Effect of Ischemic Preconditioning on

Endurance Performance Does Not
Surpass Placebo
Graduate Program in Translational Medicine, Federal University of São Paulo, São Paulo, BRAZIL; 2Laboratory of Exercise
Physiology, Olympic Center of Training and Research, São Paulo, BRAZIL; 3São Paulo Association for Medicine Development,
São Paulo, BRAZIL; 4Department of Physiology, Federal University of São Paulo, São Paulo, BRAZIL; and 5Department of
Surgery, Federal University of São Paulo, São Paulo, BRAZIL

Effect of Ischemic Preconditioning on Endurance Performance Does Not Surpass Placebo. Med. Sci. Sports Exerc., Vol. 49, No. 1,
pp. 124–132, 2017. Purpose: Recent studies have reported ischemic preconditioning (IPC) can acutely improve endurance exercise
performance in athletes. However, placebo and nocebo effects have not been sufficiently controlled, and the effect on aerobic metabolism
parameters that determine endurance performance (e.g., oxygen cost of running, lactate threshold, and maximal oxygen uptake [V̇O2max])
has been equivocal. Thus, we circumvented limitations from previous studies to test the effect of IPC on aerobic metabolism parameters and
endurance performance in well-trained runners. Methods: Eighteen runners (14 men/4 women) were submitted to three interventions, in
random order: IPC; sham intervention (SHAM); and resting control (CT). Subjects were told both IPC and SHAM would improve
performance compared to CT (i.e., similar placebo induction), and IPC would be harmless despite circulatory occlusion sensations (i.e.,
nocebo avoidance). Next, pulmonary ventilation and gas exchange, blood lactate concentration, and perceived effort were measured during
a discontinuous incremental test on a treadmill. Then, a supramaximal test was used to verify the V̇O2max and assess endurance
performance (i.e., time to exhaustion). Results: Ventilation, oxygen uptake, carbon dioxide output, lactate concentration, and perceived
effort were similar among IPC, SHAM, and CT throughout the discontinuous incremental test (P 9 0.05). Oxygen cost of running, lactate
threshold, and V̇O2max were also similar among interventions (P 9 0.05). Time to exhaustion was longer after IPC (mean T SEM, 165.34 T
12.34 s) and SHAM (164.38 T 11.71 s) than CT (143.98 T 12.09 s; P = 0.02 and 0.03, respectively), but similar between IPC and
SHAM (P = 1.00). Conclusions: IPC did not change aerobic metabolism parameters, whereas improved endurance performance. The
IPC improvement, however, did not surpass the effect of a placebo intervention. Key Words: ISCHEMIC PRECONDITIONING,

schemic preconditioning (IPC; brief cycles of ischemia and blood vessels, if translated to exercising muscles, could,
followed by reperfusion) is well known to induce pro- supposedly, enhance efficiency of ATP use and resynthesis
tection against ischemia–reperfusion injury (9,26,36). by the aerobic metabolism, as well as could increase skeletal
Adenosine triphosphate (ATP) sparing (36) and increase of muscle blood flow, leading to higher oxygen delivery and
electron mitochondrial flux (9) are some of the mechanisms metabolites removal. The hypothetical effects of IPC on mi-
responsible for the IPC protection. In addition, IPC abolishes tochondrial and vascular function have, consequently, driven
the endothelial function impairment induced by ischemia– studies that investigated the ergogenic effect of IPC on en-
reperfusion (26), which is mediated by the autonomic nervous durance performance (19). A meta-analysis recently reviewed
system (26). The beneficial effects of IPC on mitochondria 8 studies in this area (38), and concluded the IPC induces a

small beneficial effect on endurance performance. Of note,
however, no study has sufficiently controlled placebo and
nocebo effects (37).
Address for correspondence: Bruno Moreira Silva, P.T., Ph.D., Botucatu St
862, Biomedical Sciences Building, 5th Floor, São Paulo, SP04023-062, Previous studies have compared the IPC to a sham inter-
Brazil; E-mail: silva.bruno@unifesp.br. vention where cuffs have been inflated at low pressure and
Submitted for publication June 2016. subjects have not been informed about the possible effect of
Accepted for publication August 2016. IPC on endurance performance (2,3,12–14,37). Such ap-
0195-9131/17/4901-0124/0 proach can possibly bias the interpretation about the IPC
MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ effect on endurance performance, because IPC induces pain
Copyright Ó 2016 by the American College of Sports Medicine during circulatory arrest and relief during reperfusion (25),
DOI: 10.1249/MSS.0000000000001088 which do not occur during the low cuff inflation. Thus, the net


Copyright © 2016 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.

and 2) both IPC leg (2). capillary blood lactate concentration. Each chamber was 36 cm long jects that IPC and SHAM would similarly improve perfor. Unauthorized reproduction of this article is prohibited. proximately 50% of well-trained subjects during a continu. Among the 18 subjects that com- beneficial (i. The reason for that is that uncertainty about an inter. Brazil) at the posterior tibial SHAM effect (i. may still be at.367) approved the study. They had been training ingestion of a capsule reduced sprint performance by 1.5 yr. and crossed-over. and so.14). commonly use therapeutic ultrasound in an attempt to However. placebo) or harmful (i. a man was excluded due to a accelerate the healing process of musculoskeletal injuries. a sessions to allow adequate recovery from training. ous incremental test (30). subjects were exposed to IPC.effect on subjects_ expectancy about the interventions is muscle injury. No pulse was detected in any subject while cuffs were inflated. controlled.7 T 1.0 T 2.e. in random order. Thus. (2.e. such that subjects may think the IPC is either related to menstruation. Sub- IPC. similarly improve performance compared to CT. V̇O2max = 56. One of these studies. 9. and its use would be helpful to 15 (i.38). the other was pothesized that 1) IPC would improve aerobic metabolism deflated (2). HR.11).6% 6 times per week.. Cuffs sensations (i.8%) and four women (age = 24. and verification protocol has been developed to confirm the subjects were assessed only if they reported score of at least V̇O2max identification (30). ethics committee of the Federal University of São Paulo The effect of IPC on aerobic metabolism parameters (process 610. in turn. they covered at least 80% of mance compared with CT (i.e. which may reduce precision of performance continuous incremental test. and IPC formance. and not to ingest caffeine or alcoholic beverages for 24 h. because subjects Study design.3 T 0. Each cuff had a Velcro strap that.e. (23). we tomized cuffs (16).17. One of the researchers told the sub.6% T showed a placebo supplement ingested during a cycling time 0. Circulatory and SHAM would improve endurance performance com. Therefore. and control. and perceived effort Interval between visits was 7 d.7%). Twenty subjects volunteered to participate. one of outcomes. Then. we used a were inflated to 220 mm Hg for 5 min and deflated to 0 mm APPLIED SCIENCES verification protocol to confirm the V̇O2max (30). and 4. The SHAM procedure consisted of simulating the ad- METHODS ministration of therapeutic ultrasound. familiarization with the interventions and execution of a formance (11).3% (11). thus the IPC procedure lasted 40 min. Moreover. Ischemic preconditioning. but the IPC improvement would surpass the vascular 610B. IPC mance in well-trained runners circumventing limitations was performed with subjects in supine position.8 mLIkgj1Iminj1. nocebo avoidance). V̇O2max = 66. and double. using cus- from previous studies. V̇O2 plateau is observed in only ap. In addition.. Visit 1 was used for vention increases individual variability in endurance per. rive fully hydrated. and all subjects signed that determine endurance performance has been equivocal an informed consent form before participating in the study. and other criteria may be Training intensity was reduced on the day before the testing insufficient to confirm the V̇O2max attainment (34). artery. ingest a light meal 2 h before the tests. All subjects were nonsmokers and were not taking trial enhanced performance by 4. perhaps.5 yr. and close to the groin as possible. good recovery) in the total quality recovery scale elucidate the effect of IPC on the V̇O2max. SHAM.2 mLIkgj1Iminj1. Visits occurred at the same time of day for a given subject. Hg for 5 min (2). medications. 14 were men (mean T SEM. We hy. age = and nocebo effects. with supervision of a coach (4). ISCHEMIC PRECONDITIONING AND AEROBIC EXERCISE Medicine & Science in Sports & Exercised 125 Copyright © 2016 by the American College of Sports Medicine.e. blinded studies (4. chambers installed in series. jects visited the laboratory four times.24. MEDMEGA. on aerobic metabolism parameters and endurance perfor.12–14.1% T 0. tributed to the lack of strict criteria to confirm its measure. occlusion was confirmed with a vascular Doppler (Doppler pared with CT. for example.14. could possibly mask a small effect of IPC the researchers told subjects that IPC and SHAM would on both aerobic metabolism parameters and endurance per. One cuff was placed in each thigh.e. and 17..12.. in this visit. Previous studies have used traditional criteria based discontinuous incremental test and a supramaximal test. for 5. as compared IPC with a sham intervention (SHAM).. Together. To dissect the placebo effect. on attainment of V̇O2 plateau and a given level of RER. placebo effect).. during the study. or another study showed negative information provided about presented history of chronic diseases. placebo- have not been told about the potential ergogenic effect of controlled and nocebo-controlled. in part. The cebo and nocebo effects. nocebo).24). Cuffs had two independent resting control (CT).6. However. In addition. Placebo pleted all the study_s visits. particularly. surrounded the tight at least two times. Four pressure cycles were performed on each parameters compared to SHAM and CT. . The study was randomized.9 yr.5 cm wide. due to possible biases from pla. the isolated effect of IPC on endurance per. they had been formance remains unclear. The varied effect of IPC on the maximal oxygen would be harmless despite circulatory occlusion sensations. and next submitted to a ment. Only one subject_s visit had to be postponed 1 d to The aim of this study was to investigate the effect of IPC allow adequate recovery. or CT.0 T 0. could per se modify exercise 22. graduated in physical education. competing in official middle and long distance races.18. similar placebo induction). body fat = 23. the thigh_s circumference. sham. supplements. When one cuff was inflated. according to randomized.4 T 1. and IPC would be harmless despite circulatory occlusion in most cases. On the other hand.12. 3. on visits 2. treating orthopedic injuries. Physical therapists Subjects. uptake (V̇O2max) (2. Subjects were asked to ar- (2. body fat = performance. and a woman was excluded due to symptoms unpredictable.

) informed the subjects that the beneficial effects of visit 1.S. After velocity was set at 0. because it increases deep tissues tem. Italy). conducted on (J. subjects and 65%. and relative humidity between 45% the CT day. anterior leg. it was impossible for the subjects to notice The treadmill velocity was firstly set for 2 min at 60% of the that the device was not delivering ultrasound. Before followed by 1 kmIhj1 increase in velocity per stage until applying the ultrasound. and all had a positive belief that avoidance. (J. Next. 3. All tests were conducted at temperature be- jects were instructed to compare their performance versus tween 21-C and 23-C. the previous visits.L. However. which totaled recovered standing on the treadmill for 3 min. Each stage lasted 3 min and the ultrasound to simulate the adjustment of settings and. or blinded about the test results and the intervention that was worse than the performance on the previous visit(s)?’’ Sub. Boehringer 126 Official Journal of the American College of Sports Medicine http://www. peak velocity (Vpeak)]. Nev. and posterior leg. and the ultrasound and.) asked the following question: ‘‘Do the test was always the same for a given subject and was you think your performance today will be equal. using ambi- analyzed as IPC better than CT). The discontinuous incremental test started with 6 min of The ultrasound device was plugged in a power socket. Subjects were blinded about the mill to be instrumented for the exercise tests. The continuous incremental test. In our study. baseline at velocity 1 kmIhj1 lower than the velocity where turned on. researcher executed these methods.S. Cosmed. researcher conducted all exposures to IPC. A vasodilator ointment was asked the question about performance expectancy. provided data to define the discontinuous incre- ultrasound application could not only heal musculoskeletal mental test. The subjects lie down before and during data for the oxygen cost of running interpretation (39). SHAM. always pushed the timer button. they stepped off the treadmill probe was rubbed over the muscles of the anterior thigh. O2 and CO2 analyzers were calibrated tistical analyses (e. Twenty-five microliters of blood mance compared with CT. Noteworthy. this researcher pushed buttons on voluntary exhaustion (Fig. this researcher discontinuous incremental test. Next. treadmill velocity was reduced to zero and subjects alternating the application between limbs. supposedly. active administration of therapeutic ul. AD subjects that IPC and SHAM would similarly improve perfor. Inbrasport. The same CO2). the ultrasound heating effect exhaustion. and 4.. which emitted a sound. and recovery at 5 kmIhj1 for 5 min. Australia).). as soon as subjects could.S. and subjects incremental test. the discontinuous incremental test consisted of 3 min at placed close to the subjects_ leg and its panel was facing the velocity 2 kmIhj1 higher than the baseline velocity.). This researcher was also responsible to inform the AD Instruments. than the After the recovery period from the discontinuous incre- sensations provoked by gel application and probe movement mental test. Exercise tests were performed on a ertheless.g. better. If the CT was used on visit 4.. subjects stood on a tread. At the end last. Exercise tests. Moreover. Australia) to quantify HR (LabChart. if the CT was used on visit 2.acsm-msse. administered. Instruments. In detail. These questions were used to ent air and gases with known concentration (16% O2 and 4% assess the placebo induction and nocebo avoidance.. After the ultrasound application. The continuous in- injuries but also enhance exercise performance. Brazil). researcher that conducted the procedure (J. used on visits 2. which aimed to obtain steady state V̇O2 did not notice that. a supramaximal exercise test was started (Fig. IPC better Measurements. one study. and its front lights were on.L. the response CT worse than IPC was according to the manufacturer_s specifications. litional exhaustion (30). or only on visit 4. recovery walking for 7 min at 5 kmIhj1. Thus. At the end of treadmill velocity and all other data collected during the the instrumentation. Just one used to arterialize blood samples (Finalgon.L. Ultrasound gel was applied on the skin.5 kmIhj1 higher than Vpeak until vo- the interventions administration. on visits 3 and 4. tion. and later responses were inverted for sta. 1).e. and CT Electrocardiogram was continuously recorded (Powerlab. in part. The sham increased to the next stage. to standardize the placebo induction and nocebo sometime before the study.S. one of the researchers ning (39).org Copyright © 2016 by the American College of Sports Medicine. The researcher that gave verbal encouragement during of the researchers (J. uous incremental test [i. The ultrasound device was that. compared the IPC and SHAM versus CT (e. When subjects reached exhaus- ultrasound application was done for 5 min in each region. trasound does not provoke any relevant sensation. Unauthorized reproduction of this article is prohibited. the start the ventilatory threshold was identified on the continuous button to deliver the ultrasound was not pushed. belt. They stood for blood sampling and then velocity was posterior thigh. subjects had little or none infor. Ventilation and pulmonary gas ex- than CT). Subjects were not allowed to sleep during this period. and IPC would be harmless despite were draw from the earlobe during the breaks of the circulatory occlusion sensations. it could aid the treatment of musculoskeletal injuries. The flow meter was calibrated using a 3-L syringe. with grade set at mation about the mechanisms involved on the ultrasound 1% to approximate the energy expenditure of outdoor run- therapeutic effects. at was followed by a 30-s break for blood sampling. on the skin. the treadmill velocity was reduced to zero. of each stage. 1). (15) was used to support the researcher_s explanation. according with a system- perature (15). velocity of last completed stage on the previous discontin- The CT procedure consisted of lying supine for 40 min. treadmill (Super ATL. All subjects had been treated with ultrasound atic ritual. subjects were asked change were recorded breath by breath throughout the APPLIED SCIENCES on this visit to compare their expected performance versus exercise tests using a metabolic analyzer (Quark CPET. If subjects cremental test consisted of baseline at 8 kmIhj1 for 3 min. . they 40 min. before the study.g.L. had doubts or were interested to know more details about the 1 kmIhj1 increase in velocity per minute until voluntary possible mechanisms involved.

significance was accepted for P G 0. USA). was confirmed in all cases. In addition. and statistical between the observed lactate values and the fitted values (31). Yellow lected at exhaustion and the third minute of recovery. All analyses were two-tailed. in random order. were used for sta.14).05. We firstly exposed subjects exposed to IPC. Time was recorded using a tolerance of measurement error (i. 80%. When there was no interventions (2.FIGURE 1—Illustration of the study_s experimental procedures conducted on visits two. As a result. mean difference of 3% in endurance performance among latory threshold using 20-s mean data. USA). the V̇O2max subjects asked to interrupt the test (i. Due to technical problems. we conducted a discontinuous incremental test and a supramaximal test. Pulmonary ventilation and gas exchange to 70%. In our study. fort during the discontinuous test were linearly interpolated tistical analyses. and CT. USA). 90%. Rating of perceived exertion was The highest 20-s mean V̇O2 during the exercise tests was assessed during the continuous and discontinuous incremen. The highest reduced to 16. Two Dusseldorf University. and perceived ef- supramaximal velocity. until test was the highest value obtained from blood samples col- analysis of lactate concentration (YSI 1500 SPORT. viations from the mean of a 15-breath window). considered the peak oxygen uptake (V̇O2peak). Time to exhaustion was used the discontinuous and supramaximal tests was within the to assess endurance performance. The Greenhouse–Geisser correction was equivalent of CO2 (V̇E/V̇CO2) plotted versus time. Beat by beat HR was reduced to despite strong verbal encouragement. SHAM. based on that. without increase in ventilatory SHAM. The following criteria would be necessary to conduct the study. blood samples were only obtained common velocity among the interventions was considered from the first 14 subjects that participated in the study. Lactate used to adjust ANOVA results. the V̇O2max was digital stopwatch. the sample size to compare data throughout the test among the in- was 15. Oxygen cost Statistical analyses. Blood was collected using heparinized obtained from the blood sample collected after the last com- and calibrated capillaries.3. and then stored in Eppendorfs pleted stage. and 95% were identified were filtered to exclude aberrant breaths (two standard de. volitional exhaustion). 85%. If V̇O2peak of tal tests using 0–10 Borg scale. Mannheim. the sample size for peak terventions (Origin. Germany). Then. and peak HR were terpolation was done using 20-s mean data. V̇O2.e.. Sample size was calculated con- of running was calculated as the average V̇O2 of the last 2 min sidering the endurance performance as the main endpoint of baseline of the discontinuous incremental test. divided by in one-way repeated measures ANOVA (G*Power 3. V̇O2 and V̇CO2 in- ventilation. and four. As a APPLIED SCIENCES agreement on the independent identification. interpolated data corresponding Data analyses. the absolute velocities presented in the Y axis are merely an example. . Unauthorized reproduction of this article is prohibited. 2%). and the highest value was achieved the target supramaximal velocity. Time to exhaustion was 20-s means. for this variable. Thus. when significant F values were found. peak pulmonary gas exchange. P value at 0. V̇CO2.. as well as considering a experienced investigators independently identified the venti.05 and power at 0. whenever sphericity was vi- threshold was determined using a mathematical model that olated in the Mauchly test. three. Statistical analyses Peak lactate concentration in the discontinuous test was were done using the software STATISTICA (Statsoft. anticoagulant). investigators result. Springs Instruments. The Bonferroni post hoc was used identified the point of intersection between two linear re. ISCHEMIC PRECONDITIONING AND AEROBIC EXERCISE Medicine & Science in Sports & Exercised 127 Copyright © 2016 by the American College of Sports Medicine. for a given subject.80. and peak HR was the highest value during each recorded from all subjects.. and used for statistical analyses. The chronometer was started when subjects assumed to be achieved (30). The baseline velocity was individ- ualized. lactate concentration. All variables were used (1): 1) break point in CO2 output (V̇CO2) plotted showed normal distribution in the Shapiro–Wilk test.1 the corresponding velocity in kilometers per minute (39). the sample size calculation indicated that 15 subjects reviewed the identification together. Peak lactate concentration in the supramaximal containing 50 KL of 1% NaF (i. 75%. One- versus V̇O2. Results are presented gressions that yielded the least sum of squared differences as mean T SEM. Germany). and stopped when used for statistical analyzes. or CT. but only data obtained at the same test.e. and 2) increase in ventilatory equivalent of O2 way repeated measures ANOVA was used to compare IPC.e. (V̇E/V̇O2) plotted versus time. 100% and. Microcal.

10 T 00.8 T 1.6 T 1.93).5 9.15 1 1160. similar among IPC.e.70 126. the effect of pla- the effect of IPC on aerobic metabolism parameters and cebo induction on endurance performance also depends on endurance performance in well-trained runners.00 T 0.u. Most subjects. Fig. 90% APPLIED SCIENCES TABLE 1.01 1. mmolILj1 14 9. RESULTS TABLE 2. 16 1.00 10.70 851. because than CT (143.89 115. fourth minute.04 T 1. a.6 64. metabolic.01 0.00 T 0.u.u.38 T 11. Percent values were calculated in relation to the corresponding world record. 39. but similar between IPC and SHAM. P = 0.00 T 0.05.95. mLIkgj1Iminj1 16 64. men and Incremental test women_s best time were.82 Borg.09 s.71 s) may be explained by the question used in the study. which may explain part of the showed no effect of IPC on aerobic metabolism parameters.4 T 0. *With steeplechase.37 T 0.93 mLIkgj1Iminj1.01 T 0.03 T 0.2 T 0.01 1.4 0. as the interlocutor interaction with the sub- sixth minute.40 1771.91 4 114. with the performance on previous visits.acsm-msse.5 7.97 230.92 HR.02 and 0.29 T 0. The majority of the subjects expected per. SHAM: jects can modulate the placebo effect in clinical studies (7). 22%.47 134. SHAM.26 scale was similar among interventions (IPC: 16.07 — — — 3000* 473. the results indicate that 1) the improvement in of IPC on endurance performance (effect size. which indicates that.70 T 29.5 T 0.41).01 1.48 122.00).00 T 00.. mLIkgj1Iminj1 16 64.05. However. SHAM.81 2 679.9 T 0.00 538. These results indicate that V̇O2 was at steady successful. V̇O2 was similar Only one of the researchers interacted with the subjects to between the fourth and sixth minute of baseline within all induce placebo and avoid nocebo.8 63. Score on the total quality recovery [La].01 0. P = 0.03. 83%. in fact.66 mLIkgj1Iminj1. P = 0.37 and 150 mm Hg. a. vs CT: 16.67 131.u. The lack of unanimity SEM.u. expected IPC and SHAM would im- 39.70 mLIkgj1Iminj1 vs tematic ritual. Note that no difference was found for any variable among IPC. and CT.80 subjects that participated in the study. V̇CO2.00 T 0. and V̇O2max were also similar among in- nocebo effect related to circulatory occlusion sensations. on the other hand.50 T 11. and it varied between 140 [La]. 0%). CT: fourth minute.42 above the world record). worse.43 T 4.6 8.17 Occlusion pressure during IPC was recorded in the first four HR. instead of V̇O2.4 7. and to avoid a possible lactate threshold.00 136.3 T 0. On average.01 T 1. The percentage of subjects who responded performance after IPC did not surpass the effect of a placebo performance would be better versus CT was statistically similar intervention.8 T 0.5 0. vs Supramaximal test SHAM: 16.3 a. 39. mmolILj1 14 7. Subject_s best time in official races.15 T 3.98. P = 0. Fig.3 T 0.64 T 3. subjects were asked to compare their expected performance but similar between IPC and SHAM (P = 1.u.53 3 2076. and perceptual data at peak of the discontinuous incremental test and the supramaximal test. equal.71 RER.74 mLIkgj1Iminj1 vs sixth minute.8 64.org Copyright © 2016 by the American College of Sports Medicine.03 — — — 1500 206.5 9. mediated by the IPC. was longer in the IPC terventions effect. 39.5 0.67 T 65.7 T 1. 123% T 3% and 130% T V̇O2. terventions (P 9 0. a. respectively.7 64.3 T 0. 128 Official Journal of the American College of Sports Medicine http://www. P = 0.34 T 12. 0. 3). formance would better after IPC than CT (better. 2).000 1577. Time to exhaustion was longer after IPC (mean T terventions effect was not unanimous. 18 8. and SHAM versus CT. 17%.63 1 518. In addition.90 5000 757. 39. in general.5 T 0. 165. worse. and perceived effort were change in metabolic responses. ~23% and ~30% RER.20 T 14. the placebo induction and nocebo avoidance was P = 0. 39.34 s.4 T 1. the time that was closer to the world record was reported.7 T 0.5 T 0.00 2 252. If a subject had time recorded in more than one type of race. The response to this question may rely not only on the researcher_s explanation about the possible effect of interventions but also on any DISCUSSION factor that may modulate the subject well-being and moti- We circumvented limitations from previous studies to test vation on the experiment day.00 109. neural mechanisms related to placebo induction.08 T 0..4 0.35 4 1020. lactate concentration. The data the subjects_ personality (6). according with a sys- interventions (IPC: fourth minute.10 3% of the corresponding world record (i. and CT throughout the discon- The present study sought to induce similar placebo effect tinuous test (P 9 0. bpm 16 190 T3 191 T3 189 T 3 0.3 0. Data are mean T SEM. The subject_s best time is reported and compared with the n IPC SHAM CT P corresponding world record in Table 1.91 113.51. respectively). V̇O2. A recent meta-analysis reported a small beneficial effect Therefore. and 2) the improvement in perfor- Peak data were similar among interventions in the dis- mance after IPC and SHAM was probably mediated by continuous and supramaximal tests (Table 2).52). Men (n = 14) Women (n = 4) Meters World Record (s) n Best Time (s) Best Time (%) World Record (s) n Best Time (s) Best Time (%) 800 100.85 mLIkgj1Iminj1. Noteworthy. . equal.00 132.78 1 2340.6 T 1. on the IPC and SHAM interventions. which refuted the ergogenic effect specifically between IPC and SHAM (83% vs 78%.75 T 3. prove performance compared with CT.02 T 0.3 a.9 T 1.39 a. Oxygen cost of running. between-subject variability on expectancy about the in- Time to exhaustion.02 1.4 8. Physiological. Fig. Ventilation. bpm 16 189 T3 188 T3 189 T 3 0.3 T 0.00 Data are mean T SEM of absolute and percent values. 0%) and after SHAM than CT (better.78 mLIkgj1Iminj1 vs sixth minute. the positive expectancy about the in- state. 4) and SHAM (164. Unauthorized reproduction of this article is prohibited.98 T 12. 16 1. 78%.

90%. and. oxygen cost of and symptoms of IPC. and 30 min) before the perfor- and nocebo effects. 24 h. and ratio of perceived effort (panel D. including determinants of oxygen delivery and A recent study from our group. n = 18) throughout the discontinuous incremental test. a researcher told subjects that IPC and a sham ercise intensities (2. which approximated signs threshold. between IPC and low-pressure cuff inflation. The highest common velocity among the interventions was considered 100%. tics may be related to the distinct effect of IPC between these sus resting CT. The sham intervention consisted of formance (20.22).24). a sham intervention. They found both interventions improved studies. In our study. n = 14).35–0. as genic effect of IPC on a 100-m time trial and a bout of lower well as the testing protocol (constant velocity at supramaximal limb resistance exercise (29). that is oxygen cost of running. The assessment used in the present study. (28) attempted to exclude the placebo effect to test the ergo. but there was no difference of IPC to enhance exercise performance. 0. effects of IPC and amplified the IPC effect (26. panel C. lactate short-time circulatory occlusion. panel B.32). and low cuff effort (27). Authors told subjects_ IPC and intensity vs repeated sprints). Note that no difference was found for any variable among IPC. performance. Most subjects in fact believed IPC exercise performed at submaximal intensity. 85%. Unauthorized reproduction of this article is prohibited. based on the analysis of eight sham intervention did not. and that IPC and sham intervention would efficiency of the aerobic metabolism during whole body cause absolutely no harm.FIGURE 2—Data are mean T SEM of the oxygen uptake (V̇O2. and 95% were identified and used for statistical analyses. 10 min before the per- However. these characteris- low-pressure cuff inflation would improve performance ver. Nevertheless.18. Marocolo et al.24. Similarly to the study has reported reduced oxygen cost at submaximal ex- present study. utilization (20). The lack of IPC and sham intervention would improve performance. n = 16). Some of these studies specifically investigated effect specifically mediated by the IPC. which should be further investigated to enable the use performance compared with CT.13. and cycling at maximal intensity (13). and CT. however. Consequently. as far as we know. three variables summarize most of APPLIED SCIENCES inflation on swimming performance in a repeated sprint the contribution of aerobic mechanisms to endurance per- swimming task (16). and V̇O2max (20. 75%.14. the exercise mode was different (running vs swimming). lactate concentration ([La]. interpolated data corresponding to 70%. which does not Multiple mechanisms are known to regulate endurance support the ergogenic effect specifically mediated by the IPC. n = 16). which is similar to the endurance mediated ergogenic effect on endurance performance. carbon dioxide output (V̇CO2. confidence interval. . the effect of IPC on time to exhaustion during constant In the present study. because IPC induces ATP sparing (36) and ISCHEMIC PRECONDITIONING AND AEROBIC EXERCISE Medicine & Science in Sports & Exercised 129 Copyright © 2016 by the American College of Sports Medicine. At the effect on the aerobic metabolism during exercise is some- end. which supported the ergogenic studies (38). whereas the what surprising. present study. without attaining enough duration running was unaffected by IPC and. data did not support that IPC per se workload tasks (3. the IPC enhanced swimming performance. we applied IPC on endurance performance did not sufficiently control placebo three occasions (48 h. IPC prolonged time to findings herein presented are therefore in contrast to those from exhaustion during rhythmic handgrip exercise (3). panel A. SHAM. In this sense. we applied IPC once. com. and mechanisms that modulate perceived pared the effect of IPC. no that could possibly induce ergogenic effect. Altogether. on the other hand.22). which may have summed early and late the isolated effect of IPC (37). 80%.40). cycling at the recent study of our group (16). which complicate the interpretation about mance assessment. the present intervention would improve performance compared with the and previous findings suggest that IPC does not change the CT condition. In addition.67). these and other studies about the effect of IPC on formance assessment. based on that. in the heavy intensity (24). Of note. In the former study.

acsm-msse. and Patterson et al. measurements may not exactly reflect the V̇O2 and lactate may not be the same to the protective effects mediated by IPC during prolonged ischemia and subsequent reperfusion. These findings have been previously reported in discontinuous incremental tests (30). (2) reported that IPC decreased blood lactate concentration during an incremental treadmill test. Conse- quently. Nevertheless. instead of a close-ended task (i. (21).. (8) manipulated the meaning of a painful experience from negative to posi- tive through verbal suggestions. doubts about the V̇O2max attainment could have been raised. the present results supported that IPC did not change blood lactate levels during an incremental treadmill test in well-trained runners. threshold (LT. and rest–exercise transitions (10). SHAM. and maximal oxygen uptake (V̇O2max. independent from changes in metabolic responses (27. the verification protocol strengthens the interpretation that IPC did not change the V̇O2max in the present study. but others did not corroborate this finding (2. The manipulation resulted in increased pain endurance. therefore. In contrast. lactate (i. and CT. the mechanisms that mediate ergogenic lungs and lactate concentration at ear capillaries. the end is fixed) panel C. . n = 14). without any change in metabolic responses. Bailey et al. de Groot et al. n = 18). Note that Tlim was higher in the IPC and SHAM versus CT. These effects of IPC during whole body aerobic exercise. without the use of the verification protocol. panel B. Therefore. Jean-St-Michel et al. as well as on the lactate threshold. a real sport event and is more physiologically complex. (13) but there was no difference between IPC and SHAM. the low peak RER has been attributed to increase in en- dogenous CO2 stores during rest–exercise transitions (10). panel A. but the mechanisms specif- ically involved in placebo-induced exercise performance enhancement are unknown (5). which trended to dislocate the onset of blood lactate accumulation to APPLIED SCIENCES higher running velocity. Note that no difference performed at subject_s preferred pace.. However. the end is not fixed) performed at constant velocity.32). One of the study_s limitations was the assessment of en- durance performance using an open-ended laboratory test FIGURE 3—Individual data (dashed lines) and mean T SEM (bars and whiskers) of the oxygen cost of running (OCR. although peak RER was relatively low and peak perceived effort was not always at score 10. Unauthorized reproduction of this article is prohibited. SHAM. In fact. Of note. all previous IPC studies did not use strict criteria to confirm the V̇O2max. there was no effect of IPC on the blood lactate concentration throughout exercise inten- sities. that some mechanisms already described in clinical settings may be involved. we used a veri- fication protocol. In the present study. In the present study.e. which was mediated by coactivation of opioid and cannabinoid pathways (8). Crisafulli et al.e. after con- trolling placebo and nocebo effects. Thus. however. tions. The effect of IPC on the V̇O2max has also been equivocal.12). de Groot et al. and CT. For instance. (12). n = 16) in the IPC. our findings may not be extrapolated to other situa- augment electron mitochondrial flux during prolonged ische. Another limitation was the measurement of V̇O2 at the mia (9). The latter is nearer to was found for any variable among interventions. n = 15) in the IPC. (14) and Cruz et al. Benedetti et al. if any. 130 Official Journal of the American College of Sports Medicine http://www.org Copyright © 2016 by the American College of Sports Medicine. The protocol successfully confirmed the V̇O2max in all subjects. (33) found no effect of IPC on blood lactate concentration during varied exercise tests. reported IPC increased V̇O2max during cycling tests. FIGURE 4—Individual data (dashed lines) and mean T SEM (bars and whiskers) of the time to exhaustion (Tlim. For example. It is possible. Given that IPC and SHAM similarly enhanced endurance performance. neural mechanisms related to placebo induction could be responsible for the performance enhancement. (14). strong evidences support that neural factors can per se determine endurance exercise performance. Thus.

2011.25(3):356–64. Hopman 27. Burr JF. 2011. Med Sci Sports Exerc.106(3): humans. Is- 3. Placebo and the new physiology of the doctor-patient of time trial performance and maximal incremental exercise in relationship. Foad AJ. 2012. The IPC improvement. Manlhiot C. 2013. the au- parameters. 1991. falsification.32(9):1642–7. J Am Coll Cardiol. Rate of temperature increase in C. 2004. Panagiotidou AT. Med Sci 2015. we assessed conduct the study.39(4):313–29. B. 1995. Manning V. Braz ID.17(3):259–69. Ting H. 10 min before the performance as.111(5): 8. et al.3(5):e12395. 2009. formance after IPC and SHAM was probably mediated by genic effects in well-trained subjects. Sports Med. Ley O. Rasmussen P. Clin Physiol Funct of the muscle improves maximal exercise performance but not Imaging.302(10):H1974–82. 2005. et al. J. Foster 15. Modeling: optimal marathon performance on the basis mitochondrial electron transport chain proteins and improved of physiological factors. 23. At last. Sabino-Carvalho JL. Remote preconditioning positive co-activates opioid and cannabinoid systems. de Aguiar RA. J Appl Physiol. Tangianu F. Unauthorized reproduction of this article is prohibited. but instead. Ellenkamp R. Cruz RS. who was the trainer of most of the athletes that participated in the men and women. Coleman DA. Foad AJ. grant: 461516/2014-4) to which deserves further investigation.154(3):361–7. Subudhi AW. Castel D. Kido K. Ischemic preconditioning stored during early exercise.46(4):531–44. high altitude in trained male cyclists. Sanchez M. Blanchard C. Sommerlad SM. Eisenman P. 2. REFERENCES 1. et al. Jacobs RA. Physiol Rep. 1422–30. 1998. Atkinson G. instead of effect of IPC in well-trained subjects is blunted compared with change in metabolic responses. tem. model. et al. 2011. but our sample size was not enough to study. Overtraining and recovery. Crisafulli A. 19. carbohydrate feedings during a 40-km cycling time trial. Med Sci Sports Exerc. 2016.93(3):1207–46. A conceptual Am J Physiol Heart Circ Physiol. Ziemba EA. In conclusion. Westerdahl DE. received scholarship from the São Paulo Research IPC may not change metabolic responses. alternatively. et al.111(2): 26. Staiano W. Hopkins WG. Effects provides early and late protection against endothelial ischemia– of ischemic preconditioning on maximal constant-load cycling reperfusion injury in humans: role of the autonomic nervous sys- performance. Donald A. 2012. Thijssen DH. Use of temperature al- 12. and T. the neural mechanisms related to placebo induction. Foad AJ. Beedie CJ. whereas improved endurance performance in thors declare that the results of the study are presented clearly. brief review. J Appl Physiol. IPC the results refute that the ergogenic effect specifically me- was applied just once. human muscle during 1 MHz and 3 MHz continuous ultrasound. Turnes T. Walker J. less fit subjects. Sports Med. Clark VR. Pain as a reward: changing the meaning of pain from negative to 21. Furthermore. Positive and negative placebo 18. M. Loukogeorgakis SP. Sports Exerc. J Appl Physiol. such as muscle activation 25683-6 and 2014/24294-6) and the National Counsel of Technolog- (13) and/or rate of muscle contraction and relaxation (3). Lopes TR. Scand J Med Sci Sports. Draper DO.179(2–3):248–53. 2000. Ferreira TN. 9. Jean-St-Michel E. received funding from FAPESP (grant: 2014/ ifies neuromuscular mechanisms. de Groot PC. et al. S. Caputo F. Otsuka T. Burke LM. 2011.43(7):1280–6. 2016. Identification of placebo preconditioning on human exercise performance. Med Sci 2013. IPC did not change aerobic metabolism Authors have no conflict of interest to disclose. Aerobically generated CO(2) 24. 5. J Sports Sci Med. J Orthop Sports Phys Ther. well-trained runners. We are grateful to Luis Gustavo Andrade Candido. has been reported for the ergogenic effect of nitrate supplementation (35). ical and Scientific Development (CNPq. Int J Sport Nutr Exerc Metab. 2007. Pain. 1999. Thoen W. 2015. for example. Foster GP. Castel JC. diated by the IPC and suggest that the improvement in per- sessment. which may have not been enough to induce ergo. Gregson W. Or. nocebo study. ISCHEMIC PRECONDITIONING AND AEROBIC EXERCISE Medicine & Science in Sports & Exercised 131 Copyright © 2016 by the American College of Sports Medicine. 2010. Hsu JV. Mental fatigue impairs MT. for collaboration with subjects_ enrolment and scheduling of dissect whether gender modulates the effect of IPC. Med Sci Sports Exerc. Millar PJ. 4. Kenttä G. Barbosa TC. 2011. Marcora SM. honestly. . responsive participants in 40km laboratory cycling perfor. or inappropriate data manipulation. Cabrera JA. Eur J Appl Physiol.40(1):65–71. Physiol Neurobiol. J Appl Physiol. S. Benedetti F. L.44(11):2084–9. re- spectively). improves maximal performance in highly trained athletes. 530–6. The placebo effect in sports performance: a 2015. et al. Determinants 7. et al. Remote ischemic preconditioning 13. mod. et al.concentration at contracting skeletal muscles nor differentiate not surpass the effect of a placebo intervention. tilatory threshold. highly trained endurance athletes. Ischemic Thijssen DH. Pereira KL. Respir ercise. 857–64. which.48(10):1967–75. Physiol Rev. Arduino C. Machado AC. et al.70(2):683–7. 14.87(3):1048–58. Foundation (FAPESP. Bailey TG. Ischemic preconditioning improves maximal performance in physical performance in humans. 2009. Remote ischemic chemic preconditioning of the lower extremity attenuates the nor- preconditioning delays fatigue development during handgrip ex.7(1):166–75. Nash MS. J Appl Physiol. 10. Beedie CJ. Jones H. however. Hittinger EA. An evaluation of the predictive validity and reliability of ven.22(4):142–50. Chuang ML. Tocco F. Siebenmann C. Cable NT. The results of the present study do not constitute endorsement by ACSM. myocardial energetic state during late ischemic preconditioning. 16.108(1):141–6. Vighetti S. Li J. Incognito AV. The effects of ischemic 6. Beedie CJ.46(3):450–6. 2008. Also. Suga T. Foster LA. Broadhead MW. Deanfield JE. MacAllister RJ. grants: 2014/15877-8 and 2015/03572-0. Anholm JD. 20. 17. Sports Exerc. Sports Med.26(1):1–16. Altered expression of 22. mal hypoxic increase in pulmonary artery systolic pressure. Effect of ischemic preconditioning on lactate preconditioning and repeated sprint swimming: a placebo and accumulation and running performance.31(1):66–72. Tanaka D. Maher JL. 25. Coleman DA. accelerates muscle deoxygenation dynamics and enhances APPLIED SCIENCES 11. Ischemic preconditioning effects resulting from the deceptive administration of an ergogenic does not improve peak exercise capacity at sea level or simulated aid. Amann M. Therefore. mance. Placebo effect of exercise endurance during the work-to-work test. Benedetti F. Shultz B. Appl Physiol Nutr Metab. J Appl Physiol. Joyner MJ. O.36(10):1716–22. experimental visits. Dhindsa M. Hassmén P. maximal oxygen uptake in humans. 2015.119(9):961–7. Hawley JA. Colbert R. Ischemic preconditioning terations to characterize vascular reactivity. did and without fabrication. metabolic responses between subtypes of skeletal fibers.

partly a placebo effect? Int J Sports Med.19(3):313–22. Scand J Med Sci uptake and muscle deoxygenation during exercise? Physiol Rep. blood lactate endurance markers. Newell J. 2016. Appl Physiol. Marocolo IC. Okano AH. 2004. Reimer KA. Montenegro RA.acsm-msse. Sabino-Carvalho JL.org Copyright © 2016 by the American College of Sports Medicine. Int J Sports Physiol Perform. da Mota GR. Appell Coriolano HJ. 2015. 31. Pyne DB. Hawley JA. Marocolo M. 1986. Med Sci Sports Exerc. 2016. Four Simao R. Cond Res. Bellistri G. Telford RD. Madden N. ertion and performance during maximal exercise. 40. Higgins D.101(6):677–92. Ischemic preconditioning and exercise performance: a 32. J Sports Sci. Ribeiro da Mota G. 2008. et al. Jones AM. Fontes EB. Aerobic fitness affects the beneficial effects of ischemic preconditioning on performance the exercise performance responses to nitrate supplementation. Brain stimulation systematic review and meta-analysis. Lisboa FD. 2015. Midgley AW. Salvador AF. Sports. modulates the autonomic nervous system. What is the effect of 30. Re- 34. Glaister M. Pelegrini V. Marocolo M.34(7):465–85. Factors affecting 33. Eur J vention and potential underlying mechanisms. Am J Physiol. rating of perceived ex- 2016. Ischemic preconditioning and placebo inter. Thijssen DH. Are 35. Cable NT. Med Sci Sports Exerc. Unauthorized reproduction of this article is prohibited. Yamasawa I. Br J Sports Med. Pereira KL.30(5):1462–9.47(8):1643–51. 2015. The effect of running economy in trained distance runners. Pattison JR.36(10):822–5. Porcelli S. brief periods of myocardial ischemia cause no cumulative ATP vention improves resistance exercise performance. 39.251(6):H1306–15. 29. De Aguiar RA. Cruz RS. Software for calculating 38. J Strength loss or necrosis. Emergence of the verification phase ischemic preconditioning on the kinetics of pulmonary oxygen procedure for confirming Ftrue_ VO(2max). et al. 36. Wilkerson DP. Ramaglia M. APPLIED SCIENCES 132 Official Journal of the American College of Sports Medicine http://www. et al. . Murry CE. Saunders PU. Hill ML. Caputo F. Jennings RB. Bezodis NE.102(4):403–10. Poole DC. Validity of criteria for peated ischaemic preconditioning: a novel therapeutic inter- establishing maximal O2 uptake during ramp exercise tests. 2015. Patterson SD. Carroll S. Jones H. 2015. Willardson JM. 37. Maxwell J. Exp Physiol. ischemic preconditioning on repeated sprint cycling performance. 2009.3(9):e12540. Barbosa TC.11(1):4–14. Silva BM. 28.25(12):1403–9. Maior AS.47(8):1652–8. Sports Med.49(18):1213–8. Green DJ. 2007.