Effects of Individualized Ischemic Preconditioning on Protection Against Eccentric Exercise–Induced Muscle Damage: A Randomized Controlled Trial

Abstract

Background:

The effects of ischemic preconditioning (IPC) versus a deceptive sham protocol on indirect markers of exercise-induced muscle damage (EIMD) after the application of individualized occlusion pressure were examined. The goal of using a sham protocol is to control for the potential effect of placebo.

Hypothesis:

IPC would surpass the sham protocol in protecting against EIMD.

Study Design:

A randomized, double-blinded, clinical trial.

Level of Evidence:

Level 1.

Methods:

Thirty healthy young men were randomly assigned to an eccentric exercise for the knee extensor muscles preceded by IPC (4 × 5 minutes of individualized total occlusion pressure) or sham protocol (4 × 5 minutes using 20 mm Hg). Maximal voluntary isometric torque (MVIT), rate of torque development, muscle soreness, pressure pain threshold, knee range of motion, thigh girth, and creatine kinase (CK) activity were assessed before IPC or sham protocol and up to 72 hours after the eccentric EIMD. Affective valence and perceived exertion were also evaluated.

Results:

MVIT decreased 17.1% in the IPC and 18.1% in the sham groups, with no differences between groups. Differences from baseline were observed in the sham group for muscle soreness at 48 hours (P < 0.001) and 72 hours (P = 0.02), and for CK activity at 72 hours (P = 0.04). Muscle soreness was reduced in the IPC group at 48 hours compared with the sham group (∆ = 15.8 mm; P = 0.008) but without achieving the minimal clinically important difference. IPC induced a smaller perceived exertion than the sham protocol (∆ = 1.1 a.u.; P = 0.02). The remaining outcomes were not statistically different in both groups.

Conclusion:

IPC does not surpass the sham protocol to protect against mild EIMD of the knee extensors muscles.

Clinical Relevance:

Although IPC is a noninvasive, low-cost, and easy-to-administer intervention, the IPC effects can, in part, be explained by the placebo effect. In addition, individualized IPC promotes attenuation in perceived exertion during eccentric exercise.

Unaccustomed exercise can result in exercise-induced muscle damage (EIMD), particularly as a consequence of the eccentric phase of the muscle contraction. It is characterized by the loss of strength and range of motion (ROM), as well as delayed-onset muscle soreness (DOMS), swelling, and increased serum creatine kinase (CK) activity.^9,30 Several techniques are commonly employed to accelerate recovery after exercise, minimize impairments in muscle performance, and improve the adherence to exercise programs that induce muscle damage. ¹⁴

Alternatively, some prophylactic interventions have been used before exercise to mitigate muscle damage.^10,41 A novel method proposed to protect against EIMD is ischemic preconditioning (IPC), ²⁰ which consists of periods of total vascular occlusion followed by reperfusion.^37,38 IPC has acute (lasting up to 4 hours) and late (12-72 hours) repercussions.^24,38 It is widely known that IPC acutely may act as an ergogenic aid after an ischemic stimulus. However, its late effects on skeletal muscle are still little studied.^7,37

Elevated intramuscular acidosis and increases in reactive oxygen species and immune activity are common responses to IPC and damaging exercise. ²⁰ The late effects of IPC may contribute to the protection against EIMD through improvements in metabolic efficiency secondary to the increase in mitochondrial electron flow and blood flow, and attenuation of ATP (adenosine triphosphate) depletion due to the elevated adenosine levels after ischemia.^3,24,36 In fact, a recent study ¹⁹ observed that IPC applied immediately before an eccentric exercise for the elbow flexor muscles was able to blunt muscle damage responses. However, it is worth noting that, owing to some methodological issues, the real effectiveness of using IPC to mitigate muscle damage is still unclear. First, the control group did not undergo any interventions before the muscle damage protocol, ¹⁹ so it is difficult to conclude whether the IPC effects are superior to placebo (sham protocol). This is a frequent question, and the acute ergogenic effects of IPC might not be superior to the sham protocol.^28,36 Second, few studies reviewed individualization of occlusion pressure. Although the application of occlusion pressure has been recommended to completely occlude blood flow, ³⁷ arbitrary pressures may induce different stimuli between subjects due to individual factors, such as limb circumference, body composition, sex, and systemic blood pressure.^6,15,25 Nevertheless, even if arbitrary pressure is sufficient to totally occlude the blood flow in all subjects, ¹⁶ the occlusion level may exceed the minimum amount necessary to fully occlude blood flow in some participants, thus increasing the perception of pain or discomfort during IPC.

Third, it is unclear whether IPC is sufficient to mitigate a reduction in torque and rate of torque development (RTD) after EIMD. Although Franz et al ¹⁹ have evaluated muscle contractility using tensiomyography, torque and the RTD are considered important functional markers of muscle damage.^11,34 Finally, and considering that the EIMD magnitude may be lower in the thigh than in the arm muscles,^9,26 it is relevant to investigate the effects of IPC on the knee extensors since only the elbow flexors have been studied. ¹⁹

Thus, the purpose of this study was to investigate the effects of IPC with individualized occlusion pressure on indirect markers of EIMD in knee extensor muscles and compare with sham protocol. Given the recent evidence,^19,20 it was hypothesized that IPC would overcome the sham protocol in protecting against EIMD.

Methods

Participants and Ethical Approval

Healthy men, aged 18 to 35 years, volunteered for this study. The sample size was calculated based on a trial with similar experimental design ⁴² considering an effect size of 1.0, an alpha of 0.05, a power (1 − β) of 0.80, and a 10% difference in the maximal voluntary isometric torque (MVIT) value between the IPC and sham groups 3 days after the induced muscle damage. These parameters indicated a minimum sample size of 15 subjects per group. The participants (1) who have not participated in lower-limb strengthening programs in the past 3 months, (2) with no previous experiences with IPC or blood flow restriction training, (3) with body mass index between 18.5 and 30 kg/m², (4) without chronic disease or musculoskeletal injury, and (5) who did not report the use of dietary supplements or medications that would contraindicate the performance of intense physical training were included in the study. Those who wished to drop out of the study, presented health problems that would impair the physical performance, used any pharmacologic or therapeutic resources that might interfere the outcomes, or performed any unusual or strenuous physical activity during the study period were excluded. The participants were requested to restrain from strenuous physical activity and avoid the use of any therapeutic form of pain relief or performance improvement during the study period. The local research ethics committee approved all experimental procedures according to the Declaration of Helsinki. The study was prospectively registered (RBR-8brxg7).

Experimental Design

This is a 2-arm, randomized sham-controlled and double-blind trial. To avoid the Repeated Bout Effect, the present study did not include a crossover design. Each subject participated in 5 laboratory sessions (Figures 1 and 2). During the first session, anthropometric data (age, height, body mass, and body mass index), physical activity level, systemic arterial pressure, and total occlusion pressure (TOP) were taken.

Figure 1.

Flowchart describing the participation of individuals in each stage of the study. IPC indicates ischemic preconditioning group.

Figure 2.

Experimental protocol of the study. CK, creatine kinase; IPC, ischemic preconditioning; MVIT, maximal voluntary isometric torque; Post-Ex, after exercise; PPT, pain pressure threshold; ROM, range of motion; RTD rate of torque development; VAS, visual analogue scale.

In the second session, which occurred 3 to 5 days after the first session, systemic arterial pressure and quadriceps muscle soreness (using the visual analogue scale [VAS]) were evaluated, and blood samples were collected to measure serum CK activity. The knee ROM, pain pressure threshold (PPT), thigh girth, and MVIT of the knee extensor muscles were also assessed. After MVIT evaluation, the IPC or sham protocol was applied, followed by EIMD. The MVIT was reassessed immediately after the EIMD protocol (after exercise). In the subsequent sessions (ie, 24, 48, and 72 hours after EIMD), blood samples, muscle soreness, PPT, thigh girth, ROM, and MVIT were reevaluated. Evaluations were always performed at the same time of the day to minimize the circadian cycle interference. All measurements and interventions were performed in the nondominant limb (the dominant limb was the one used for kicking a ball).

Randomization and Allocation Procedures

Participants were randomly assigned to the IPC or sham group. The randomization was performed using a random numerical sequence generated on the website www.randomization.com. The allocation of the participants was concealed in sequentially numbered and sealed opaque envelopes that were prepared before the beginning of the study by a researcher who was not involved in the study. The researcher that assessed the outcome measures was not aware of the allocation, while the researcher (D.K.) responsible for determining both the TOP and the application of the protocol did not participate in the assessments or allocation procedures.

TOP Determination

The TOP was determined using a portable vascular Doppler (DV 6010B Medmega). All participants were instructed to avoid strenuous exercise and alcohol intake within the 48 hours before the TOP evaluation. Participants were placed in a relaxed supine position with arms and legs at the side of the body for 10 minutes in a climatized (23°C) and silent room. Right after, the Doppler transducer was positioned on the posterior tibial artery (mean distance between the medial malleolus of the tibia and the Achilles tendon), while the nylon cuff (20 cm wide; Aneroid sphygmomanometer Premium) was positioned around the subinguinal region with the cuff bladder on the medial portion of the thigh, covering the femoral artery. ³⁹ The cuff bladder was manually inflated based on a prior protocol, ⁴ and TOP was defined as the minimum pressure required to abolish the arterial pulse.

MVIT and RTD

The participants were positioned in the isokinetic dynamometer chair (Biodex Multi-Joint System 3, Biodex Biomedical System Inc) following the recommendations of the equipment manufacturer (axis of rotation aligned with the femoral condyle). After an initial familiarization (3 submaximal efforts using ~50% MVIT), participants were instructed to complete 3 maximal isometric contractions of the knee extensors (knee flexed at 60°; 0° = total knee extension) for 5 seconds, with a 30-second interval in between. Participants received strong and standardized verbal commands to contract as fast and as strong as possible and maintain the contraction for 5 seconds. ²¹ The same effort was used to determine the RTD. Absolute RTD was calculated as the average slope of the torque-time curve (∆torque/∆time; sampling rate of 100 Hz) over the time intervals of 0-30, 0-50, 0-100, and 200 milliseconds relative to the onset of muscle contraction (defined as the time point at which the torque curve exceeded the baseline by 2.5% of the difference between baseline torque and the MVIT). ²¹ Torque and RTD were defined as the average of the values recorded during the 3 maximal contractions.

Muscle Soreness and PPT

The VAS was used to assess DOMS in the anterior thigh, and consisted of a 100-mm line anchored by a “no pain” descriptor at one end (0 mm) and a “very, very painful” descriptor at the other end (100 mm). Subjects were asked to indicate on this line the perceived pain during the measurement of knee flexion ROM. The pain level was determined by the distance between the beginning of the VAS (0 mm) and the point marked by the volunteer. ⁸ PPT was evaluated in the rectus femoris muscle using algometry (Wagner Force TenTM FDX50; Wagner Instruments; 1 cm² pressure tip) at points corresponding to 50% of the distance between the anterior superior iliac spine and the base of the patella. The tip of the algometer was positioned perpendicular to the evaluation point, while pressure was applied with progressive increases of 1 kgf until the volunteer report that the pressure began to feel painful. The average from 3 measurements was included in data analysis.

Blood Sampling and Analysis

Venous blood was collected (~10 mL from the antecubital vein) and, after centrifugation of the samples for 10 minutes, the serum was removed and stored at −80°C. Serum CK activity was measured using an enzymatic kinetic assay method (Labtest).

ROM and Thigh Girth

Knee ROM was measured by a previously trained researcher (I.M.D.F.) using a plastic goniometer (Carci). The participants were placed in ventral decubitus with knees in total extension and exceeding the limit of the examination bed. Measures were obtained from a full flexion position by measuring the angle between the fibula and the midline of the femur. The average of 3 ROM measurements was taken to account in the analyses. The girth was measured at the thigh midpoint (distance from the anterior superior iliac spine to the base of the patella) using a measuring tape. Three measurements per day were performed, and the average of each day was used in data analysis.

IPC and Sham Interventions

The positioning of the participants and the cuff settings during IPC and sham interventions were similar to that described for the TOP determination. IPC consisted of 4 cycles of cuff inflation (TOP determined individually) interspersed by 5 minutes of reperfusion (0 mm Hg). The sham protocol was performed similarly to IPC but applying a 20-mm Hg pressure during the cuff inflation phase. ³¹

All participants were previously informed that the applied pressure would be sufficient to minimize muscle damage and improve performance, and would be harmless despite circulatory occlusion sensations. Also, the procedures were performed in an individualized manner to difficult subjects commenting to each other about the magnitude of the sensation evoked by the compression.

Damaging Exercise

Right after the IPC and sham procedures, the subjects performed 5 minutes of warm-up (moderate running) followed by the familiarization with the EIMD protocol (3-5 submaximal isokinetic eccentric actions). Participants performed 120 maximal eccentric actions of the knee extensor muscles (10 sets of 12 repetitions, 30-second interval between sets). The interval between the interventions (IPC or sham) and the eccentric EIMD was ~15 minutes.

Before each contraction, the volunteers’ knee was passively positioned at 30° of flexion (0° = total extension). The subjects were asked to perform a brief knee extension to trigger the dynamometer, which then pushed the segment up to 90° of knee flexion (total range of 60°) at an angular velocity of 60 deg/s. The participants were instructed to resist as much as possible the knee flexion movement imposed by the dynamometer. Each eccentric action lasted for 1 second, followed by 1 second of passive limb extension. After completing the EIMD protocol, the participant’s knee was positioned at 60° to a new MIVT evaluation. ²

Affective Valence and Perceived Effort

The affective valence (pleasure/displeasure feeling) concerning IPC or sham protocol was assessed using the Feeling scale, an 11-point scale with values ranging from −5 (very poor) to +5 (very good) and that is a valid and reliable assessment of a wide spectrum of affective states. ⁵ The Feeling scale was applied immediately after IPC or sham protocols, and the participants were instructed as follows:

Use the numbers on this scale to indicate how you felt during the intervention. If you felt that the intervention was very good (pleasant or comfortable), then the corresponding answer was +5. If the sensation was very bad (unpleasant or uncomfortable), then the corresponding answer will be −5. If you are feeling in a neutral way (between pleasure and displeasure), then the corresponding answer will be 0. According to your perception, your answer may also be at an intermediate point between the extremities.

The rating of perceived exertion was measured using the modified Borg scale, ¹⁸ which ranges from 0 (no effort) to 10 (maximum effort). The Borg scale was applied immediately after the EIMD protocol, and participants were instructed to think on the level of effort that they exerted during the entire protocol.

Statistical Analysis

Data normality and homoscedasticity were verified using Kolmogorov-Smirnov and Levene tests, respectively. All variables showed normal distribution and homoscedasticity. Variables with 2 measures were compared using the unpairedt test, whereas more than 2 repeated measures were compared via repeated-measures 1-way analysis of variance (for within-group comparisons) and mixed linear model (for between-group comparisons). In the event of a statistically significant difference, Bonferroni post hoc test was applied to identify the differences (mixed models having training protocol and time as fixed factors, and subjects as random factor). Data are shown as mean ± SD, unless otherwise stated. The mean differences and 95% CI for both the within and between-group comparisons were reported and interpreted as a measure of effect size. ²³

All participants were included in the final analysis following an intention-to-treat approach. Inferential analyses were performed using the SPSS 22.0 statistical package (IBM Corporation). For all statistical analyses, a significance level of <0.05 (2-tailed) was adopted.

Results

Age, height, body mass, body mass index, systolic and diastolic pressures, and total restriction pressure did not differ between groups (Table 1). There were no dropouts during the study period.

Table 1.

Subject characteristics

	IPC, Mean ± SD	Sham, Mean ± SD
Age, y	22.1 ± 3.3	21.7 ± 2.9
Height, cm	176.0 ± 7.0	175.0 ± 6.0
Body mass, kg	72.7 ± 1.8	71.1 ± 10.7
BMI, kg/m2	23.6 ± 1.9	23.4 ± 3.3
SBP, mm Hg	115.3 ± 5.1	118.7 ± 5.16
DBP, mm Hg	73.3 ± 4.9	74.3 ± 8.2
TOP, mm Hg	143.3 ± 6.2	138.0 ± 15.2

BMI, body mass index; DBP, diastolic blood pressure; IPC, ischemic preconditioning; SBP, systolic blood pressure; TOP, total occlusion pressure.

MVIT and RTD

There were no differences in MVIT and RTD at baseline between groups. Overall, MVIT declined as a result of the eccentric exercise in both groups, but without significant differences compared with baseline (Table 2). The IPC group exhibited a MVIT decline of 14.6%, 17.1%, 10%, and 4.2% immediately (after exercise) and 24, 48, and 72 hours after the EIMD protocol, respectively. For the sham group, the MVIT decline was 18.1% (after exercise), 13.2% (after 24 hours), 4.7% (after 48 hours), and 1.2% (after 72 hours). There were no significant interactions between IPC and sham groups for MVIT (Table 3). Within- and between-group comparisons were not significant for RTD (Figure 3 and Appendix Tables A1 and A2, available in the online version of this article).

Table 2.

Indirect markers of muscle damage at baseline and after eccentric exercise with IPC (n = 15) or SHAM (n = 15) ^a

							Within-Group Score Changes
Outcome	Groups	Baseline	After Exercise	After 24 h	After 48 h	After 72 h	After Exercise − Baseline	24 h − Baseline	48 h − Baseline	72 h − Baseline
MVIT, N·m
	IPC	199.9 ± 40.2	170.8 ± 31.6	165.6 ± 34.8	179.8 ± 50.3	191.4 ± 45.8	−29.1 (−72.6 to 14.5)	−34.2 (−77.7 to 9.3)	−19.9 (−63.5 to 23.5)	−8.4 (−51.9 to 35.1)
	Sham	204.7 ± 44.5	167.6 ± 32.2	177.5 ± 41.8	195.1 ± 40.5	207.1 ± 41.8	−37 (−79.8 to 5.6)	−27 (−69.9 to 15.6)	−9.6 (−52.3 to 33.1)	2.4 (–40.3 to 45.11)
Muscle soreness, mm
	IPC	0 ± 0	N/A	11.4 ± 14.6	9.4 ± 15.2	8 ± 16.5	N/A	11.4 (−1.9 to 24.8)	9.4 (−3.9 to 22.8)	8.0 (−5.4 to 21.4)
	Sham	0 ± 0	N/A	14.4± 16.4	25.2 ± 15.3	17.6 ± 21.7	N/A	14.4 (−1.2 to 30.1)	25.2 (9.6 to 40.9)*	17.6 (1.2 to 33.2)**
PPT, kgf
	IPC	3.4 ± 1.7	N/A	2.6 ± 0.9	2.8 ± 0.9	2.9 ± 1.1	N/A	−0.8 (–2.7 to 0.4)	−0.7 (−1.9 to 0.5)	−0.5 (−1.7 to 0.7)
	Sham	3.3 ± 1.1	N/A	2.6 ± 0.9	2.5 ± 0.9	2.7 ± 1.1	N/A	−0.7 (−1.8 to 0.3)	−0.9 (−1.9 to 0.2)	−0.7 (−1.8 to 0.3)
CK activity, IU/L
	IPC	179.8 ± 79.5	N/A	439.3 ± 312.9	506.1 ± 415.2	588.9 ± 715.1	N/A	258.5 (−184.8 to 701.8)	326.3 (−116.9 to 769.6)	409.1 (−34.2 to 852.4)
	Sham	158.9 ± 48.9	N/A	382.8± 281.1	417.7 ± 380.3	550.2 ± 619.8	N/A	142.6 (−166.3 to 613.9)	258.8 (−131.3 to 648.9)	391.2 (1.14 to 781.4)***
Thigh girth, cm
	IPC	57.4 ± 4.6	N/A	58.3± 4.8	58.8 ± 4.6	57.7 ± 4.6	N/A	0.9 (−3.7 to 5.6)	0.7 (−4.1 to 5.3)	0.3 (−4.3 to 5.1)
	Sham	56.5 ± 5.7	N/A	57.7± 5.6	57.7 ± 5.6	57.4 ± 5.7	N/A	1.2 (−4.5 to 6.9)	1.2 (−4.5 to 6.9)	0.9 (−4.8 to 6.6)
ROM, deg
	IPC	121.2 ± 12.1	N/A	118.6 ± 13.5	117.8 ± 11.6	119.8 ± 10.8	N/A	−2.6 (−14.7 to 9.44)	−3.3 (−15.4 to 8.7)	−1.4 (−13.5 to 10.6)
	Sham	123.7 ± 7.7	N/A	121.5 ± 11.3	119.6 ± 10.5	122.3 ± 9.1	N/A	−2.2 (−11.9 to 7.5)	−4.11 (−13.9 to 5.6)	−1.4 (−11.2 to 8.3)

CK, creatine kinase; IPC, ischemic preconditioning; MVIT, maximal voluntary isometric torque; N/A, not applicable; PPT, pressure pain threshold; ROM, range of motion.

^aValues are expressed as means ± SD and within-group change score (95% confidence interval).

^*Statistically different from baseline at 48 hours (P < 0.001).

^**Statistically different from baseline at 72 hours (P = 0.02).

^***Statistically different from baseline at 72 hours (P = 0.04).

Table 3.

Score changes (∆) between groups after eccentric exercise ^a

Outcome	IPC − Sham After Exercise	IPC − Sham After 24 h	IPC − Sham After 48 h	IPC − Sham After 72 h
MVIT, N·m	∆ = 3.2 (−27.1 to 20.7)	∆ = −11.9 (−40.6 to 16.9)	∆ = −15.2 (−18.9 to 49.4)	∆ = −15.6 (−17.1 to 48.4)
Muscle soreness, mm	N/A	∆ = −3 (−14.6 to 8.6)	∆ = −15.8 (−27.2 to −4.4)*	∆ = −9.6 (−24.1 to 4.8)
PPT, kgf	N/A	∆ = 0.06 (−0.7 to 0.8)	∆ = 0.3 (−0.4 to 1.1)	∆ = 0.3 (−0.5 to 1.2)
CK activity, IU/L	N/A	∆ = 55.5 (−167.1 to 277.9)	∆ = 88.4 (−209.4 to 386.2)	∆ = 38.7 (−461.8 to 539.2)
Thigh girth, cm	N/A	∆ = 0.5 (−3.4 to 4.5)	∆ = 0.3 (−3.5 to 4.2)	∆ = 0.3 (−3.5 to 4.2)
ROM, deg	N/A	∆ = −2.9 (−12.2 to 6.4)	∆ = −1.7 (−10.1 to 6.5)	∆ = −2.4 (−9.9 to 4.9)

CK, creatine kinase; IPC, ischemic preconditioning; MVIT, maximal voluntary isometric torque; N/A, not applicable; PPT, pressure pain threshold; ROM, range of motion.

^aValues are expressed as mean difference (95% confidence interval).

^*Statistically between-group differences (P = 0.008).

Figure 3.

Changes in RTD over the 0 to 30 (A), 0 to 50 ms (B), 0 to 100 ms (C), and 0 to 200 ms (D) intervals at baseline (Pre), immediately after (Post-Ex) and 24, 48, and 72 hours after eccentric isokinetic exercise. Data are expressed in mean ± standard error of mean. IPC, ischemic preconditioning; Post-Ex, after exercise; RTD, rate of torque development.

Muscle Soreness and PPT

None of the participants reported pain or PPT at baseline. After EIMD, the perceived pain increased significantly in the sham group at 48 and 72 hours compared with baseline values, with no differences in the IPC group. Regarding pain, significantly lower values were found in the IPC group at 48 hours compared with the sham group. There were no significant differences between the IPC and sham groups for PPT as well as no interaction between groups (Tables 2 and 3).

CK, ROM, and Thigh Girth

Serum CK activity was significantly higher only in the sham group at 72 hours compared with baseline values. ROM and thigh girth were not significantly altered in both groups. Neither differences nor interactions between groups were found for the ROM and thigh girth measures (Tables 2 and 3).

Affective Valence and Perceived Exertion

Affective valence was 2.33 ± 1.75 in the IPC group and 3.46 ± 1.99 in the sham group but without significant between-group differences (∆ = −1.13 [95% CI: −0.27 to 2.53]; P > 0.05). Perceived effort was 6.7 ± 1.3 in the IPC group and 7.8 ± 1.42 in the sham group with a significant interaction between groups (∆ = 1.1 [95% CI: 0.09 to 2.1]; P = 0.02) in favor of IPC.

Discussion

This study aimed to evaluate the effects of IPC with individualized occlusion pressure on indirect markers of EIMD after eccentric exercise and compare with a sham protocol. Contrary to the hypothesis, the results suggest that IPC was not different from the placebo effect in protecting against mild EIMD.

The hypothesis was based on previous studies showing that IPC and EIMD induce common cellular alterations, such as intracellular accumulation of Ca²⁺, increased production of reactive oxygen species and apoptotic signaling, as well as infiltration of leukocytes into the damaged soft tissue. ²⁰ Based on this, it has been proposed that a damaging exercise preceded by IPC may blunt muscle damage responses. ¹⁹ No studies evaluated the placebo effect of the IPC on the protection against EIMD. This is a relevant aspect since IPC applied as an ergogenic aid may not differ from placebo.^27,28,36 Thus, it is reasonable to consider that the benefits of IPC on muscle damage, as proposed by Franz et al ¹⁹ may have resulted in part from the placebo effect.

This study found no differences in the MVIT after EIMD probably because the damaging protocol induced only small muscle damage. However, declines up to 20% in the force-generating capacity indicate mild damage ³³ ; so, considering a maximal percentage reduction of 18% in MVIT and the significant increase in CK levels observed in the present study, it is reasonable to assume that the eccentric exercise protocol was suitable to produce mild muscle damage.^17,33 It is worth noting that moderate- to high-magnitude damage in the knee extensors are challenging to be induced, and small maximum decreases (8% to 17%) in quadriceps torque have been reported.^1,45

These results indicate that IPC was not able to mitigate reductions in MIVT compared with sham protocol. This is a novel finding since no study evaluated the force-generating capacity after eccentric loading preceded by IPC. Recently, IPC attenuated impairments in the contractile function through a smaller reduction in maximal radial displacement. ¹⁹ However, these results cannot be compared with this study, because Franz et al ¹⁹ did not assess the force-generating capacity directly. Also, the absence of a sham-controlled group hinders the influence of the placebo effect on the results by Franz et al. ¹⁹ In this sense, this study adds new information about the inability of the IPC to overcome the placebo effect and mitigate force impairments after a damaging protocol, which is considered the primary indirect marker of EIMD.^11,44 As for torque, there were no differences in RTD after eccentric EIMD as well as between the IPC and sham conditions. Future investigations should verify whether IPC can overcome the placebo effect and minimize reductions in both the MIVT and RTD after an EIMD protocol of greater magnitude than that observed herein.

Although the force-generating capacity was not altered, the participants in the IPC group reported significantly lower soreness than those in the sham group. In the same direction, IPC was able to attenuate soreness when compared with the control group (no intervention). ¹⁹ Despite this, the minimal clinically important difference of 36 mm⁴³ was observed neither in this study nor in a previous study. ¹⁹ This is an important aspect since the minimum threshold has not been reached in most of the studies that proposed IPC as an ergogenic aid. ²⁹

Serum CK activity was significantly elevated (391.2 IU/L) at 72 hours after EIMD only in the sham group but with no between-group differences. A previous study ¹⁹ showed a very elevated peak serum CK activity (24316.0 IU/L) at 72 hours in the control group (no preconditioning) that was higher than the IPC group (996.1 IU/L). Overall, these findings suggest that IPC could minimize serum CK elevation, especially considering moderate muscle damage. ¹⁹ Although the serum CK activity is an useful biomarker, it presents high interindividual variability ³² and may not have relationships with functional activities. ³⁵ Despite smaller muscle soreness and serum CK activity were observed in the present study, the lack of differences in other indirect markers of inflammation and swelling, such as ROM and thigh girth, suggests no major influence of the IPC on pro-inflammatory responses induced by mild muscle damage.

These findings indicated that IPC minimized the perceived exertion during isokinetic eccentric exercise, despite no influence on the attenuation of force impairment after exercise. In line with this finding, a recent study ⁴⁰ verified that IPC attenuates perceived exertion but without improvements in performance. These results, together with the smaller muscle soreness observed in the present study, indicate that IPC may influence the perceptual responses to exercise. Also, no differences were observed in the affective valence between groups, which suggests that IPC with individualized TOP was as tolerable as the sham protocol and not unpleasant. This is an important aspect since IPC performed with high pressures can be uncomfortable. ¹³ In this sense, this novel information supports the use of individualized occlusion pressures to reduce the perceived exertion, improve the adherence to IPC protocols, and minimize the likelihood of a nocebo effect. ⁶

Limitations

It is important to acknowledge limitations in the present study. The EIMD protocol was able to generate only mild muscle damage, which may have limited the observed between-group differences. However, from a practical point of view, several sport modalities induce mild rather than moderate or severe muscle damage,^12,22 thus improving the clinical application of this study. Additionally, the signs and symptoms commonly evoked by IPC, such as pain, limb temperature reduction, and skin color changes are limiting aspects of the sham model used herein. Nevertheless, this limitation was minimized once subjects were naive to the IPC or sham protocols, and interventions were individualized to hinder communication between subjects regarding the perception of occlusion pressure. Last, these results refer to eccentric contraction modes only and cannot easily be transferred to concentric contractions.

Clinical Relevance

The current findings have some practical implications. Although IPC is a noninvasive, low-cost, and easy-to-administer intervention, the lack of statistical and clinical significance after interventions highlighted that the IPC effects can, in part, be explained by the placebo effect. In addition, this is the first study reporting the effects of IPC with individualized TOP. This approach may have a pivotal role to all subjects receive a similar stimulus while also minimizes possible discomfort due to the unnecessary application of very high occlusion pressures. ⁶ Finally, this study design sought to overcome critical methodological limitations of the previous literature, such as the lack of a placebo group and the allocation concealment. ¹⁹

Conclusion

The results of the present investigation suggest that IPC does not surpass the placebo effect after a mild EIMD of the knee extensors muscles. Also, IPC minimizes the perceived exertion during an isokinetic eccentric exercise and is well tolerated when individualized TOP is delivered. Further experimental protocols should investigate the effects of IPC on the protection against moderate and severe muscle damage and compare with the sham protocol.