciate ligament reconstruction and in those immobilized with casting (5,36). While further research and studies are needed, P-BFR may be a useful tool to help prevent atrophy and deconditioning in select patients.
Aerobic only BFR, usually performed with treadmill walking or low-intensity cycling, has shown promising results. Studies that have tested this method have used BFR (often applied to both thighs while exercising) with aerobic activity at low intensities, such as at 45% heart rate reserve or 40% V˙O2max, and compared them to controls performing exercise of similar intensity and duration without BFR (37). However, the cuff pressure and width protocol has been variable (37,38). The application of BFR with aerobic activity has been associated with not only increased muscle hypertrophy and strength, but also increased aerobic capacity as measured by V˙O2max by 6.4% (37). This improvement in strength and aerobic capacity with BFR training also has been linked to improved performance of functional activities of daily living (39). With further supporting research, aerobic BFR could be considered for deconditioned patients and potentially in elite athletes as well (1).
In addition to its use in musculoskeletal rehabilitation, LL-BFR has been evaluated for use in older individuals for increasing muscle mass and strength (40). A meta-analysis examined the use of BFR for reducing sarcopenia, the decrease of both muscle mass and strength, in the elderly population. The ultimate goal of this treatment was to reduce negative outcomes, such as falls and mortality (41). BFR with LL-RT improved muscular adaptations when compared with the same exercises without blood flow restriction. As with prior meta-analyses, BFR with LL-RT had lower strength increases when compared with HL-RT, again highlighting its primary value in individuals who cannot tolerate heavy loads but still require resistance training.
Screening and Possible Contraindications to BFR
There is ample evidence to support the utilization of BFR in a variety of clinical scenarios. However, like most clinical treatments, BFR brings with it a small amount of risk. It is important to be aware of the physiologic responses induced by BFR use and how they may affect patient safety.
As previously discussed, the use of BFR can cause significant increases in systemic vascular resistance with a subsequent decrease in cardiac output, although it is often less severe than what is seen with traditional HL-RT (10). Because of this, LL-BFR training may be a safe alternative to HL exercise in patients with elevated cardiovascular risk (42). However, not all authors have agreed with this conclusion. Spranger and colleagues (9) assert that individuals with hypertension, heart failure, and peripheral arterial disease share the same potential cardiovascular risks during exercise as they do during BFR. They suggest that although BFR is often performed during LL exercise, muscle perfusion is mechanically attenuated and thus the muscular mechanoreflex and metaboreflex activate the sympathetic nervous system causing similar effects as higher-load exercise. Therefore, they advise caution with the use of BFR in patients with underlying cardiovascular disease. It is advisable to thoroughly assess a patient's cardiovascular risk factors before initiating BFR interventions. Prior to starting any medical intervention, obtaining a thorough medical history and screen is recommended (26,43). Table 1 outlines some possible contraindications for BFR.
Table 1 -
Possible BFR contraindications [Bond 2019 (
26), de Quieros 2021 (
43)].
| • Active cancer/tumors
a
|
• Open fractures
a
|
| • Arterial calcification
a
|
• Peripheral vascular compromise
a
|
| • Cardiovascular disease |
• Poor circulatory system |
| • Crush injuries
a
|
• Renal compromise
a
|
| • Extremity infection |
• Respiratory disease |
| • Family history of clotting disorders |
• Severe uncontrolled hypertension
a
|
| • Hemophilia |
• Sickle cell anemia trait
a
|
| • History of thrombosis |
• Smoker |
| • Lymphectomies
a
|
• Uncontrolled diabetes mellitus |
| • Medications that increase clotting risk |
• VTE |
| • Obesity
a
|
|
aAlso may be associated with Risk Factors for VTE.
This list (while listed in alphabetical order) is not comprehensive, and some may be precautions based on clinical judgment.
Early research suggested that complete vascular occlusion may increase the risk of thrombus formation and may cause microvascular occlusion even after reperfusion has occurred (10). Subsequent studies assessing D-dimer and thrombin-antithrombin III complex instead demonstrated that coagulation activity does not appear to increase after LL-BFR exercise (10,44,45). Tissue plasminogen activator, an indicator of fibrinolytic potential, also appears to be increased with BFR, a response that also is observed with traditional resistance training. It is unclear if this fibrinolytic activity is a result of the exercise, the BFR stimulus, or both in combination. Consequently, BFR does not appear to increase the coagulation factors associated with venous thromboembolism (VTE) risk and in fact may decrease VTE risk (10,45). The rate of incidence for a VTE event during application of Kaatsu was 0.06% in Japan, a country that heavily uses BFR (45). This rate was lower compared to the rate of VTE in their general population. Patients in the immediate postoperative period have an inherently elevated VTE risk. However, BFR carries little risk of directly causing a VTE (26). Other medical conditions that increase VTE risk include history of oral contraceptive use, pregnancy, postpartum, genetic blood clotting disorders, family history of VTE, and individuals with spinal cord injury or multiple lower-extremity fractures sites (1,10,26). Age and obesity also contribute to an elevated risk of VTE (1,10,26). Table 2 lists some of the risk factors associated with VTE that could be considered when contemplating the use of BFR (1,26). No studies to date have demonstrated evidence of significant increases in the rate of VTE associated with the use of resistance exercise with BFR.
Table 2 -
Risk factors for VTE [Patterson 2019 (
1), Bond 2019 (
26)].
| • Age ≥40 yr |
• Lymphectomies |
| • Arterial calcification |
• Major general/orthopedic surgery |
| • Atherosclerotic vessels |
• Multiple traumas |
| • Blood clotting disorders |
• Nonhealing soft tissue injuries |
| • Cancer/tumor |
• Obesity |
| • Central catheter |
• Open fractures |
| • Crush injuries |
• Oral contraceptives |
| • Diabetes |
• Peripheral vascular disease |
| • Dialysis |
• Physical inactivity |
| • Fractures of pelvis, hip, or long bones |
• Pregnancy (perinatal, postnatal) |
| • Grafts (skin, vascular) |
• Prior history or family history of VTE |
| • Hypertension |
• Renal compromise |
| • Immobility |
• Sickle cell anemia |
| • Implanted medical device |
• Spinal cord injury |
| • Increased intracranial pressure |
• Stroke |
| • Infection (general or local) |
• Varicose veins |
This list (while listed in alphabetical order) is not comprehensive, and some may be precautions based on clinical judgment.
Oxidative stress refers to an increase in free radicals and exhaustion of antioxidants, which, if sustained, can lead to inflammation and impaired function of lipids, proteins, and DNA (46). Oxidative stress occurs transiently with acute exercise. Goldfarb et al. (47) showed that low-intensity BFR (30% 1-RM) did not elevate oxidative stress markers (blood glutathione, protein carbonyls) while moderate resistance exercise (70% 1-RM) and BFR without exercise both demonstrated elevations in these oxidative stress markers. This suggests that oxidative stress does not increase in low-intensity BFR training. However, more research is warranted to make a definitive conclusion on this topic.
Exercise has the potential to cause muscle damage, particularly when the acute load exceeds the load that an individual is accustomed to (25). The amount of muscle damage is considered to be proportional to the relative load. Rhabdomyolysis, or excessive skeletal muscle breakdown, also can rarely occur with excessive volume or intensity of exercise. Muscle damage can be measured via subjective muscle soreness scores or by objective measures such as maximal volitional strength or serum creatine kinase and myoglobin levels. Nielsen and colleagues (48) reported that BFR does not demonstrate myocellular damage in active individuals as measured by creatinine kinase and inflammatory markers post-BFR exercise. LL-BFR appears to cause significantly less muscle damage when compared to eccentric or concentric higher-load exercises (1,10). There has been recent debate in the literature regarding the risk of rhabdomyolysis associated with BFR. Thompson et al. (49) argued that rhabdomyolysis may occur as a side effect of BFR, but at a very low rate of incidence of 0.07% to 0.2% in published studies and 0.008% in Japan where BFR is commonly done. Wernbom et al. (21) contested this, citing a number of smaller studies demonstrating imaging, serologic, and strength evidence of muscle damage. Both authors' arguments have their merits, but approach the issue from different perspectives. Many of the studies used to calculate Thompson's incidence range used LL-BFR without working to failure and more closely reflect the use of LL-BFR in rehabilitation.
Wernbom's referenced studies almost exclusively used protocols that required exertion to muscle failure and thus may reflect the risks of protocols that lead to muscle energy depletion, rather than risk intrinsic to the use of BFR itself (21).
Transient numbness has been described as a potential side effect of BFR treatment (10). However, Clark et al. (44) demonstrated that nerve conduction velocity was unchanged after 4 weeks of LL BFR training. This is not surprising given the transient nature of reported numbness following BFR training sessions. Overall, BFR has been proven to be a consistently safe tool and it is important to tailor the specific treatment protocol to each patient.
Conclusion
Blood flow restriction therapy has received significant attention in recent years. Although its popularity is widespread, an understanding of the underlying physiology of BFR and its clinical considerations is important for health care professionals to understand. Evidence to date suggests that BFR is generally safe to use and particularly useful for promoting muscle hypertrophy, increasing muscle strength, and increasing function in patients undergoing rehabilitation.
The authors declare no conflict of interest and do not have any financial disclosures. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of Fort Belvoir Community Hospital, the Defense Health Agency, Department of Defense, or U.S. Government.
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