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SYSTEMATIC REVIEW

The Effects of Ischemic Preconditioning on Human ExercisePerformance

Anthony V. Incognito1 • Jamie F. Burr1 • Philip J. Millar1

Published online: 8 December 2015

� Springer International Publishing Switzerland 2015

Abstract

Background Ischemic preconditioning (IPC) is the

exposure to brief periods of circulatory occlusion and

reperfusion in order to protect local or systemic organs

against subsequent bouts of ischemia. IPC has also been

proposed as a novel intervention to improve exercise per-

formance in healthy and diseased populations.

Objective The purpose of this systematic review is to

analyze the evidence for IPC improving exercise perfor-

mance in healthy humans.

Methods Data were obtained using a systematic com-

puter-assisted search of four electronic databases (MED-

LINE, PubMed, SPORTDiscus, CINAHL), from January

1985 to October 2015, and relevant reference lists.

Results Twenty-one studies met the inclusion criteria. The

collective data suggest that IPC is a safe intervention that

may be capable of improving time-trial performance.

Available individual data from included studies demon-

strate that IPC improved time-trial performance in 67 % of

participants, with comparable results in athletes and recre-

ationally active populations. The effects of IPC on power

output, oxygen consumption, rating of perceived exertion,

blood lactate accumulation, and cardiorespiratory measures

are unclear. The within-study heterogeneity may suggest

the presence of IPC responders and non-responders, which

in combination with small sample sizes, likely confound

interpretation of mean group data in the literature.

Conclusion The ability of IPC to improve time-trial

performance is promising, but the potential mechanisms

responsible require further investigation. Future work

should be directed toward identifying the individual phe-

notype and protocol that will best exploit IPC-mediated

exercise performance improvements, facilitating its appli-

cation in sport settings.

Key Points

This systematic review examined the effects of

ischemic preconditioning (IPC) on exercise time-

trial performance, power output, and oxygen

consumption in healthy individuals.

Although, large between-study variability exists, the

most consistent benefit of IPC is for an improvement

in time-trial performance in exercise tests of

predominantly lactic anaerobic and aerobic capacity.

Future trials must strive to determine the optimal IPC

and sham-control protocols and to limit the presence

of known confounders.

1 Introduction

Ischemic preconditioning (IPC) is the exposure to brief

periods of circulatory occlusion and reperfusion to protect

local or systemic (remote IPC) organs against subsequent

ischemia-reperfusion injury [1–4]. Since the discovery of this

& Philip J. Millar

[email protected]

1 Department of Human Health and Nutritional Sciences,

University of Guelph, 50 Stone Road East, Guelph, ON

N1G2W1, Canada

123

Sports Med (2016) 46:531–544

DOI 10.1007/s40279-015-0433-5

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phenomenon in 1986 [2], research has focused primarily on

the clinical utility of IPC to protect against organ damage and

cellular injury, such as during myocardial infarction or

perioperative periods [5–7]. Although the mechanisms

responsible for these actions are incompletely understood,

IPC has been shown to improve metabolic efficiency by

attenuating ATP depletion [8–10], glycogen depletion [11],

and lactate production [8, 9] during prolonged ischemia. In

addition, IPC may improve skeletal muscle blood flow by

inducing conduit artery vasodilation [12], enhancing func-

tional sympatholysis [13], and preserving endothelial and

microvascular function during stress [1, 14–16]. Based on

these findings, IPC has garnered interest as a novel inter-

vention to improve exercise capacity and performance.

The most common IPC protocol involves three or four

cycles of 5 min circulatory occlusion and reperfusion [2,

17, 18]. As this method is easily administered, non-inva-

sive, and inexpensive, it would represent an attractive

ergogenic aid for athletes to improve exercise performance

and gain a competitive advantage [18–20]. Although the

first proof-of-concept study reported that IPC increased

maximal oxygen consumption (VO2max) and peak power

output in trained cyclists during graded maximal cycling

[17], the benefit of IPC on exercise capacity and perfor-

mance in subsequent studies remains equivocal.

With adherence to the Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA)

guidelines [21, 22], the objective of this systematic review

is to examine the current state of evidence for IPC

improving exercise performance. We investigate both

mean and individual data in order to better capture the

impact of IPC on exercise capacity and performance, and

attempt to elucidate factors delineating responders and

non-responders. In addition, we discuss potential mecha-

nisms responsible for the reported improvements and

conclude with recommendations for future investigations

required for advancing IPC into sport practice.

2 Methods

2.1 Literature Search

Potential studies were identified by two unbiased reviewers

using MEDLINE, PubMed, SPORTDiscus, and CINAHL

databases. Common search terms used to address exercise

performance and IPC were ‘‘sports’’, ‘‘exercise’’, and ‘‘per-

formance’’, and ‘‘ischemic preconditioning’’, ‘‘ischemic

conditioning’’, and ‘‘preconditioning’’, respectively. For both

sets of search terms, relevant predefined database-specific

terms were added to broaden the search. For each database,

the date range was limited to January 1, 1985 (since the first

discovery of IPC was in 1986 [2]) to October 18, 2015. The

language was limited to English. Reference lists of articles

retrieved were manually checked for additional articles.

2.2 Eligibility Criteria for Potential Studies

Primary research studies published in or accepted by peer

reviewed journals were eligible for review. Animal studies,

case studies, study proposals, and review articles were

excluded. No restrictions were placed on participant age or

fitness level. Studies in disease populations were excluded to

yield a more focused review and to avoid confounding

conclusions that may arise from grouping participants with

different health status. IPC interventions were defined as any

procedure that performed multiple cycles of skeletal muscle

blood flow occlusion and reperfusion prior to exercise. These

protocols have been shown to be effective for cytoprotection

from ischemia-reperfusion injury [2]. Occlusion to both

exercising (IPC) and non-exercising (remote IPC) limbs were

included in the analysis since both have been shown to elicit

comparable cytoprotective effects [1–4]. Further, although

remote IPC requires a neurohumoral signal transduction

factor, considerable overlap in mechanisms between the two

forms of conditioning exist (e.g., triggering stimuli: nitric

oxide, adenosine, bradykinin, opioids; intracellular media-

tors: protein kinase C, hypoxia-inducible factor-1a, reper-fusion injury salvage kinase, microRNA-144; intracellular

effectors: mitochondria ATP-dependent potassium channel;

see Heusch [23]). Studies were only eligible if participants

were randomized into the IPC or control/sham interventions

(i.e., randomized control or crossover designs).

2.3 Study Selection

All studies investigating the effects of IPC on exercise

capacity or performance and meeting the eligibility criteria

indicated above were selected. Studies were first screened

by title and/or abstract, and then the manuscript was

reviewed if the study appeared to satisfy the eligibility

criteria and purpose of this systematic review (Fig. 1). This

process was conducted independently by two reviewers

(A.V.I. and P.J.M).

2.4 Data Collection

The primary study outcomes related to exercise capacity or

performance included measures of time-trial performance,

power output, VO2 [maximal (VO2max) or peak (VO2peak)],

rating of perceived exertion (RPE), and blood lactate

accumulation. Secondary study outcomes included relevant

cardiorespiratory variables (e.g., heart rate, blood pressure,

and ventilation). Studies investigating the effect of IPC on

time-trial performance and power output were classified

532 A. V. Incognito et al.

123

based on the predominant energy systems utilized during

the test. This was determined based on test duration, with

alactic anaerobic capacity predominating between exercise

initiation and 10 s, lactic anaerobic capacity predominating

between 10 and 75 s, and aerobic capacity predominating

for exercise longer than 75 s [24]. An exception was made

for activities requiring breath holds, which were defined as

tests of predominately lactic anaerobic capacity. Studies

investigating the effects of IPC on VO2 were subdivided

into tests of VO2max/peak and tests of submaximal VO2.

Authors were contacted if their article examined time-

trial performance or VO2max/peak but had unreported or

unclear individual participant data on responders and non-

responders. Five [25–29] out of nine contacted authors

responded to our request for individual participant data.

These data are presented in Table 1 and are included in

response rate calculations.

3 Results

3.1 Study Selection

Following article screening, 21 studies were selected for

review, totaling 374 participants (309 men, 65 women).

All major study characteristics are summarized in

Table 2. Twenty studies were designed as randomized

crossover trials, 12 of which used a sham-control and

eight of which used a time-control; the remaining study

was a randomized control trial with a parallel design.

Individual participant responses were obtained from 13 of

the 21 studies (through the article and/or authors) and

used to calculate the proportion of IPC responders and

non-responders (Table 1).

3.2 Effects of Ischemic Preconditioning (IPC)

on Exercise Performance

3.2.1 Time-Trial Performance

3.2.1.1 Tests of Predominantly Alactic Anaerobic Capac-

ity IPC had no effect on 30 m running sprint time [27].

3.2.1.2 Tests of Predominantly Lactic Anaerobic Capac-

ity IPC improved (-1.1 % [18]) and had no effect [30]

on 100 m swim sprint time. IPC also improved under-

water swimming distance (?8.2 % [31]) and mean static

breath hold duration (?17.2 % [31]). IPC had no effect

on three sets of submaximal bilateral knee extension to

failure [32].

Fig. 1 Flow diagram of the

study selection process based on

eligibility criteria for a

systematic review examining

the effects of ischemic

preconditioning (IPC) on

exercise performance

Ischemic Preconditioning and Exercise Performance 533

123

3.2.1.3 Tests of Predominantly Aerobic Capacity IPC

improved 5 km treadmill running time (-2.5 % [19]), 1 km

rowing sprint time (-0.4 % [31]), time to failure during

graded maximal cycling (*?3.6 % [33]) and constant load

cycling (*?15.8 % [28] and ?7.9 % [26]), and time to

failure during submaximal rhythmic handgrip (?10.6 %

[34]). IPC had no effect on 5 km outdoor running time [29],

time to failure during graded maximal cycling [19, 25] or

constant load cycling at 130 % of peak power [33], or time

needed to cycle 100 kJ of total work [35].

3.2.1.4 Overall Findings IPC improved time-trial per-

formance in nine of 17 exercise performance tests. After

examination of the available individual responses,

improvements and no effects in 118 and 57 participants

(Fig. 2a), respectively, were noted, which corresponds to a

67 % response rate [18, 19, 25, 27–31, 33, 34]. Dividing

the studies on the basis of exercise test duration demon-

strated improvements in 11 and no effects in 14 partici-

pants [27], respectively, in tests of predominantly alactic

anaerobic capacity (44 % response rate). There were

improvements in 32 and no effects in 11 participants [18,

31] within tests of lactic anaerobic capacity (74 % response

rate), and 75 and 32 participants [19, 25, 26, 28, 29, 31, 33,

34], respectively, in tests of predominantly aerobic capac-

ity (70 % response rate).

3.2.2 Power Output

3.2.2.1 Tests of Predominantly Alactic Anaerobic Capac-

ity IPC increased (?2.3 % [36]) and had no effect [37,

38] on peak power output during repeated 6 s cycling

sprints.

3.2.2.2 Tests of Predominantly Lactic Anaerobic Capac-

ity IPC had no effect [38] and detrimental effects [39] on

peak power output during a Wingate test.

3.2.2.3 Tests of Predominantly Aerobic Capacity IPC

increased (?3.7 % [17] and ?1.6 % [33]) and had no effect

[40] on peak power output during graded maximal cycling

tests. Additionally, IPC had no effect on submaximal

cycling workload required to reach target heart rate [41].

3.2.2.4 Overall Findings IPC increased peak power in

three of eight exercise tests, and had no effect on sub-

maximal power output in one exercise test.

3.2.3 Oxygen Consumption

3.2.3.1 Tests of Maximal Oxygen Consumption IPC

increased (?2.8 % [17]) and had no effect [33] on VO2max

determined using a graded maximal cycling test. Addi-

tionally, IPC had no effect on VO2max/peak during a graded

maximal treadmill test when tested acutely [19] or after

8 weeks of repeated IPC treatments [42]. IPC was also

shown to increase (?2.8 %) VO2max/peak during constant

load cycling to failure at 100 % peak power [26] but had no

effect at 130 % peak power [33] or at 89 % VO2peak [28].

3.2.3.2 Tests of Submaximal Oxygen Consumption IPC

had no effect on mean VO2 during a 5 km running time

Table 1 Responders vs. non-responders to ischemic preconditioning (IPC) in studies reporting individual differences in time-trial performance

and maximal oxygen uptake

References Effects of IPC IPC benefit IPC null

de Groot et al. [17] : VO2max 12 3

Jean-St-Michel et al. [18] ; 100 m swim time 14 3

Crisafulli et al. [33] : Time to failure 10 7

$ VO2max 6 9

Clevidence et al. [25] $ Time to failure 6 6

Bailey et al. [19] ; 5 km running time 11 2

Gibson et al. [27] $ 30 m sprint time 11 14

Kjeld et al. [31] ; 1 km row time 11 3

: Underwater swim distance 9 2

Tocco et al. [29] $ Mean 5 km running speed 5 6

Barbosa et al. [34] : Handgrip time to failure 9 4

Kido et al. [28] : Time to failure 13 2

Marocolo et al. [30] $ 100 m swim time 9 6

Cruz et al. [26] : Time to failure 10 2

: VO2peak 8 4

: Increase, ; decrease, $ no change, max maximal, VO2 oxygen consumption


123

Table

2Summaryofstudycharacteristicsandexercise

perform

ance

andphysiologychanges

withischem

icpreconditioning(IPC)

Study

Studydesign

Population

IPC

protocol

IPC

limb

Exercise

test

EffectsofIPC

deGroot

etal.[17]

Randomized,

controlled

crossover

12M,3F;27±

6years;

trained

cyclists

39

5min

at

220mmHg

Bilateral

upper

leg

Graded

max

cycling

:VO2max

:W

peak

$BL2min

post

cycling

Jean-St-

Michel

etal.[18]

Randomized,sham

-

controlled

crossover

9M,9Ffor100m

swim

;

19±

3years;8M,8Ffor

200m

intervals;

19±

3years;elitesw

immers

49

5min

at15mmHg

aboverestingSBP

Unilateral

upper

arm

100m

swim

;100m

swim

time

79

200m

swim

intervals

$BL2min

post

each

200m

Crisafulli

etal.[33]

Randomized,

controlled

crossover

17M;35±

9years;

recreationally

active

39

5min

at50mmHg

aboverestingSBP

Bilateral

upper

leg

Graded

max

cycling

:Tim

eto

failure

:W

peakandW

total

$VO2max

Alloutcyclesprintat

130%

Wpeakto

failure

(W

determined

byagraded

max

cyclingtest)

$Tim

eto

failure

$VO2max

$W

total

$BLpostcyclesprint

Foster

etal.

[35]

Randomized,

controlled

crossover

6M,2F;39±

10years;

experiencedcyclists

49

5min

at20mmHg

aboverestingSBP

Unilateral

upper

leg

Cyclesprintto

100kJ

$Cyclesprinttime

Clevidence

etal.[25]

Randomized,

controlled

crossover

12M;27±

9years;

competitiveam

ateurcyclists

39

5min

at220

mmHg

Alternate

unilateral

upper

leg

Graded

max

cycling

$Tim

eto

failure

$BL5min

post

cycling

Baileyet

al.

[19]

Randomized,sham

-

controlled

crossover

13M;25±

6years;healthy,

moderatelytrained

49

5min

at220

mmHg

Bilateral

upper

leg

5km

treadmillrun

;5km

runningtime

;RPEduringfirst1000m

;BLduringsubmax

running

Graded

max

treadmillrunning

$Tim

eto

failure

$VO2max

$BL3min

postgraded

max

running

ElMessaoudi

etal.[41]

Randomized,

controlled

crossover

10M,10F;22±

4years;

healthyvolunteers

39

5min

at200

mmHg

Bilateral

upper

arm

70min

cyclingat

80%

HRmax

orreserve;

15min

oruntil

failure

at95%

HRmaxor

reserve

$W

required

fortarget

HR

Gibsonet

al.

[27]

Randomized,sham

-

controlled

crossover

16M,9F;23±

3years;

competitiveteam

sport

athletes

39

5min

at

220mmHg

Alternate

unilateral

upper

leg

39

30m

runningsprints

$30m

sprinttime

Paixao

etal.

[39]

Randomized,sham

-

controlled

crossover

15M;30±

7years;

competitiveam

ateurcyclists

49

5min

at250

mmHg

Alternate

unilateral

upper

leg

3Wingatetestsseparated

by

10min

rest

;W

peakin

thefirstWingateandW

total

infirstandsecondWingatetests

$BL6min

post

each

Wingate

Kjeld

etal.

[31]

Randomized,

controlled

crossover

10M,4F;23years;elite

oarsm

en;10M,1F;

29years;elitefree

divers

49

5min

at40mmHg

aboverestingSBP

Unilateral

upper

arm

1km

row

;1km

row

time

Staticbreathhold;underwater

distance

swim

:Staticbreathhold

timeand

underwater

swim

distance


123

Table

2continued

Study

Studydesign

Population

IPC

protocol

IPC

limb

Exercise

test

EffectsofIPC

Jones

etal.

[42]

Randomized,

controlled

18M;22±

2years

IPC,

26±

5yearscontrol;healthy

volunteers

49

5min

at

220mmHg,39/

week,8weeks

Unilateral

upper

arm

Graded

max

treadmillrunning

$VO2peak

Patterson

etal.[36]

Randomized,sham

-

controlled

crossover

14M;30±

4years;

recreational

team

sport

athletes

49

5min

at220

mmHg

Bilateral

upper

leg

129

6scyclesprints

:W

peakandW

meanforsprints

1,2,3

$RPE

$BLim

mediately

postsprint4,8,12

Hittinger

etal.[40]

Randomized,

controlled

crossover

15M;30±

7years;

competitivecyclistsand

triathletes

49

5min

at15mmHg

aboverestingSBP

Bilateral

upper

leg

Graded

max

cycling

$W

peak

$RPE

Lalondeand

Curnier

[38]

Randomized,sham

-

controlled

crossover

8M,9F;29±

8years;healthy

students

andam

ateur

triathletes

49

5min

at50mmHg

aboverestingSBP

Unilateral

upper

arm

69

6scyclesprints;Wingate

test

$W

peakandW

meanforeither

test

;RPEduringWingate

Toccoet

al.

[29]

Randomized,sham

-

controlled

crossover

11M;35±

8years;

competitiverunners

39

5min

at50mmHg

aboverestingSBP

Bilateral

upper

leg

5km

run

$5km

runningtime

$BL1min

post

running

Gibsonet

al.

[37]

Randomized,sham

-

controlled

crossover

7M,9F;24±

3years;

competitiveteam

sport

athletes

39

5min

at220

mmHg

Alternate

unilateral

upper

leg

59

6scyclesprints

$W

peakandW

total

$RPE

;BL3min

postfifthsprintin

women

Barbosa

etal.

[34]

Randomized,sham

-

controlled

crossover

13M;25±

4years;

recreationally

active

39

5min

at

200mmHg

Bilateral

upper

leg

Rhythmic

handgripat

45%

MVC

tofailure

(60

contractions/min)

:Tim

eto

failure

Kidoet

al.

[28]

Randomized,

controlled

crossover

15M;24±

1years;habitually

active

39

5min

at

[300mmHg

Bilateral

upper

leg

3min

cyclingat

30W,4min

cyclingat

90%

GET,until

failure

at70%

ofdifference

betweenGETandVO2peak

:Tim

eto

failure

$VO2peak

$BLduringsubmax

and

immediately

post

cycling

Marocolo

etal.[30]

Randomized,sham

-

controlled

crossover

15M;21±

4years;

competitiveam

ateur

swim

mers

49

5min

at220

mmHg

Alternate

unilateral

upper

arm

100m

swim

$100m

swim

time

Cruzet

al.

[26]

Randomized,sham

-

controlled

crossover

12M;20–36years;

recreationally

trained

cyclists

49

5min

at220

mmHg

Bilateral

upper

leg

100%

Wpeakto

failure

(W

determined

byagraded

max

cyclingtest)

:Tim

eto

failure

:VO2peak

;RPE

$BLim

mediately

post

cycling

Marocolo

etal.[32]

Randomized

sham

-

controlled

crossover

13M;26±

5years;resistance

trained

49

5min

at220

mmHg

Alternate

unilateral

upper

leg

3setsofbilateral

legextension

tofailure

(12repetitionmax

load)

$Repetitionsper

set

$RPE

$BL4min

post

set3

Agedataaremean±

SD

:Increase,;decrease,$

nochange,BLbloodlactate,Ffemale,GETgas

exchangethreshold,HRheartrate,M

male,maxmaxim

um/m

axim

al,MVCmaxim

alvolitionalcontraction,postafter,

RPEratingofperceived

exertion,SD

standarddeviation,submaxsubmaxim

al,SBPsystolicbloodpressure,VO2oxygen

consumption,W

workload

orpower


123

trial [29], repeated 6 s cycle sprints and associated recov-

ery periods [36], or submaximal VO2 during graded cycling

[17, 25] or during 4 min of cycling at a workload corre-

sponding to *55 % of VO2max [28].

3.2.3.3 Overall Findings IPC increased VO2max in two of

seven exercise tests, and had no effect on mean or sub-

maximal VO2 in five exercise tests. Examination of the

available individual responses noted VO2max/peak improve-

ments and no effects in 26 and 16 participants (62 %

response rate; Fig. 2b), respectively [17, 33].

3.2.4 Rating of Perceived Exertion

IPC decreased RPE during a Wingate test (*1 point on a

Borg 1–10 scale [38]), during the first 1000 m of a 5 km

treadmill time trial (*1–2 points on a Borg 6–20 point scale

[19]), and during the first 4 min of cycling to failure at

100 % power output (0.8 points on a Borg 6–20 point scale

[26]), but had no effect during a graded maximal cycling test

[40], three sets of submaximal bilateral knee extension to

failure [32], or repeated 6 s cycling sprints [37, 43].

3.2.5 Blood Lactate

IPC attenuated blood lactate accumulation during sub-

maximal treadmill running (-1.07 mmol-1 or -25.4 %

[19]), but had no effect during submaximal cycling [28].

IPC decreased blood lactate 6 min post cycling exercise in

women (-1.4 mmol-1 or -15.9 % [37]), but had no effect

on post-exercise blood lactate accumulation in all other

studies, though the non-statistically significant mean results

ranged from 7.1 % lower to 8.7 % higher [17–19, 25, 26,

28, 29, 32, 33, 39, 43].

3.3 Effects of IPC on Cardiorespiratory Variables

During Exercise

3.3.1 Heart Rate

IPC increased (*?2.4 % [32]) and had no effect [17, 28]

on maximal heart rate during graded maximal cycling; no

effect on maximal [26, 28] or submaximal [28] heart rate

during constant load cycling to failure; no effect on max-

imal or submaximal heart rate during cycling to 100 kJ of

total work [35]; and no effect on maximal [19] or mean

heart rate [29] during a 5 km running time trial. Similarly,

IPC had no effect on peak heart rate during rhythmic

handgrip exercise to failure [34] or during a 100 m swim

time trial [18]. IPC had no effect on heart rate during

submaximal interval swims [18], submaximal cycling

workloads [17, 28], submaximal treadmill running [19], or

submaximal rhythmic handgrip [34]. IPC did increase heart

rate at a submaximal intensity of 30 % maximal cycling

power output (?5.1 % [25]).

3.3.2 Blood Pressure

IPC had no effect on submaximal mean arterial pressure, but

increased maximal mean arterial pressure (?11 mmHg or

?9.2 % [34]) during rhythmic handgrip exercise to failure,

compared with control conditions. IPC had no effect on

maximal mean arterial pressure [33] or systolic or diastolic

blood pressure [17] during graded maximal cycling. Addi-

tionally, IPC attenuated hypoxia-induced increases in pul-

monary artery systolic pressure at rest (-22.5 % [35]).

3.3.3 Respiratory Variables

IPC had no effect on respiratory exchange ratios during a

5 km running time trial [29], nor during graded maximal

cycling [25]. IPC increased (*?8.1 % [33]) and had no

effect on maximal minute ventilation during graded max-

imal cycling [17, 25], and no effect on maximal or sub-

maximal pulmonary VO2 during submaximal cycling to

failure [28]. Additionally, IPC had no effect on maximal or

submaximal minute ventilation during graded maximal

treadmill running [19] or on mean pulmonary ventilation

during a 5 km running time trial [29].

3.4 Safety and Tolerability

Although no studies sought specifically to investigate the

safety of IPC, no adverse clinical events were reported in

Fig. 2 Number of responders

and non-responders to ischemic

preconditioning (IPC)-mediated

effects on a time-trial

performance, and b maximal

oxygen consumption


123

any of the reviewed studies. The IPC procedure has been

reported to elicit a score of ‘‘4’’ on a 1–10 pain scale in

healthy participants [38], suggesting it is uncomfortable but

not painful for the average participant.

4 Discussion

4.1 Summary of Findings

IPC has been proposed as a novel intervention to increase

exercise capacity and performance [20, 44]. The results of

this systematic review highlight the considerable equipoise

in the literature and variability in IPC-mediated exercise

benefits between studies. The most consistent evidence was

for an improvement in time-trial performance (nine of 17

exercise tests; 67 % individual response rate), detected

only in exercise modes lasting 10–75 s (three of five

exercise tests; 74 % individual response rate) and [75 s

(six of 11 exercise tests; 70 % individual response rate),

which were characterized in this review as tests of pre-

dominantly lactic anaerobic and aerobic capacity, respec-

tively. The effects on power output, VO2, RPE, and blood

lactate accumulation were less clear; as were changes in

cardiorespiratory measures. An examination of individual

participant data supports the hypothesis that IPC respon-

ders and non-responders may exist [45], which could

explain the large variability observed in exercise perfor-

mance responses within and between studies. The present

results are best used to catalyze future research questions,

study designs, and hypotheses, to establish the utility of

using IPC as an ergogenic aid. Future research must aim to

determine the phenotype most likely to respond to IPC,

optimal IPC protocols, and the mechanisms involved in

mediating the potential beneficial effects on exercise

performance.

4.2 Potential IPC Responders and Non-Responders

The responsiveness to any therapy or treatment can vary

between individuals on the basis of genetic, pathological,

and/or environmental profiles. It is acknowledged that such

heterogeneity even exists in the responsiveness to exercise

training [46]. Whether a similar range of responsiveness

exists to IPC has recently been postulated [45] to explain

the discrepancy between the widespread cytoprotective

success in experimental models [2, 4, 8–11] and the

inconsistency of benefits in clinical trials [47, 48]. Exam-

inations of clinical IPC responsiveness have reported

reduced or absent cardioprotection in women, diabetics,

and older patients with coronary artery disease [48, 49],

suggesting a phenotype for ‘‘responders’’ and ‘‘non-re-

sponders’’ may exist. This could explain the large

variability observed in exercise performance responses

within and between studies (Table 1 and 2) and highlights

the potential limitation of conventional statistical approa-

ches based on aggregate data.

4.3 Potential Sources of Between-Study Variability

In addition to potential differences in IPC responsiveness,

it is difficult to compare results between studies as partic-

ipant characteristics (e.g., sex, training status) and study

methods (e.g., exercise mode, pre-study restrictions, IPC

protocol) differ widely. The following sections will assess

the potential impact that this between-study variability may

have on the results.

4.3.1 Study Participants

Participant characteristics differed widely between stud-

ies. Females were not included in eight of 21 studies and

only represent 17 % of participants overall, raising the

question of whether a sex-based difference in IPC

responsiveness may exist. To our knowledge, this has not

been investigated formally in humans. Peak exercise

capacity and training status were also highly variable. We

attempted to classify the studies into categories based on

one or a combination of participant VO2max/peak, peak

power output, and author-reported fitness status. We

identified five studies with highly trained participants [18,

29, 31, 39, 40], 12 studies with trained participants [17,

19, 25–27, 30, 32, 33, 35–38], and four studies with

recreationally active participants [28, 34, 41, 42]. Within

the highly trained population, two of five studies (40 %)

reported improvements in exercise performance following

IPC [18, 31], compared with five of 12 studies (42 %) in

the trained population [17, 19, 26, 33, 36] and two of four

studies (50 %) in the recreationally active population [28,

34]. Available individual participant time-trial response

rates were 81, 57, and 79 % for the highly trained, trained,

and recreationally active population, respectively. It must

be acknowledged that although we attempted to catego-

rize participant fitness status, we only identified two elite

athlete populations [18, 31]. Broadening the continuum of

fitness status is required to understand the role of fitness

and/or sport-specific training status on IPC efficacy.

Understanding these potential trends may explain vari-

ability in results and give insight into the IPC responder

phenotype.

4.3.2 Exercise Mode

The mode of exercise performed differed dramatically

between studies (Table 2). To help stratify the results, we


123

grouped exercise mode by duration and predominant

energy systems. With respect to time-trial performance, the

results demonstrate clearly that the majority of observed

benefits were in exercise tests lasting longer than 10 s,

although no differences in IPC responsiveness were

observed between tests of predominantly lactic anaerobic

and aerobic capacity. While the large variability in exercise

modes makes it difficult to compare directly between

studies, the reported benefits across a variety of tests pro-

vide support for a generalized effect.

4.3.3 IPC Protocols

The optimal methodology for implementing IPC is

unknown [50], with variability in the size (muscle mass)

of the occluded limb, the number of ischemia-reperfusion

cycles or cycle length, and the time lag between IPC and

the start of exercise. The protective effects of remote IPC

against brachial artery endothelial ischemia-reperfusion

injury have been shown to be similar when occlusion was

completed three times in the arms and legs [51]; however,

whether the effects on exercise performance are propor-

tional to the muscle mass is uncertain. No clear rela-

tionships were evident from the present data as time-trial

performance was improved by implementing IPC to the

arm [18, 31] or leg [19, 26, 33, 34]. The number of

ischemia-reperfusion cycles may also be important, and

interact with the amount of muscle mass. Two cycles of

5 min circulatory occlusion in the legs, but not the arms,

prevents brachial artery endothelial ischemia-reperfusion

dysfunction [51]. All of the studies included in this review

completed either three or four cycles of 5 min occlusion

and reperfusion; however, no clear relationships with

exercise performance were present. Lastly, IPC is known

to exert an early (1–2 h) and late (12–72 h) window of

effectiveness on ischemia-reperfusion injury [52]. The

optimal time lag between IPC and the start of exercise has

not been investigated. Current studies ranged from 5–105

min, with no clear relationships with exercise perfor-

mance. Future investigations establishing optimal proto-

cols for the implementation of IPC prior to exercise are

warranted.

4.3.4 Pre-Study Restrictions

A notable limitation of the existing literature is the

inconsistency in limiting confounders known to modulate

the effects of IPC, such as caffeine, alcohol, and physical

activity [33, 53–55]. Of the 21 studies, only 14 reported

pre-study instructions, 13 restricted caffeine, 12 restricted

alcohol, and 11 restricted physical activity. The timelines

for these restrictions were also not standardized.

With respect to caffeine, studies implemented 48 h

(n = 2), 24 h (n = 7), 12 h (n = 1), 6 h (n = 2), and 2 h

(n = 1) restrictions. A plasma concentration of *6 mg/L,

the equivalent of drinking two to four cups of coffee, has

been shown to abolish the cytoprotective effects of IPC

compared with plasma concentrations of *0.2 mg/L,

achieved by asking participants to abstain from caffeine for a

minimum of 24 h [55]. Given that caffeine is reported to

have a half-life in plasma of roughly 5.5 h [56], two to four

cups of coffee would take roughly 27.5 h to reduce to con-

centrations of 0.2 mg/L. This information should encourage

caffeine restriction for at least 24 h prior to IPC testing.

The captured studies implemented a 48 h (n = 2) and

24 h (n = 10) abstinence from alcohol. The protective

effects of IPC against myocardial ischemia have been

shown to be abolished when blood ethanol concentrations

were between 16 and 34 mg/dL, 30 min after oral admin-

istration of 40 g of ethanol (approximately three standard

alcoholic drinks in North America) compared with the

placebo group [54]. As alcohol has a clearance rate of

*13 mg/dL/h [57], the commonly used 24 h abstinence

prior to IPC testing is likely sufficient.

With regards to physical activity, studies implemented a

pre-study restriction of 5 days (n = 1), 48 h (n = 2), and

24 h (n = 7). One study restricted physical activity for 1

week between crossover study visits, but did not commu-

nicate a pre-study restriction. Since physical activity may

elicit a similar preconditioning response to IPC [33, 53],

and the effects of IPC can persist for up to 48 h [1],

restrictions on physical activity should extend for a mini-

mum of 48 h prior to IPC testing.

It is acknowledged that the implementation of these

restrictions may compromise the practicality of research in

athletes. For example, caffeine represents a common

ergogenic aid employed by endurance athletes to improve

performance [58], while restricting exercise for 48 h (or

longer) would likely alter the training schedule of most

athletes and lead to sub-optimal performances during

subsequent testing. It is recommended that careful docu-

mentation of these confounders be collected and reported

in all future research.

4.4 Potential Mechanisms for IPC-Mediated

Improvements in Exercise Performance

Whether the factors regulating the clinical benefits of IPC

for protecting organs against prolonged ischemia are

the same as those needed for potential improvements in

exercise performance is unclear. In animal models testing

ischemic tolerance, IPC acts via a blood-borne sub-

stance(s) that requires the presence of adenosine [59, 60],

nitric oxide [60], and an intact nervous system [60,

61]. The following sections briefly review potential


123

mechanisms that may be responsible for IPC’s ability to

alter exercise performance.

4.4.1 Metabolic Efficiency

With the exception of Patterson et al. [43], IPC-mediated

improvements were observed in exercise performance tests

classified as predominantly utilizing lactic anaerobic or

aerobic energy systems [17–19, 28, 31, 33, 34]. This sug-

gests that IPC may not have as strong of an impact on

alactic anaerobic capacity [24]. In support of a metabolic

mechanism, animal-based investigations using prolonged

ischemia of skeletal muscle have demonstrated that IPC

attenuates ATP depletion [8–10, 62] secondary to mito-

chondrial ATP-sensitive potassium (mKATP) channel

opening [51, 62], skeletal muscle opioid receptor activation

[8], and preservation of ischemia-induced reductions in

muscle energy charge potential [9]. IPC has also been

shown to attenuate ischemia-induced mitochondrial dys-

function [63, 64]. This may be the result of IPC-mediated

increases in nitric oxide [65–67], as nitrate supplementa-

tion in humans has been shown to improve basal mito-

chondrial efficiency through enhancement of ADP

sensitivity [68]. Furthermore, IPC has been observed to

reduce ischemia-induced glycogen depletion [11] and lac-

tate production [8, 9] in skeletal muscle. These studies

suggest that IPC can reduce muscle energy demand and

improve metabolic efficiency in times of ischemic stress.

Evidence of IPC improving metabolic efficiency in

humans is scarce. Bailey et al. [19] reported attenuations in

submaximal exercise blood lactate accumulation in healthy

participants, but whether this was due to reduced produc-

tion or increased clearance is unclear. IPC has been shown

to increase peak forearm deoxygenation during handgrip

exercise to failure [34] and mean forearm deoxygenation

during a static breath hold [31], which may represent

increased oxygen extraction by the muscle. However, both

of these investigations also reported increased time to task

failure following IPC; therefore, the enhanced deoxy-

genation reported with IPC may reflect the greater time

available for oxygen extraction [31, 34]. When compared

at equal time points during submaximal exercise, IPC does

not alter the magnitude of deoxygenation, rather, it alters

the kinetics, speeding up deoxygenation at the onset of

moderate cycling exercise [28], which would reduce the

oxygen deficit. In addition, IPC has recently been shown to

increase VO2peak partially through increasing the amplitude

(not the delay) of the slow component of whole body VO2

[26]. This change may have been driven by the recruitment

of additional motor units towards the end of exercise [26].

Overall, human evidence for IPC improving metabolic

efficiency requires further investigation.

4.4.2 Blood Flow

IPC has been observed to increase muscle oxygen satura-

tion during 6 s cycle sprints [43] and rhythmic handgrip

exercise at 25 % maximal volitional contraction [13],

reflecting a disproportional increase in muscle blood flow

compared with oxygen demand. IPC-mediated increases in

muscle blood flow during exercise are likely secondary to

the ability of IPC to protect against exercise-induced and

ischemia-induced endothelial [1, 15, 19] and microvascular

[16] dysfunction. Additionally, IPC can induce conduit

artery vasodilation of the contralateral limb [12]. IPC can

also enhance functional sympatholysis [13], likely medi-

ated by increases in nitric oxide [65–67] or decreases in

sympathetic activity [12, 69]. Therefore, IPC may improve

skeletal muscle blood flow by preserving endothelial and

microvascular function, as well as attenuating neurogenic

restraint on peripheral vasculature. Since endothelial and

microvascular function and sympathetic activity are

impacted by nitric oxide [16, 65, 70], these mechanisms

may work in concert to enhance skeletal muscle blood flow

during exercise. Arguing against increases in blood flow,

remote IPC failed to increase brachial artery diameter or

blood flow compared with control during rhythmic hand-

grip, even though time to failure was increased [34]. Fur-

ther work in humans is required to confirm that IPC-

mediated vascular effects are involved in improving exer-

cise performance.

4.5 Potential Clinical Benefits

The value of IPC for improving exercise performance in

clinical populations remains largely unstudied. In patients

with coronary [44] or peripheral artery disease [71, 72], IPC

had no effect on exercise time to failure or oxygen uptake,

but did alter clinically relevant markers, such as increasing

time to claudication [71] and cardiac ischemia [44], and

lowering peak systolic blood pressure and rate pressure

product [44]. The ability of IPC to prolong the onset of

myocardial ischemia during exercise [44] may be due to

improved metabolic efficiency and increases in myocardial

blood flow, similar to the above mechanisms described in

skeletal muscle. Compared with control conditions, remote

IPC was shown to preserve mitochondrial respiration in

atrial [73] and ventricular [74] tissue after aortic cross-

clamping in patients undergoing coronary artery bypass graft

surgery. Furthermore, remote IPC has been shown to

increase coronary artery blood flow in animals [75] and

humans [76]. Together, these results suggest that prolonged

onset of exercise-induced cardiac ischemia following IPC

may be due to improved myocardial oxygen utilization or

delivery.


123

One important unanswered question is whether clinical

patients fully respond to IPC. In patients with heart failure

[77], IPC had no effect on VO2peak, exercise duration, or

power output. Blood drawn from these heart failure

patients following IPC did not attenuate infarct size in a

mouse heart Langendorff model of infarction [77], com-

pared with a 38.6 % reduction previously reported with

healthy athletes [18]. Further, IPC does not protect against

endothelial ischemic-reperfusion injury in heart failure

patients [78]. The reduced efficacy in patients with heart

failure with reduced ejection fraction may highlight the fact

that these patients are already preconditioned due to

chronic exposure to a low flow state. Although potential

disease-specific differences in IPC responsiveness may

exist, the therapeutic benefits of IPC on exercise capacity

and performance for clinical populations warrant further

study. It is known that exercise capacity is a strong marker

of overall mortality in cardiovascular disease [79–82] and

that the benefits of exercise rehabilitation are dose/volume

dependent [83]. Interventions to increase exercise duration

or tolerance may allow patients to perform more exercise

and reap greater overall benefits.

4.6 Future Directions

To better establish the effects of IPC on human exercise

performance, more strictly controlled and mechanistic

studies are needed. Overall, sample sizes need to be

increased to account for the large variability in between-

subject IPC responsiveness and to detect the modest 1–3 %

improvements in exercise performance that have been

reported to date. Additionally, there is a need for a direct

comparison between different IPC protocols, exercise

modalities, individual fitness levels, and sport-specific

backgrounds to determine if these factors play a role in IPC

effectiveness and to better understand the potential IPC

responder and non-responder phenotypes. Pre-study

restrictions on caffeine, alcohol, and physical activity are

recommended to be implemented for a minimum of 24, 12,

and 48 h, respectively. In athletes, these restrictions may

not be practical, and it is recommended that careful data

collection on these confounders be reported. Further, a

major confounder with all human studies remains the

inability to effectively sham-control IPC treatments.

Highlighting the potential influence of placebo effects on

results, a recent study noted that 67 % of participants

improved 100 m swim time following a sham-IPC condi-

tion compared with a time-controlled condition when they

were told that sham-IPC would improve exercise perfor-

mance [30]. At a minimum, studies should seek to record

participants’ knowledge of IPC-mediated exercise effects

[38], while the use of deception may be required.

5 Conclusion

Current evidence suggests that IPC may be efficacious as

an ergogenic aid to improve exercise performance and gain

a competitive advantage. Of the 21 investigations

reviewed, 10 reported statistically significant exercise

performance benefits such as improved time-trial perfor-

mance, increased VO2max/peak, increased power output, or

reduced ratings of perceived exertion. The mechanisms

responsible for these improvements are unknown, but

likely involve changes in both metabolic and vascular

pathways. However, despite these positive findings, 11

studies demonstrated no effect of IPC on exercise perfor-

mance, three of which were completed with short-duration

exercise modes utilizing predominantly alactic anaerobic

metabolism. The large between-subject variability of

results may be impacted by populations of IPC responders

and non-responders, and therefore caution should be used

in the interpretation of mean group changes in exercise

performance. Future IPC research should focus on (1)

increasing the statistical power to detect the modest

changes in exercise performance and account for the

variability in IPC responsiveness, (2) improving our

understanding of the physiological mechanisms involved,

(3) identifying the participant phenotype or IPC protocol

mediating beneficial exercise responses, and (4) deter-

mining the applicability for clinical populations engaged in

exercise rehabilitation. Overall, the application of IPC as

an ergogenic aid and adjunct clinical rehabilitation therapy

is promising, but requires further investigation.

Compliance with Ethical Standards

Funding Anthony Incognito is supported by a Fredrick Banting and

Charles Best Canada Graduate Scholarship. Jamie Burr and Philip

Millar are both supported by National Science and Engineering

Research Council (NSERC) Discovery Grants.

Conflicts of interest Anthony Incognito, Jamie Burr, and Philip

Millar declare that they have no conflicts of interest relevant to the

content of this review.

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