Effects of Remote Limb Ischemic Conditioning to Enhance Muscle Power, Dynamic Balance, and Walking Performance in Children With Cerebral Palsy
Phase: NA
Conditions: Cerebral Palsy
Sponsor: East Carolina University

 
Remote Limb Ischemic Conditioning to Enhance Muscle Power, Dynamic 
Balance, and Walking Performance in Children with Cerebral Palsy 
 
 
 
 
 
 
 
10/15/2020 
 

1 
 
Remote Limb Ischemic Conditioning to Enhance Muscle Power, Dynamic 
Balance, and Walking Performance in Children with Cerebral Palsy 
Study Objectives 
The objective of this research study is to determine if remote limb ischemic 
conditioning (RLIC) can enhance quadriceps muscle power, dynamic 
balance and walking performance in children with cerebral palsy (CP). 
Background & 
Rationale 
Ischemic conditioning is an endogenous phenomenon in which exposing a 
target organ or tissue to one or more brief episodes of ischemia results in 
protection of that organ against subsequent ischemia.1 The effects of 
ischemic conditioning are not confined within an organ but can be can be 
transferred from one organ to another, a technique called remote ischemic 
conditioning.2 A clinically feasible method for this is remote limb ischemic 
conditioning (RLIC), where episodes of ischemia and perfusion are induced 
with a blood pressure cuff placed on the arm.3 
 
In humans, the cardioprotective effects of RLIC have been demonstrated.4,5 
For example, applying an inflated blood pressure cuff to the upper or lower 
limb has shown efficacy for protection in people undergoing cardiac 
surgeries,4,6 elective surgery to repair abdominal aortic aneurysm,7 
experiencing myocardial infarction,5 and with symptomatic intracranial 
arterial stenosis. Subsequent studies have shown RLIC as neuroprotective8 
and improves exercise performance in healthy young adults.9-12 Based on 
the promising results of our clinical trials which demonstrated that when 
paired with training, RLIC improves muscle strength and motor learning in 
healthy young and older adults respectively.13,14 Therefore, we postulate that 
the effects of RLIC might extend in neurological population such as CP. 
 
Our central hypothesis is that the multifactorial mechanisms of RLIC can be 
harnessed as a neurorecovery agent to enhance rehabilitation and 
outcomes in children with CP. This research will focus on improving 
quadriceps power and dynamic balance since quadriceps weakness and 
impaired balance performance are often cited as major factors that limit the 
mobility and walking performance of children with CP.15-17 The results of our 
randomized controlled trials have shown that RLIC facilitates motor learning 
and muscle strength, and retention of these changes in older and young, 
neurologically intact adults.13,14 However, these learning and strength effects 
have only been seen only in healthy population. Hence, the next step is to 
investigate if RLIC can enhance performance of an ecologically valid motor 
task such as dynamic balance task, increase skeletal muscle power, and 
increase walking performance in children with CP. 
 

2 
 
This study is important because if eventually effective, RLIC could have 
profound effect on the rehabilitation and recovery of brain plasticity and 
muscle performance in children with CP and other neurological population.  
Study Design 
Between groups repeated measures design.  
Groups 
Group 1: Children with CP receiving RLIC 
Group 2: Children with CP receiving sham conditioning 
Children who qualify and consent will be randomly assigned to either group 
1 or 2.  Participants will be blinded to the group assignment and the assessor 
will be blinded to the participant’s group assignment. 
Number of 
Subjects & Power 
Analysis 
Sample size estimates are based on peak knee extension power data from 
Moreau et al.18 A total of 24 participants (12 in each group) will provide 80% 
power to detect an effect size of 0.62 at significance level of 0.05.  
The sample size was calculated based on a two-sided Wald test of 
regression coefficients in linear mixed effects model adjusting for design 
effect and correlation of repeated measures from the same subjects.19  
 
Inclusion & 
Exclusion Criteria 
Inclusion Criteria:  
1. Children diagnosed with unilateral or diplegic CP 
2. Gross Motor Function Classification System (GMFCS) levels I-III  
3. 6-13 years of age 
 
Exclusion Criteria:  
1. Children with other developmental disabilities such as autism, 
developmental coordination disorders, etc. 
2. Children with cognitive deficits or communication problem 
3. Children with balance disorders such as vestibular disorders, posterior 
fossa tumor etc. 
4. Children with known cardiorespiratory dysfunctions 
5. Children who are receiving other adjunct therapies such as TMS, tDCS, 
vagal nerve stimulation etc. 
6. Presence of lower extremity condition, injury, or surgery which could 
compromise conditioning and training 
7. Children with sickle cell disease 
 
RLIC and Sham 
Conditioning 
 
Remote limb ischemic conditioning will be achieved via blood pressure cuff 
inflation to 20 mmHg above resting systolic blood pressure up to 200 
mmHg.20,21 Sham conditioning will be achieved via blood pressure cuff 
inflation to 25 mmHg on the more involved thigh. Conditioning will involve 5 
cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 
minutes of cuff deflation. Subjects will be blinded to their group assignment 
(RLIC or sham conditioning). Conditioning requires 45 minutes. RLIC or 
sham conditioning will be performed on visits 1-14. 

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Behavioral 
Training  
Three tasks will be used for behavioral training on visits 3-14.  
 
1) Power training task (20-30 minutes) 
2) Balance training task (15 minutes; rest breaks as needed) 
3) Treadmill training (15 minutes) 
 
Power Training: Prior to training and at the beginning of each training week, 
we will obtain 1 repetition maximum (1 RM) on each leg. 60-80% of the 1 RM 
will be used as training intensity with progression toward 80% based on that 
week’s 1 RM. Training will involve unilateral and bilateral leg presses (Total 
Gym GTS, San Diego, CA), 3 times/week for 4 consecutive weeks (12 
sessions). Each session will begin with 5 minutes of warm-up exercises. 
Each participant will perform 6 sets of 5-7 concentric extension contractions 
with maximum efforts, and with one-three minutes rest after each set.22 
Balance Task: The balance task requires subjects to stand on a movable 
platform (Stability Platform, model 16030L, Lafayette Instrument) and to 
keep the platform in a balanced, horizontal position.23 This task was selected 
because it can be easily modified to the appropriate level of difficulty in 
accordance with each subject’s motor abilities. 
Treadmill Training: We will use short burst interval treadmill training. We 
will use the self-selected and fast walking speeds determined by the 10-
meter walk test as the training intensity for the child for each session. Short 
burst interval training will consist of 30 seconds fast followed by 30 seconds 
of slow walking. We chose this type of training since it closely resembles the 
walking performance of a child in the community. 
Descriptive 
measures 
Demographic information, including age, dominant side, gender, ethnicity, 
race, level of physical activity, height, body weight, school grade, GMFCS 
level, prenatal, natal, or postnatal history, co-morbidities, current 
medications, history of any surgery, and current and past rehabilitation will 
be collected on all subjects on visit 1. Performing all these descriptive 
measures on visit 1 will allow us to determine the inclusion/exclusion of the 
participant in the study. 
Outcome Measures The outcomes measured include- 
Performance on: 
           1. Quadriceps power 
           2. Electromyography 
           3. Balance  
           4. Walking 

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Quadriceps power: will be measured using Humac Norm Isokinetic testing 
device (Computer Sports Medicine Inc, Stoughton, MA). Quadriceps power over 
5 maximal test repetitions at 90̊/sec will then be calculated every 10 ms (velocity 
x torque).  
 
Electromyography (EMG): The EMG data will be used to quantify the 
electrical amplitude of quadriceps muscle. Increase in the amplitude of EMG 
is an indicator of neurophysiological adaptation to strength training.24,25 We 
will simultaneously record the EMG activity of quadriceps muscle while 
performing isokinetic testing. EMG data will be gathered 6-channel EMG 
system (Delsys Inc, USA) with the sampling frequency set at 1000 Hz). Surface 
EMG sensors will be placed at the muscle belly in the direction of muscle fibers, 
according to surface EMG for non-invasive assessment of muscles (SENIAM) 
guidelines (http://www.seniam.org). EMG data will be processed off-line in 
MATLAB R2016a (MathWorks, Natick, MA) with custom-written software using 
cutoff frequencies of 20 and 500 Hz for lower and upper band-pass, respectively 
and by averaging by averaging the amplitude of the EMG activation during the 
middle 3000 ms for each trial.  
 
Performance on the standing balance task will be quantified by identifying 
the number of seconds in a 30-second trial that an individual is able to 
maintain the platform within ±5° of horizontal. 
Walking Performance: 
 
Walking performance will be measured with: 
 
1. Walking speed: Self-selected and fast walking speeds will be 
measured using 10-meter walk test. Children will complete three 
trials at each speed and the average of the respective trials will be 
considered for analysis. During these tests, children will walk across 
a GaitRITE digital mat (CIR Systems, Sparta, NJ) and we will quantify 
walking speed, step length, step width, and cadence. 
 
2. Gait analysis: Lower extremity walking kinetics and kinematics will 
be measured using a 10-camera motion analysis system (Qualisys 
Inc., Gothenburg, Sweden) sampling at 200 Hz.  Specific kinematic 
variables are hip, knee, and ankle joint angles at midstance, peak hip 
extension, peak knee extension, and peak ankle plantarflexion during 
stance phase. Kinetic dependent variables include peak hip, knee, 
and ankle sagittal plane joint moments and total support moment, 
and peak positive and negative hip, knee, and ankle sagittal plane 
joint power. 
 
3. Accelerometry: Lower extremity activity will be measured using 
accelerometers worn on bilateral ankles for 24 hours. Specific 
accelerometry variable will be number of steps. 
 

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Order of 
Experiment/Study 
Visits 
This study involves 16 total visits. Participants will be in the study for up to 8 
weeks.  Please refer to Table 1 for a timeline of study visits. 
Visit 1: We will provide informed consent and assent and gather 
demographic data. Next we will perform baseline assessments for the 
performance on the quadriceps power, EMG, balance, and walking. 
            Then, we will quantify power of bilateral knee extensor by recording 
peak knee extensors toque and electromyography of bilateral rectus femoris, 
vastus lateralis, and vastus medialis. 
            Next, we will gather measurements on balance task.  
            Next, we will assess walking performance using 10-meter walk test, 
3-D gait analysis, and accelerometry.  
            Subjects will then be randomized to their treatment group. After 
randomization, subjects will undergo RLIC or sham conditioning (see RLIC 
and Sham Conditioning for the details). This visit will take approximately: 
3 hours. 
Visit 2: Subjects will undergo RLIC or sham conditioning This visit will take 
approximately: 1 hour. 
Visit 3-14: Subjects will undergo RLIC or sham conditioning.  Next, 
behavioral training will commence (power training task and balance training). 
The order of behavioral training task practice will be randomized. Visits 3-14 
will occur every alternate business day. These visits will take 
approximately: 2-2.5 hours. 
Visit 15: Subjects will complete post-testing which will include a) quadriceps 
power; b) EMG; c) balance task, and d) walking performance. Visit 15 will be 
on the next business day after visit 14. During this visit, participants will not 
receive RLIC or sham conditioning. This visit will take approximately: 2 
hours.  
Visit 16: Post-test performance assessment on power, EMG, balance, and 
walking will be performed after 4-weeks from the visit 15. Participants will not 
receive RLIC or sham conditioning during the follow-up visits. Participants 
will fill out a survey on the follow-up visit indicating whether they think that 
they received RLIC or sham treatment. This visit will take approximately: 
2 hour. 
Data Analysis 
Data will be analyzed using a mixed model ANOVA with time (pretest, 
posttest, and follow-up) as within subject factor and group (RLIC vs. sham 
treatment) as between subject factor.  
Safety 
Considerations & 
Monitoring 
The risks of participating in the rehabilitation intervention are minimal and 
are similar to the risks encountered during routine physical and occupational 
therapy services.  
Conditioning:  

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The likely risks are:  
       1. Bruising on the conditioning thigh: To avoid bruising from the pressure 
cuff, participant’s arm will be covered with a folded cotton pillowcase. 
       2. Discomfort:  To avoid discomfort in the conditioning thigh during each 
conditioning cycle, we will ask the participant about discomfort. If the 
participant reports discomfort, we will reposition the pressure cuff on the 
thigh and allow the participant to move the thigh during 5-minutes of deflation 
cycle. 
      3. Pain or tingling on the conditioning arm: To avoid pain or tingling in the 
conditioning thigh during the conditioning cycle, we will ask the participant 
about pain and tingling. If the participant reports pain or tingling, we will 
reposition the pressure cuff on the thigh and allow the participant to move 
the thigh during 5-minutes of deflation cycle. 
Power Training:  
The likely risks are 
1. Knee or thigh pain: To avoid the knee or thigh pain, participants will 
perform warm-up exercises for 5 minutes before starting the 
strengthening. 
2. Muscle fatigue and delayed onset muscle soreness: Power training 
on every alternate day will allow sufficient time to recover from 
muscle fatigue and delayed onset muscle soreness.  
 
Balance:  
The less likely risks are 
1.  Falling from the balance board: To avoid falling from the balance 
board, participants will be permitted to use a handrail as needed for 
safety during balance task and up to two research team members will 
supervise the balance performance. Participants will also wear a gait 
belt for safety, which will help the research team member to catch the 
participant if they start to fall. 
 
Treadmill: 
The less likely risks are 
1. Muscle fatigue and falling from the treadmill: To avoid falling from the 
treadmill, participants will be provided sufficient rest. Participants will 
also be allowed to use a handrail as needed and will also wear a gait 
belt for safety. 
 
In order to monitor for further overall safety, we will continuously monitor 
lightheadedness, respiratory distress, cyanosis, and spasms. We will record 
and monitor heart rate, blood pressure, and oxygen saturation before, 
during, and after each session of RLIC. Sessions will be terminated if heart 
rate <60 bpm or >160 bpm, systolic BP <70 mmHg or >130mmHg, diastolic 

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BP <40 or >90 mmHg, O2 saturation <90%, or if pain is >6 on 10-point Likert 
pain scale. Moreover, during the follow up session, all subjects will be asked 
questions about any adverse effects that resulted from participation in this 
study.  
Investigators 
PI: Swati Surkar, PhD, PT 
Number of Centers 
1 center: East Carolina University 
Key References 
Please see the reference list. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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References 
1. Gidday, J. M. (2006). Cerebral preconditioning and ischaemic tolerance. Nature Reviews 
Neuroscience, 7(6), 437-448.  
2. Saxena, P., Newman, M. A., Shehatha, J. S., Redington, A. N., & Konstantinov, I. E. (2010). 
Remote ischemic conditioning: evolution of the concept, mechanisms, and clinical 
application. Journal of cardiac surgery, 25(1), 127-134.  
3. Kharbanda, R. K., Nielsen, T. T., & Redington, A. N. (2009). Translation of remote ischaemic 
preconditioning into clinical practice. The Lancet, 374(9700), 1557-1565.  
4. Hausenloy, D. J., Mwamure, P. K., Venugopal, V., Harris, J., Barnard, M., Grundy, E., ... & 
Hayward, M. (2007). Effect of remote ischaemic preconditioning on myocardial injury in patients 
undergoing coronary artery bypass graft surgery: a randomised controlled trial. The 
Lancet, 370(9587), 575-579.  
5. Bøtker, H. E., Kharbanda, R., Schmidt, M. R., Bøttcher, M., Kaltoft, A. K., Terkelsen, C. J., ... & 
Lassen, J. F. (2010). Remote ischaemic conditioning before hospital admission, as a complement 
to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a 
randomised trial. The Lancet, 375(9716), 727-734.  
6. Meng, R., Asmaro, K., Meng, L., Liu, Y., Ma, C., Xi, C., ... & Jia, J. (2012). Upper limb ischemic 
preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology, 79(18), 1853-
1861.  
7. Ali, Z. A., Callaghan, C. J., Lim, E., Ali, A. A., Reza Nouraei, S. A., Akthar, A. M., ... & Gaunt, M. E. 
(2007). Remote ischemic preconditioning reduces myocardial and renal injury after elective 
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I-98.  
 
8. Liu, Z. J., Chen, C., Li, X. R., Ran, Y. Y., Xu, T., Zhang, Y., ... & Ji, X. M. (2016). Remote ischemic 
preconditioning‐mediated neuroprotection against stroke is associated with significant alterations 
in peripheral immune responses. CNS Neuroscience & Therapeutics, 22(1), 43-52. 
 
9. Jean-St-Michel, E., Manlhiot, C., Li, J., Tropak, M., Michelsen, M. M., Schmidt, M. R., ... & 
Redington, A. N. (2011). Remote preconditioning improves maximal performance in highly trained 
athletes. Med Sci Sports Exerc, 43(7), 1280-1286. 
 
10. Kjeld, T., Rasmussen, M., Jattu, T., Nielsen, H., & Secher, N. (2014). Ischemic preconditioning of 
one forearm enhances static and dynamic apnea. Medicine & Science in Sports & Exercise, 46(1), 
151-155. 
 
11. Crisafulli, A., Tangianu, F., Tocco, F., Concu, A., Mameli, O., Mulliri, G., & Caria, M. A. (2011). 
Ischemic preconditioning of the muscle improves maximal exercise performance but not maximal 
oxygen uptake in humans. Journal of applied physiology, 111(2), 530-536. 
 
12. Bailey, T. G., Jones, H., Gregson, W., Atkinson, G., Cable, N. T., & Thijssen, D. H. (2012). Effect 
of ischemic preconditioning on lactate accumulation and running performance. Med Sci Sports 
Exerc, 44(11), 2084-9. 
 

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13. Surkar, S. M., Bland, M. D., Mattlage, A. E., Chen, L., Gidday, J. M., Lee, J. M., ... & Lang, C. E. 
(2020). Effects of remote limb ischemic conditioning on muscle strength in healthy young adults: A 
randomized controlled trial. PloS one, 15(2), e0227263. 
 
14. Sutter, E. N., Mattlage, A. E., Bland, M. D., Cherry-Allen, K. M., Harrison, E., Surkar, S. M., ... & 
Lang, C. E. (2019). Remote limb ischemic conditioning and motor learning: evaluation of factors 
influencing response in older adults. Translational stroke research, 10(4), 362-371. 
 
15. Damiano, D. L., Laws, E., Carmines, D. V., & Abel, M. F. (2006). Relationship of spasticity to knee 
angular velocity and motion during gait in cerebral palsy. Gait & posture, 23(1), 1-8. 
 
16. Steele, K. M., Damiano, D. L., Eek, M. N., Unger, M., & Delp, S. L. (2012). Characteristics 
associated with improved knee extension after strength training for individuals with cerebral palsy 
and crouch gait. Journal of pediatric rehabilitation medicine, 5(2), 99-106. 
 
17. Steele, K. M., van der Krogt, M. M., Schwartz, M. H., & Delp, S. L. (2012). How much muscle 
strength is required to walk in a crouch gait?. Journal of biomechanics, 45(15), 2564-2569. 
 
18. Moreau, N. G., Holthaus, K., & Marlow, N. (2013). Differential adaptations of muscle architecture 
to high-velocity versus traditional strength training in cerebral palsy. Neurorehabilitation and neural 
repair, 27(4), 325-334. 
 
19. Snijders, T. A. (2005). Power and sample size in multilevel linear models. Encyclopedia of statistics 
in behavioral science. 
 
20. Hyngstrom AS, Murphy SA, Nguyen J, Schmit BD, Negro F, Gutterman DD, et al. Ischemic 
conditioning increases strength and volitional activation of paretic muscle in chronic stroke: a pilot 
study. J Appl Physiol (1985). 2018;124(5):1140-7. 
 
21. Hyngstrom, A. S., Murphy, S. A., Nguyen, J., Schmit, B. D., Negro, F., Gutterman, D. D., & Durand, 
M. J. (2018). Ischemic conditioning increases strength and volitional activation of paretic muscle in 
chronic stroke: a pilot study. Journal of Applied Physiology, 124(5), 1140-1147. 
 
22. Bird, S. P., Tarpenning, K. M., & Marino, F. E. (2005). Designing resistance training programmes 
to enhance muscular fitness. Sports medicine, 35(10), 841-851. 
 
23. Cherry-Allen, K. M., Gidday, J. M., Lee, J. M., Hershey, T., & Lang, C. E. (2015). Remote limb 
ischemic 
conditioning 
enhances 
motor 
learning 
in 
healthy 
humans. Journal 
of 
neurophysiology, 113(10), 3708-3719. 
 
24. Christie, A., & Kamen, G. (2010). Short‐term training adaptations in maximal motor unit firing rates 
and afterhyperpolarization duration. Muscle & Nerve: Official Journal of the American Association 
of Electrodiagnostic Medicine, 41(5), 651-660. 
 

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25. Carroll, T. J., Selvanayagam, V. S., Riek, S., & Semmler, J. G. (2011). Neural adaptations to 
strength training: moving beyond transcranial magnetic stimulation and reflex studies. Acta 
physiologica, 202(2), 119-140. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1: Order of the 16 study visits. Testing occurs on Study Visits 1, 15, and 16. Conditioning 
which involves 5 cycles of 5 minutes of lower extremity peripheral ischemia (or sham), alternating 
by 5 minutes of no ischemia, occurs on Study Visits 1-14. Training occurs on Study Visits 3-14 
(Study Visits 4-14 occur every other business day, excluding weekends and holidays) and 
includes power, balance and treadmill training. 
 
 
Assessment
s 
 
 
Visits 
 
1 
(D1) 
2 
(D2) 
 3 
(D3
) 
4 
(D5
) 
5 
(D7
) 
6 
(D9) 
7 
(D11) 
8 
(D13) 
9 
(D15) 
10 
(D17) 
11 
(D19) 
12 
(D21) 
13 
(D23) 
14 
(D25) 
15 
(D26
) 
16 
(4 
weeks 
from 
visit 15) 
 
Consent/ 
Demographic 
details 
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-testing  
✔ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Conditioning  
(RLIC/ 
Sham) 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
 
 
 
 
 
 
✔ 
 
 
Training 
 
 
 
✔ 
✔ 
✔ 
✔ 
✔ 
 
 
 
 
 
 
✔ 
 
 
Post-testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✔ 
✔ 
 
*D= business day 
 
1. Pre-testing includes: Performance on the- 1) Power task, and 2) balance task, and 3) walking 
task. 
2. Training includes: Training on the- 1) Bilateral Knee Extensor Strengthening, 2) Balancing 
task on the balance board, and 3) Short burst treadmill training. 
3. Post-testing includes: Performance on the- 1) Power task, 2) balance task, and 3) walking 
task. 
 
 
 
 
 
 

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