Exercise with blood flow restriction: an effective alternative for the non‐pharmaceutical treatment for muscle wasting

Abstract

Significant muscle wasting is generally experienced by ill and bed rest patients and older people. Muscle wasting leads to significant decrements in muscle strength, cardiorespiratory, and functional capacity, which increase mortality rates. As a consequence, different interventions have been tested to minimize muscle wasting. In this regard, blood flow restriction (BFR) has been used as a novel therapeutic approach to mitigate the burden associated with muscle waste conditions. Evidence has shown that BFR per se can counteract muscle wasting during immobilization or bed rest. Moreover, BFR has also been applied while performing low intensity resistance and endurance exercises and produced increases in muscle strength and mass. Endurance training with BFR has also been proved to increase cardiorespiratory fitness. Thus, frail patients can benefit from exercising with BFR due to the lower cardiovascular and join stress compared with traditional high intensity exercises. Therefore, low intensity resistance and endurance training combined with BFR may be considered as a novel and attractive intervention to counteract muscle wasting and to decrease the burden associated with this condition.

Rationale to the application of partial blood flow restriction as a treatment against muscle wasting

Skeletal muscle wasting, or myopenia, occurs in specific conditions such as muscle fibre denervation, reduced mechanical loading (i.e. unloading), and prolonged fasting. In general, muscle wasting is triggered by limiting diseases (e.g. renal failure), syndromes (e.g. cancer cachexia), or ageing (e.g. sarcopenia). Significant muscle wasting is associated with decrements in muscle strength, cardiorespiratory capacity (<30 mL·min⁻¹·kg⁻¹), functional capacity, and quality of life, greatly increasing mortality rates. Additionally, muscle wasting can occur rapidly and irreversibly in some conditions. For instance, gastric cancer patients exhibit muscle wasting of ~10% within 7 days after surgery, similar to the values observed after 5 days of bed rest in elderly. Thus, strategies able to reduce muscle wasting and/or increase muscle mass are needed.

Different interventions (e.g. nutritional, pharmacologic, and physical exercise training) have been tested to minimize muscle wasting. Thus far, moderate to high intensity resistance training (RT) [i.e. ~70–85% of one repetition maximum (1‐RM)] has been shown to effectively counteract muscle wasting increasing muscle strength and cross sectional area (i.e. muscle hypertrophy) in many patients. However, moderate to high intensity RT may not be suitable for physically frail patients due to the significant cardiorespiratory stress or after joint surgery due to the high mechanical load. In this regard, alternative therapeutic approaches that may induce lower cardiovascular stress and joint load, while counteracting muscle wasting, in physically frail patients should be considered.

Blood flow restriction (BFR) has been tested as a new therapeutic approach to counteract muscle wasting. It uses a pneumatic pressure cuff wrapped around the proximal region of the target limb, which is maintained inflated throughout the session to reduce the blood flow to the limb. Evidence has demonstrated that 14 days of BFR are more effective than isometric exercise to prevent muscle waste and weakness induced by immobilization and unloading. Moreover, BFR has been applied during exercise training to further minimize muscle wasting.

Two of the most common training methods are the low intensity RT and endurance training (ET) associated with BFR. Several randomized controlled trials and meta‐analyses have shown that RT with BFR (RT‐BFR) produces similar muscle hypertrophy response to high intensity RT, in different populations. The similar muscle hypertrophy response between low intensity RT‐BFR and high intensity RT may be due to the fact that both training strategies activate similar physiological/molecular mechanisms. For instance, there is evidence that these training strategies produce similar changes in circulating anabolic hormones (e.g. growth hormone and testosterone), activation of intracellular signalling pathways that control muscle protein synthesis (e.g. Akt–mTOR pathway), satellite cell activity, myocyte transcriptome, and motor unit recruitment pattern. Besides the similarities in the activation of physiological/molecular mechanisms, in a recent meta‐analysis, our group showed that both high intensity RT and RT‐BFR increase muscle strength, but to a lesser extent in the former (~7%), regardless of the population (i.e. young and older individuals). Similarly, we showed that 24 training sessions of low intensity (20% of 1‐RM) RT‐BFR increased muscle strength (~17%) and hypertrophy (~7%) to a similar extent to high intensity (80% of 1‐RM) RT (54% and 8%, respectively) in elderly. We also investigated the effects of low intensity RT‐BFR in a patient diagnosed with inclusion body myositis (idiopathic inflammatory myopathy that leads to remarkable muscle atrophy), to whom high intensity RT failed to produce the aforementioned muscle adaptations. After 12 weeks of low intensity RT‐BFR, we found significant increases in muscle strength (19%) and hypertrophy (5%). Furthermore, the functional capacity, measured by the timed up‐and‐go test, improved from 16 to 10 s (i.e. 37% faster). This training‐induced adaptations likely influenced the important increase (~600%) in the quality of life perception of the patient. A recent study showed that a 74‐year‐old male diagnosed with inclusion body myositis also increased muscle strength by 68% and improved the maximal horizontal gait speed by 19%, after performing 12 weeks of very low intensity RT‐BFR. Although RT‐BFR can counteract muscle wasting and improve functionality, it has small effects on cardiorespiratory capacity, which is critical for maintaining functionality.

Moderate to high intensity ET promotes significant increases in cardiorespiratory capacity, with no or small improvements in muscle strength and hypertrophy. However, when ET is performed with BFR (ET‐BFR), there is a significant increase in aerobic power (i.e. maximum oxygen consumption $\dot{\mathrm{V}}$O₂max), as well as increases in muscle strength and hypertrophy. In young subjects (~23 years), Abe et al. reported that 24 ET‐BFR sessions (15 min cycling at 40% of $\dot{\mathrm{V}}$O₂max) increased muscle strength by 7.7%, muscle hypertrophy by 5.1%, and $\dot{\mathrm{V}}$O₂max by 6.4%, suggesting BFR caused the metabolic disruption required to enhance exercise‐induced adaptations. Additionally, we compared the effects of three training interventions—low intensity ET‐BFR and high intensity RT and ET—on muscle strength and hypertrophy, and aerobic power ( $\dot{\mathrm{V}}$O₂max). Muscle hypertrophy response was similar between ET‐BFR (10.7%) and high intensity RT (12.5%), while high intensity ET increase muscle hypertrophy only by 3.8%, adding support to the efficacy of ET‐BFR to produce RT‐likely muscle adaptions. The ET‐BFR also increased muscle strength (9%) and $\dot{\mathrm{V}}$O₂max (11%), although to a lower magnitude compared with RT (35%) and ET (21%), respectively. These results suggest that ET‐BFR is a potential alternative training protocol to improve muscle strength, mass, and cardiorespiratory capacity, particularly for older adults or clinical cohorts not able to exercise with high training loads. Regarding fragile older individuals, it has been shown that low intensity (67 m•min⁻¹ for 20 min) treadmill walking with BFR, performed 5 days per week for 6 weeks, increased isometric (11%) and isokinetic (7%) knee extension torque, and isokinetic (16%) knee flexion torque. Moreover, the low intensity ET‐BFR hypertrophied thigh and shank muscles by 5.8% and 5.1%, respectively. In functional tests, elderly men and women improved their performance in the 30 s sit to stand test, 6‐minute walk test, timed up‐and‐go test, and in a modified Queen's College step test, after 6 weeks of walking with BFR (10 min walking at 4 km·h⁻¹). Importantly, there are few studies comparing ET‐BFR effects between men and women; however, current evidence does not suggest any differences in training‐induced adaptations between genders. Furthermore, no study has investigated the efficacy of ET‐BFR in patients with muscle wasting conditions.

Despite the lack of studies investigating the effects of ET‐BFR in muscle wasting conditions, it is reasonable to suggest that ET‐BFR can counteract muscle wasting and declines in cardiorespiratory capacity in patients with non‐refractory muscle wasting conditions. Accordingly, Clarkson et al. reported that the effects of ET‐BFR will be tested in end stage kidney disease patients, who experience significant muscle wasting. Authors hypothesized that the group performing ET‐BFR will present higher gains in muscle strength and hypertrophy, and in functional capacity, compared with a group that will perform the same exercise protocol but with no BFR. In confirming this hypothesis, more studies will be required to establish safe and efficient ET‐BRT training protocols to reduce muscle waste.

Is exercise with blood flow restriction safe?

The question of safety is always raised due to the partial BFR produced by the cuff pressure during a BFR exercise session. However, the BFR approach has been applied to >12 000 people in Japan across different physical conditions, such as cerebrovascular, orthopaedic, cardiac, respiratory, and neuromuscular diseases, as well as obesity, diabetes, and hypertension, with no significant side effects reported on rheological response. From 300 000 training sessions, only 0.055% of practitioners developed venous thrombus, 0.008% developed pulmonary embolism, and 0.008% of the cohort presented rhabdomyolysis. Additionally, the same authors showed that markers of intravascular clot formation, D‐dimer, and fibrin degradation product and markers of coagulation activity, prothrombin time, and thrombin time were not significantly increased after low intensity BFR exercise. Moreover, Madarame et al. demonstrated in 10 patients with ischaemic heart disease that four sets of low intensity RT‐BFR did not increase fibrinogen/fibrin degradation products and the high‐sensitive C‐reactive protein, suggesting that RT‐BFR does not affect haemostatic and inflammatory responses.

Regarding the haemodynamic response, we recently showed that the systolic blood pressure, diastolic blood pressure, and heart rate were lower after RT‐BFR than after high and low intensity RT in young men. However, young individuals have distinct haemodynamic responses to exercise compared with elderly. There is evidence that a RT‐BFR exercise session induces higher systolic and diastolic blood pressure increments and slower parasympathetic recovery compared with high intensity RT in elderly. Nonetheless, a recent meta‐analysis showed that blood pressure responses to RT‐BFR are similar to those observed during high intensity RT, regardless of the ageing group. Taken together, there is evidence suggesting that changes in blood pressure during RT‐BFR are similar to traditional high intensity RT in different populations. Carotid compliance also does not seem to be affected by RT‐BFR. Yasuda et al. showed that 12 weeks of RT‐BFR did not increase arterial stiffness or humeral coagulation factors in elderly. Similarly, Ozaki et al. showed that low intensity RT‐BFR did not affect carotid compliance, but 6 weeks of high intensity RT decreased the carotid arterial compliance in young participants, suggesting that RT but not RT‐BFR can increase systolic blood pressure over time. Despite these promising results, there is a necessity of long‐term trials to address this issue.

Regarding ET‐BFR and the cardiovascular risks, Ferreira et al. showed lower heart rate variability and haemodynamic responses after a low intensity endurance exercise with BFR (40% of VO₂max) than after a high intensity endurance exercise without BFR (70% VO₂max), in elderly. Accordingly, Barili et al.⁶³ showed that the haemodynamic response of hypertensive older individuals, as assessed by heart rate and systolic and diastolic blood pressures, was similar between low intensity ET‐BFR and moderate intensity ET, supporting the safety of the former.

Despite the alleged safety of BFR training in young and elderly individuals, long‐term studies involving patients affected by diseases like cancer, heart failure, diabetes, and pulmonary diseases are needed to ensure that exercise with BFR is safe for each specific condition/disease. Furthermore, as muscle wasting may occur both in skeletal and cardiac muscles, additional studies are also required to determine whether BFR training guidelines may be applicable to individuals experiencing different degrees of muscle wasting or whether a more individualized training parameterization is required.

Training guidelines

The characteristics of the RT‐BFR and ET‐BFR seem to affect training‐induced adaptations and, as a consequence, the ability to counteract muscle wasting. Usually, training intensity (i.e. percentage of the maximal load or capacity), occlusion pressure, cuff width, number of sets and repetitions per training session, and exercise duration are manipulated during BFR training protocols. BFR training is usually prescribed at low intensity, between 20% and 40% of the 1‐RM load for RT‐BFR and ~40% of VO₂max for ET‐BFR. Regarding the occlusion pressure, we showed that high occlusion pressure (80% of the occlusion pressure) produces greater muscle hypertrophy than moderate occlusion pressure (40% of the occlusion pressure) when exercising at low intensities (20% of 1‐RM). Conversely, occlusion pressure does not seem to play a role when exercise intensity at ~40% 1‐RM. There is a lack of studies investigating whether different occlusion pressures could interfere on muscle and cardiorespiratory adaptations when undergoing ET‐BFR. Our study suggested that 80% of individual's arterial blood pressure is effective to increase muscle strength, hypertrophy, and VO₂max after a ET‐BFR protocol.

Although cuff width may change the relative pressure, our meta‐analysis showed that using wide or narrow cuffs in a RT‐BFR protocol produces similar muscle hypertrophy compared with high RT.

Regarding the number of sets and repetitions in a typical RT‐BFR session, the standard protocol is performing four sets (1st set—30 repetitions, 2nd set—15 repetitions, 3rd set—15 repetitions, and 4th set—15 repetitions) with 30–60 s of interval between sets. The cuff should be kept inflated throughout the training session. ET‐BFR usually encompasses cycling per 15 to 30 min to increase VO₂max or walking (i.e. two to five sets of 2–3 min at 4–6 km•h⁻¹).

Future directions

There is mounting evidence that performing resistance and ET with BFR can increase muscle hypertrophy to a similar extent than high intensity RT (usual exercise prescription). In some cases, physically frail patients are not able to perform high intensity RT, and thus, low intensity resistance or ET with partial BFR could be considered as an important strategy to counteract muscle wasting in ageing and disease conditions. However, long‐term studies are needed to ensure the safety of BFR training in patients with chronic diseases diagnosed with muscle wasting (e.g. cancer patients).

Acknowledgements

The authors certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia and Muscle. The authors would like to express gratitude for the São Paulo Research Foundation (FAPESP) grants #2016/09759‐8 and #2015/19756‐3 and CNPq #303085/2015.

Conflict of interest

The authors declare no conflicts of interest.