Resistance exercise with low loads combined with blood flow restriction (BFR) has been shown to induce increases in muscle size comparable with those seen with conventional heavy resistance exercise in untrained individuals.1,2 The low loads used, typically between 20% and 50% of 1 repetition maximum (1RM), make blood flow–restricted resistance exercise (BFRRE) an attractive training modality for individuals who may not tolerate high musculoskeletal forces (eg, clinical patient groups and frail older adults).1,3
Ever since the first training studies on BFRRE appeared in the years around 2000, there have been concerns about the safety of this mode of exercise, especially with regard to the potential for muscle damage.1,3 These concerns were seemingly put to rest by Loenneke et al4 in their 2014 review, in which they categorically concluded that “the available literature suggests that minimal to no muscle damage is occurring with this type of exercise. This conclusion is drawn from the following observations: (1) no prolonged decrements in muscle function; (2) no prolonged muscle swelling; (3) muscle soreness ratings similar to a submaximal low load control; and (4) no elevation in blood biomarkers of muscle damage.”
Similarly, in a recent editorial in this journal, Thompson et al5 concluded “we would thus suggest that other physiological factors may play a more critical role in the risk of developing exertional rhabdomyolysis, especially given evidence that BFR training does not result in greater amounts of muscle membrane disruption when used with 20% 1RM loads or during walking exercise (plasma creatine phosphokinase levels, 200 IU/L). We believe that it is the underlying factor and not the exercise itself, which can acutely increase the risk of exertional rhabdomyolysis during BFR training.”
We disagree with the conclusions in both the review of Loenneke et al4 and the editorial by Thompson et al.5 For example, Loenneke et al4 did not include the case study of Iversen and Røstad6 in their review for unknown reasons. There are now no fewer than 4 case studies on rhabdomyolysis after BFRRE,6–9 all reporting peak creatine kinase (CK) values in excess of 10 000 U/L, a level accepted to be diagnostic of rhabdomyolysis.10 Furthermore, we have in 2 studies11,12 reported marked elevations of CK after acute and short-term BFRRE at 20% to 30% of 1RM. In the paper of Sieljacks et al,11 2 of the 9 subjects in the BFR group displayed peak CK values of >15 000 U/L 96 hours after a first-time bout of BFRRE at 30% of 1RM. In our recent training study,12 one of our subjects withdrew due to severe pain with a CK value of 4200 U/L on the fourth training day, and 3 of the subjects who completed the study had CK values of 1800 to 2600 U/L after 3 to 4 days of training. A CK value of >2000 U/L is commonly used to diagnose myopathy.10 Moreover, Yasuda et al13 reported mean peak CK values of 13 415 ± 7267 U/L at 96 hours after an acute bout of BFRRE at 20% of 1RM in the 3 subjects from which blood samples were drawn.
With regard to other markers of muscle damage, we and others have reported prolonged torque decrements,11,14,15 swelling,14,16 and increases in T2 relaxation time on MRI muscle images,11 as well as prolonged glycogen depletion17 and signs of stress and damage at the muscle fiber level15,17 after acute bouts of strenuous BFRRE. Delayed-onset muscle soreness (DOMS) was also reported in several studies and was the most common side effect in a questionnaire-based survey on BFR exercise.18
Thompson et al5 further wrote, “it is logical to assume that repeated bouts of BFR training, if performed at the optimal dosage (volume and intensity) with appropriate recovery among exercise bouts, will generate a protective effect against ischemic exercise.” In fact, we have demonstrated a protective effect, ie, a “repeated-bout effect,” both after acute and short-term BFRRE.11,12,16 We note that many of the studies discussed above were available at the time of the editorial of Thompson et al.5
The sequence of events leading to muscle damage and the release of CK and other muscle proteins to the circulation after excessive BFRRE remains to be clarified. Two of the primary proposed mechanisms of muscle damage and rhabdomyolysis are mechanical disruptions and ATP depletion, both of which can cause increases in intracellular calcium (Ca2+), which if unregulated in turn can lead to disintegration and necrosis of the muscle fiber.19–21 In a study on fast-twitch rat muscle, the combination of anoxia (complete hypoxia) and very low-force electrical stimulation (∼6%-8% of maximal isometric force) induced the release of lactate dehydrogenase (LDH), which correlated with increased muscle contents of Ca2+ and Na+, and which coincided with low cellular ATP levels.21 The study of Fredsted et al21 provided an important proof-of-principle that muscle membrane damage can occur even with very low-force contractions during conditions of hypoxia and ATP depletion.
Membrane disruptions resulting purely from high forces seem less likely during BFRRE due to the low loads,22 but ATP is the energy substrate for Na+/K+-ATPase and Ca2+-ATPases, and if ATP drops to low levels, this will eventually lead to increased Ca2+ and Na+ in the cytosol of the muscle fiber.19–21 We therefore propose an important role for low energy levels in the etiology of muscle damage resulting from BFRRE. A role for energy depletion in BFRRE-induced muscle damage is consistent with the observations that training to failure induces greater DOMS than nonfailure protocols,22 and that BFRRE to failure at 20% and 40% of 1RM induced similar degrees of DOMS,23 although it is presently unclear whether DOMS is related to other markers of muscle stress and damage after acute BFRRE. However, interactions between ischemia, exercise, and swelling seem possible, as all these stimuli may activate membrane-damaging pathways (discussed in the study by Wernbom et al15 and Sieljacks et al11).
We conclude that there is sufficient evidence from case studies and controlled experiments to state that very strenuous BFRRE, much like eccentric exercise, can induce several signs and symptoms of muscle damage and in some cases rhabdomyolysis in healthy but unaccustomed subjects. We maintain that BFRRE should be introduced carefully and gradually3,15 to allow for the repeated-bout effect to take place and avoid risking unnecessary muscle damage and stress.
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