Ladlow et al.

Pilot and Feasibility Studies (2017) 3:71

DOI 10.1186/s40814-017-0216-x

STUDY PROTOCOL Open Access

The effects of low-intensity blood flow

restricted exercise compared with
conventional resistance training on the
clinical outcomes of active UK military
personnel following a 3-week in-patient
rehabilitation programme: protocol for a
randomized controlled feasibility study
Peter Ladlow1,2* , Russell J. Coppack1,2, Shreshth Dharm-Datta1, Dean Conway1, Edward Sellon3,
Stephen D. Patterson4 and Alexander N. Bennett1,5

Abstract
Background: A challenge for rehabilitation practitioners lies in designing optimal exercise programmes that facilitate
musculoskeletal (MSK) adaptations whilst simultaneously accommodating biological healing and the safe loading of an
injured limb. A growing body of evidence supports the use of resistance training at a reduced load in combination with
blood flow restriction (BFR) to enhance hypertrophic and strength responses in skeletal muscle. In-patient rehabilitation
has a long tradition in the UK Military, however, the efficacy of low intensity (LI) BFR training has not been tested in this
rehabilitation setting. The aims of this study are to determine (1) the feasibility of a randomised controlled trial (RCT)
investigating LI-BFR training in a residential, multidisciplinary treatment programme and (2) provide preliminary data
describing the within and between-group treatment effects of a LI-BFR intervention and a conventional resistance
training group in military personnel.
Methods: This is a single-blind randomised controlled feasibility study. A minimum of 28 lower-limb injured UK military
personnel, aged 18 to 50 years, attending rehabilitation at the UK Defence Medical Rehabilitation Centre (DMRC) will be
recruited into the study. After completion of baseline measurements, participants will be randomised in a 1:1
ratio to receive 3 weeks (15 days) of intensive multidisciplinary team (MDT) in-patient rehabilitation. Group 1 will
receive conventional resistance training 3 days per week. Group 2 will perform twice daily LI-BFR training. Both
groups will also undertake the same common elements of the existing MDT programme. Repeat follow-up
assessments will be undertaken upon completion of treatment. Group 2 participants will be asked to rate their
pain response to LI-BFR training every five sessions.
(Continued on next page)

* Correspondence: [email protected]
1
Academic Department of Military Rehabilitation, Defence Medical
Rehabilitation Centre (DMRC), Headley Court, Epsom, Surrey, UK
2
Department for Health, University of Bath, Bath, UK
Full list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
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Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 2 of 14

(Continued from previous page)

Discussion: The results will provide information on the feasibility of a full-scale RCT. Recommendations for an
adequately powered study to determine the efficacy of LI-BFR training during in-patient rehabilitation can then be
made. The study may also provide insights into the potential effectiveness of LI-BFR training as a novel exercise modality
to induce muscle adaptations in the absence of high mechanical loading of the lower-limb.
Trial registration: ISRCTN Reference: ISRCTN 63585315 dated 25 April 2017.
Keywords: Blood flow restriction, Musculoskeletal rehabilitation, Lower-limb, Muscle, Strength, Hypertrophy, Pain

Background typically achieved via a pressurised cuff [10], tourniquet

The maintenance of adequate skeletal muscle is crucial [11] or elastic banding [12]. The external pressure applied
for maintaining the ability to undertake activities of daily to the proximal portion of the upper or lower extremities
living, ambulation, falls avoidance and general health [1]. should be low enough to maintain partial arterial inflow
Disuse of skeletal muscle, often associated with muscu- into the muscle, but high enough to occlude venous return
loskeletal (MSK) injury, can lead to relatively rapid and from the muscle [13]. During periods of immobilisation,
progressive atrophy; shortening of muscle fibres, decreased the application of BFR alone has been shown to reduce
oxidative capacity, and reduced muscle compliance [2]. It muscular atrophy [14]. However, to optimise muscular
is widely acknowledged that muscle atrophy can prolong development, BFR must be combined with an exercise
the duration of MSK rehabilitation, increase the cost to stimulus (aerobic conditioning or resistance training),
health care providers and prevent optimal recovery [3]. with the greatest muscle strength and morphological
Thus, strategies to increase or maintain muscle tissue responses achieved when BFR is combined with resist-
across the lifespan are crucial for overall health and ance training [2].
quality of life. When supervised by experienced practitioners, low-
The goal of the surgical and rehabilitative team focuses intensity BFR (LI-BFR) has been shown to be a safe
on the safe return of a patient to their previous level of and effective tool to improve strength and function in
function. MSK rehabilitation can be considered in terms athletes [15], the elderly [16, 17] healthy adults [18]
of the appropriate integration and progression of the and during MSK rehabilitation [19–24]. Additional
following broad exercise components: endurance, flexi- benefits reported with LI-BFR training, is the potential
bility, proprioception, balance, joint and soft tissue for increases in muscle hypertrophy and strength in mus-
mobility, speed and power [4]. Strength training is most cles located proximal to the applied pressure (i.e. muscles
closely associated with improvements in functional ability not direct under BFR) as a result of pre-fatigue of the mus-
during rehabilitation [5]. Therefore, maximising the potential cles below the cuff [25]. It is possible that this additional
for adaptations in muscle strength is a crucial factor in the muscle stimulus proximal to the cuff (e.g. in the Gluteus
progression of any MSK exercise rehabilitation programme. Maximus muscle during a squat or leg press) may further
A significant challenge lies in designing optimal rehabilitation enhance physical function and accelerate progression
programs that facilitate both neurological and muscular during MSK rehabilitation. Adverse events to acute ses-
adaptations whilst accommodating biological healing and sions of LI-BFR have been reported and primarily include
patient safety [4]. Historically, it has been widely accepted delayed onset of muscle soreness, numbness, fainting/diz-
that to elicit significant gains in muscle hypertrophy and ziness and bruising [26]. There have also been case study
strength requires loads equivalent to at least 70% of an reports of rhabdomyolysis [27, 28] and retinal occlusion
individual’s 1 repetition maximum (1RM) for a given [29] in the literature. However, when appropriately
movement [6, 7]. For people undergoing musculoskeletal supervised, LI-BFR is widely acknowledged as a safe
injury rehabilitation, heavy-load resistance training can be mode of exercise in healthy adults [30].
contraindicated [2] or they are limited by their symptom- It is proposed that the metabolic stress associated with
atic impairment, including pain and immobility, to attain BFR and the mechanical tension of the load lifted act syner-
the recommended heavier-loads [8]. Therefore, patients gistically to mediate numerous secondary mechanisms, all
with MSK injuries are often advised to reduce their of which stimulate autocrine and/or paracrine actions to
training load, potentially limiting the desired muscular facilitate muscle growth [31]. These proposed mechanisms
response to treatment. include muscle cell swelling [32], elevated systemic hormone
In recent years, research demonstrates that the use of production [33, 34], intramuscular anabolic/anti-catabolic
blood flow restriction (BFR) combined with low-load resist- signalling [35–37], increased fast twitch fibre recruitment
ance exercise (20–40% 1RM) can enhance the morphology [38] and the production of reactive oxygen species (ROS)
and strength response in human muscle tissue [9]. BFR is [39, 40] and its variants, including i) nitric oxide for its
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 3 of 14

influence on vascular responses [41, 42] and ii) some heat Headley Court routinely treats and manages a large variety
shock proteins [36, 39]. However, in the absence of research of lower-limb musculoskeletal disorders (See Fig. 1 for a
demonstrating a causal link, any suggested associations diagrammatic model of the rehabilitation pathway). These
between BFR training and subsequent muscle growth typically include, but are not limited to, overuse injuries
are purely speculative. (e.g. patellofemoral pain, tendinopathy, early osteoarthritis,
There is increasing evidence for the practical and and exertional lower-limb pain), post-surgical injuries (e.g.
beneficial use of BFR training as a clinical MSK rehabilita- soft-tissue and ligamentous reconstruction), bone fractures,
tion tool [43]. Any intervention that speeds the progression and hip and groin pain.
of MSK rehabilitation, whilst exercising at lower relative Of particular interest, in relation to the UK military
training loads, is of interest not only to the rehabilitation model of exercise rehabilitation (Fig. 1), is the evidence of
and sports medicine communities, but the wider commu- muscular hypertrophy and strength demonstrated with
nity health services. In military populations, the majority of high frequency (twice a day) BFR training in as little as
injuries occur in the lower limb [44]. In a cohort of 6608 6 days [46] and 12 days [47] of training. The effect of this
British Army recruits, during a 26-week period of initial novel training method is yet to be explored across the UK
military training, the overall incidence of musculoskeletal Defence Medical Services (DMS). Therefore, the purpose
injuries was 48.6% [45]. There is a large economic and of this study is to assess the feasibility of LI-BFR training
operational cost associated with lower-limb MSK injury. in a heterogeneous group of lower-limb injured military
Soldiers injured during basic training, field exercise, sport personnel, under the conditions provided during a 3-week
etc. may be unable to deploy on operations, whilst soldiers intensive residential rehabilitation centre. This includes
injured during deployment may not be fit to return to measuring the hypertrophic and strength response but
active duty [44]. The Centre for Lower-Limb Rehabilitation also reporting any potential adverse events, monitoring
at the UK Defence Medical Rehabilitation Centre (DMRC), compliance and the pain response over time and whether

Fig. 1 Lower limbs rehabilitation pathway at DMRC, Headley Court

Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 4 of 14

frequent daily use of this clinical tool is feasible in a busy Limb Rehabilitation (Defence Medical Rehabilitation Centre
MDT clinical rehabilitation setting where other potentially (DMRC), Headley Court, UK) with a MSK injury of the
conflicting clinical priorities exist. This protocol describes lower limb. Table 1 describes the inclusion and exclusion
the design and analysis plan for a randomised controlled criteria. These criteria are designed to recruit a heteroge-
feasibility study. neous group of lower-limb injured patients who are able to
engage in load bearing conventional resistance training, but
Methods/design do not have a functional status allowing a return to full
The primary aim of this study is: operational military duties. A significant majority of patients
admitted to DMRC for rehabilitation are male. In a ‘time
1. To assess the acceptability, feasibility and adverse limited’ period allocated for data collection, we could not
events associated with implementing a high-frequency predict the number of females available for recruitment into
LI-BFR intervention in a 3-week intensive residential the study. Therefore, because the primary purpose of this
MDT rehabilitation setting. study is to assess the feasibility and not the effectiveness of
2. To assess the feasibility of a future definitive RCT by the LI-BFR intervention, for ease of administration and
assessing participant eligibility, monitoring logistics, we chose to recruit males only. If feasible, any
recruitment and retention rates, group allocation future full-scale RCT will recruit both male and female
acceptance and adherence to the intervention. participants.

The secondary aim is to compare the effects of LI-BFR Randomisation and blinding
training against conventional resistance training on cross- Potential participants will be referred from their parent
sectional area (CSA) and volume of the quadriceps and military unit by a physiotherapist or medical officer. Prior
hamstring muscle groups and muscle strength in UK to admission to DMRC, the case records of individual
military personnel undergoing lower-limb injury rehabili- patients scheduled for a lower-limb rehabilitation course
tation. Changes in relevant musculoskeletal variables of will be reviewed by a specialist rehabilitation consultant
treatment routinely measured as part of the standard UK (SDD). Those who meet the preliminary inclusion criteria
military rehabilitation care pathway will also be assessed. will be contacted via telephone by a member of the
This includes walk/run assessment, balance, pain per- research team to discuss their possible inclusion in the
ceptions and compliance to the exercise rehabilitation study. Potential participants will be sent an information
programme. pack consisting of the patient information sheet (PIS)
and an accompanying consent form. Upon admission to
Study design DMRC Headley Court, potential participants will under-
This is a parallel group, two-arm, assessor-blinded rando- take a comprehensive musculoskeletal examination by a
mised controlled feasibility study. It is a two (group) by specialist consultant and experienced musculoskeletal
two (time) repeated measures design. Outcome measure- physiotherapist where a secondary screening will confirm
ments will be assessed at baseline and 3-weeks. The study the patient’s eligibility to enter the study. Participants
protocol has been developed in accordance with the Stand- meeting the eligibility criteria, who have read and under-
ard Protocol Items: Recommendations for Interventional stood the PIS and volunteer to participate will return a
Trials (SPIRIT) guidelines [48]. The overall study design is signed informed consent form, before being randomly
illustrated in Fig. 2. assigned to one of the two study groups. A block random-
isation method will be used to randomise participants into
Setting groups that result in equal sample sizes. Our decision to
The study will be conducted at a specialist UK military employ a simple form of block randomisation is because
rehabilitation centre. (a) we want to ensure an equal number of participants are
assigned to each group during a finite, time-limited period
Ethics for data collection, (b) we already have a homogenous
The study was reviewed and approved by the UK Ministry of participant group with standardised prognostic factors,
Defence (MOD) research ethics committee (study reference and (c) we will not be undertaking formal statistical testing.
protocol number: 442/MODREC/13). Any requirement A plain language statement will inform participants that
for protocol modifications will be submitted for author- they have an equal chance of receiving the LI-BFR or
isation to the MOD research ethics committee. conventional resistance training intervention. A sealed
envelope will be opened to reveal group allocation by an
Study participants independent administrator not involved in the recruitment,
We will recruit a minimum of 28 participants aged 18- treatment or assessment of study outcomes. Group
50 years admitted for treatment to the Centre for Lower- allocation will be documented and communicated to
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 5 of 14

Fig. 2 Study design

the supervising therapists by the independent administrator. to LI-BFR training. This includes using cuff widths
Prior to the study, all treating staff will have received a (~6 to 13.5 cm) for the legs and resistance training at
briefing on the randomisation process and specific inter- 50 to 80% of occlusion pressure taken at rest; a
vention for each treatment group, in line with the study detailed description of the technique used to estab-
protocol. It is not possible to blind participants to treatment lish occlusion pressure is provided in a later section
allocation in this study. The clinical staff supervising both (LI-BFR Group). BFR can be used with low-intensity
groups will be, by necessity, un-blinded. We will use trained exercise (~20–40% of 1 RM), utilising 50 to 80 repe-
blinded outcome assessors to measure and record the titions per exercise, with occlusion maintained during in-
outcome scores in this study. A diagrammatic descrip- ter-repetition rest periods of 30 to 45 s. Both single
tion of the study design can be found in Fig. 2. and multi-joint exercises can provide benefit and
clinical populations are advised to complete two to
Combined LI-BFR and resistance training protocol—current three training sessions per week; however, training
guidelines twice each day with BFR is possible. These guide-
Scott et al. [9] has provided evidence-based guidelines lines will form the foundations of our LI-BFR training
on optimal muscle hypertrophy and strength responses protocol.
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 6 of 14

Table 1 Study inclusion and exclusion criteria described elsewhere by Coppack et al. [49]. All partici-
Inclusion criteria pants will receive individualised programmes focussing on
1. Male improving range of motion, balance, aerobic conditioning,
2. 18 to 50 years of age
manual therapy and education sessions. The generic MDT
programme will be common to both groups with only the
3. Serving regular UK Armed Forces personnel
resistance training or LI-BFR intervention individualised
4. Lower limb injury (e.g. patellofemoral pain, ACL reconstruction, ankle to each participant dependent on group allocation.
injury, projectile/blast related injury)
Additional information regarding each of these compo-
5. Referred to Defence Medical Rehabilitation Centre (DMRC), Headley
Court for treatment.
nents is provided below.
6. Present with a level of function enabling engagement in conventional
load bearing exercise rehabilitation confirmed by clinical assessment Stretching and range of motion exercise
findings and recent training history.
Static and active stretching and foam-roller techniques
7. Unable to return to active duty due to physical impairment and will be employed to maintain the range of motion (ROM)
occupational limitations (e.g. medical downgrading).
required for optimal function. This forms part of routine
Exclusion Criteria
clinical practice within lower-limb rehabilitation in the
1. Female UK military.
2. History of cardiovascular disease (hypertension, peripheral vascular disease,
thrombosis/embolism, ischaemic heart disease, myocardial infarction)
Neuromuscular control and functional balance exercise
3. History of the following musculoskeletal disorders: rheumatoid
arthritis, avascular necrosis or osteonecrosis, severe osteoarthritis Balance and proprioceptive exercises will be included to
4. History of the following neurological disorders: Peripheral neuropathy, restore deficits and re-establish neuro-motor control.
Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, Progression will be applied by increasing the complexity
Parkinson’s disease, stroke, mild or severe traumatic brain injury and difficulty of the exercise, by reducing the base of sup-
5. Chronic or relapsing/remitting gastrointestinal disorders such as port, adding dynamic movements on unstable surfaces and
inflammatory bowel diseases, irritable bowel syndrome or increasing the range through which the movement is per-
gastrointestinal infections within 28 days of screening.
formed. Support for neuromuscular training in lower-limb
6. Acute viral or bacterial upper or lower respiratory infection at screening
rehabilitation has been reported in the literature [50].
7. Moderate or severe chronic obstructive pulmonary disease (COPD)
8. Amputation to the lower or upper extremity
Aerobic exercise
9. Known or suspected lower limb chronic exertional compartment
syndrome (CECS) (tourniquet raises intra-compartmental muscle pressure)
Participants will undertake light to moderate aerobic
conditioning over the intervention period. In addition to
10. Achilles or patella tendinopathy (slow heavy resistance or eccentric
exercise programme prescribed as evidence-based for confirmed the general health benefits conferred by aerobic exercise,
tendinopathy diagnosis) moderate joint loading has been shown to be beneficial for
11. ACL surgery within the last 4 weeks joint health because of mechanosensitive chondroprotec-
tive pathways [51]. No study has described the optimal
12. Surgical insertion of metal components in lower limbs (may affect
MRI results) dose of aerobic exercise for patients undergoing lower-limb
13. History of any of the following conditions or disorders not previously rehabilitation in terms of intensity, volume and duration. In
listed: diabetes, fibromyalgia, active cancer, severe obesity (i.e., body this study, the supervising ERI will determine the nature of
mass index greater than 35 kg/m2), diagnosed mental illness (e.g. PTSD, aerobic exercise (walking, cycling, swimming, cross-trainer)
depression, anxiety)
and progression in intensity based on individual examin-
14. Current or previous use of any drugs known to influence muscle ation finings and patient response to exercise.
mass or performance within previous 6 months
15. Elevated risk of unexplained fainting or dizzy spells during physical
activity/exercise that causes loss of balance Manual therapy
Manual therapy techniques will be used to modify the
Generic lower-limb rehabilitation intervention quality and range of motion of soft tissue structures, and
The total duration of treatment is 3 weeks, utilising 15-days assist with pain relief. The manual therapy intervention
of specific MDT exercise rehabilitation (Monday to Friday). will be prescribed individually for each participant on
There is no follow-up period, as the aim is to assess the basis of the physical examination findings, from a list
the feasibility and effects of the intervention(s) during of techniques including, trigger point massage, passive
the period of in-patient rehabilitation. A summary of the joint mobilisation, distraction and sustained stretches [49].
DMRC lower-limb MDT rehabilitation programme and These techniques are commonly used in the management
treatment components is provided at Fig. 1 and Table 2, of injured military personnel at DMRC and delivered by
respectively. This generic treatment approach has been their respective MSK physiotherapist.
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 7 of 14

Table 2 Components of generic in-patient rehabilitation programme

Treatment Treatment content Treatment goals Typical number of
modality sessions per week
Individualised Strengthening exercises, active range of motion exercises, Restore strength of major muscle groups of the 3–4
Exercise: led by ERI functional balance drills, gait drills, progressive lower-limb, improve core strength, increase joint
(45–60 min) coordination drills, non-weight-bearing aerobic/ range of motion, improve balance and
endurance exercise neuro-muscular control, and improve
muscle endurance.
Individualised Manual therapy techniques, muscle activation and timing Improve quality and timing of movement, 1–3
physiotherapy patterns, active and passive range of motion exercises, improve muscle strength, reduce pain, increase
(30–60 min) advice on home exercise, gait re-education training joint range of motion, induce relaxation,
promote normal walking gait.
Group Exercise: Group based circuit training that primarily involves high The same as the Individual exercise sessions, 12
led by ERI repetition muscular strengthening exercises targeting the but also the promotion of group cohesion and
(45–60 min) whole body. May also include minor team games, social support
recreational therapy, foam rolling, stretching, motor
control, running re-education, cv
Hydrotherapy/ Non-weight-bearing aerobic exercise, strengthening Improve muscle strength, improve aerobic 1 hydro
swimming exercises, active range of motion exercises, self-paced capacity, increase joint range of motion, improve 3 swim
(30/45 min) recreational swimming, progressive/assisted confidence in weight bearing, induce relaxation,
weight-bearing exercise and activity and promote enjoyment and fun.
Individualised Relaxation techniques, postural re-education, cognitive Induce relaxation, promote behavioural change, 0–3
occupational behavioural therapy techniques, self-help coping control pain, correct/improve poor posture
therapy session strategies, pain management.
(30–60 min)
Patient education Coping with pain, benefits of exercise, joint protection, Goal setting, activity modification, reduction of 4
(60 min) anatomy and pathology of their lower-limb injury, pain, promote behavioural change, weight
nutrition. management, improve knowledge of treatment
options, improve ability to relax, improve
knowledge of self-help techniques

Education of each thigh. The length of the cuff (60 or 90 cm) will
Educating the patient on factors surrounding their treatment be selected based on the participant’s thigh girth, thereby
and the importance of regular exercise is a key component ensuring sufficient overlap of the inflatable regions of
of the rehabilitation process at DMRC to optimise patient the cuff to provide occlusion to the lower-limb. The cuff
adherence to home or work-based exercise programmes. size will be recorded and then used for the entirety of that
Education and advice will be a focus of the intervention and participant’s LI-BFR training programme. The posterior
will include information on diagnosis and aetiology of their tibial or dorsalis pedis pulse is found with a MD2 vascular
injury, rationale for treatment, the benefits of exercise, joint Doppler probe (Huntleigh Healthcare Ltd., Cardiff, UK).
protection and activity modification strategies, pain manage- The wide contoured tourniquet will rapidly be inflated
ment, coping with acts of daily living (sitting, driving, using a PTSii portable tourniquet system (Delfi Med-
sleeping, work) and the importance of increasing physical ical Innovations, Vancouver, Canada) to a pressure of
activity levels in everyday life [49]. Unsupervised home- 250 mmHg [52] so that the audible pulse is lost. If the
based prescription of BFR has not been investigated and pulse is not lost at 250 mmHg, then the cuff will be
therefore not recommended in the UK Defence best inflated in increments of 10 mmHg until the pulse is
practice guidelines. Instead, the LIBFR group will be abolished. The cuff will be deflated in increments of
prescribed a conventional resistance training programme 10 mmHg until the pulse is found again. This provides
to perform upon discharge from the rehabilitation centre. an estimate to the nearest 10 mmHg. The cuff will
then be fully deflated. After a 30 s rest, the cuff will be
Intervention group 1—LIBFR group inflated to the estimate pressure + 10 mmHg. It will
Determining limb occlusion pressure then be deflated more slowly in increments of 5 mmHg,
The participant’s limb occlusion pressure will be deter- so the occlusion pressure can be determined to the
mined during a one-off procedure prior to commencing nearest ±5 mmHg. 60% of this limb occlusion pressure is
the LI-BFR training programme. The participant lies in a calculated to be used as the tourniquet pressure during the
semi-recumbent supine position on a treatment couch LI-BFR intervention [9]. Subsequent limb blood occlusion
and a contoured 66 × 10 cm or 90 × 10 cm width blood pressure assessments will be performed on day 7 and the
pressure cuff (Schuco TourniCuff, Schuco International, final training day to measure potential changes in occlu-
Watford, UK) is placed around the most proximal part sion pressure over time. Any measured changes in pressure
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 8 of 14

on day 7 will not influence the cuff pressure used during 4 min per exercise and 8 min per training session.
the trial. Training will be performed twice daily, in the morning
(between 08:00 and 09:30) and afternoon (between
LI-BFR exercise protocol 14:00 and 15:30) from Monday to Thursday and once
Participants will perform low intensity resistance training on Friday morning. Over the 15 days of rehabilitation,
combined with blood flow restriction using two exercises MDT clinical assessments will be carried out on the first
in sequence: (1) bilateral leg press using a Leg Press and last day of an admission. This allows a maximum of
Machine (Pulse Fitness, Congleton, UK), and (2) bilateral 23 LI-BFR training sessions over a total period of 13 treat-
knee extensions using a Leg Extension Machine (Pulse ment days. Daily LI-BFR sessions will always be separated
Fitness, Congleton, UK) (see Fig. 3). by interludes of at least 5 h. Assuming patients adapt over
Prior to exercise, each participant will undergo a stan- the 3 week residential programme, the 1RM is expected to
dardised 5 min progressive warm-up on a stationary bike increase and therefore even when exercising at 30% 1RM,
(Wattbike Ltd., Nottingham, UK). Wide contoured blood we would expect to increase the weight lifted by small
pressure cuffs will then be placed around the most prox- increments (e.g. 2.5 kg increase per week). Any increase
imal part of each thigh and inflated using a PTSii portable in weight lifted will be at the discretion of the exercise
tourniquet system to 60% occlusion pressure. Participants rehabilitation instructor (ERI) and participant, and training
will then perform 4 sets of 30, 15, 15 and 15 repetitions (75 load (the number of repetitions and load lifted) for each
repetitions in total) at 30% of their predicted 1RM, assessed session will be monitored and recorded accordingly.
during their 5RM muscle strength assessments with an
inter-set interval of 30 s (see secondary outcome measures Intervention 2 conventional resistance training
below for a detailed description of the 5RM muscle Participants will engage in conventional load bearing
strength assessment protocol). To ensure consistency resistance training, typically consisting of four sets of three
of lifting between patients, a metronome is set at 60 bpm, exercises (deadlift, back squat and lunges) performed three
with 1 s for the completion of the concentric phase, no times per week. A gradual and timely exercise progression
pause followed by a 1 s eccentric phase of the lift (1:0:1 is determined by the ERI based upon participant feedback,
tempo). re-assessment and individual response to training. It
The inflation pressure will be maintained for the duration should be noted that despite an abundance of information
of the exercise and then deflated for 3 min to allow the on the implementation of strength and conditioning princi-
participant a small recovery period and to move to the next ples with healthy participants, investigation regarding the
exercise/equipment station. It will then be re-inflated to application of these principles in rehabilitation programmes
the target 60% occlusion pressure and the second exercise is lacking [53]. Therefore, a relatively conservative initial
station (leg extension) will commence. Therefore, the dosage is chosen that should allow a short period of
length of time induced to restricted blood flow will be adaptation whilst controlling for pain, thereby promoting

Fig. 3 Low intensity blood flow restriction (LI-BFR) exercises: a leg press, b knee extension
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 9 of 14

exercise adherence. Patients will be educated on correct rates will be recorded to provide a measure of compliance
movement patterns before loading to volitional fatigue. with the intervention. Strengths, weaknesses and safety
Repetitions per set are typically six to eight and tailored to of LI-BFR intervention will be assessed by qualitative
the individual needs of the patient with rest intervals interviews with the project supervisor, lead exercise
between each set approximately 3 min. The dosage for rehabilitation instructor, participant feedback and examin-
strengthening exercises in this protocol aims to meet the ation of any adverse event reports. We will also aim to
ongoing challenge of designing treatment programmes provide an estimate of the recommended sample-size for
that facilitate neurological and muscular adaptations a fully-powered future RCT [55].
whilst concurrently accommodating biological healing,
recovery, and the safety of the patient. The justification for
the initial dosage of four sets of six to eight repetitions Secondary outcome measure: muscle cross sectional area
takes account of the evidence suggesting pain provoked by (CSA) and volume
exercise has been shown to reduce adherence to exercise Thigh muscle cross sectional area (CSA) (cm2) and volume
in rehabilitation programmes [54]. The load lifted is a (cm3) will be assessed prior to and 1 day following the
reflection of their best effort taking into account each subject’s rehabilitation training programme, using magnetic
individual’s respective limitations due to injury. resonance imaging (MRI) with a GE Sigma scanner 1.5 T
(General Electric, Wisconsin, USA), in accordance with
Outcome measures the method previously described by Abe et al. [56]. A
All outcome measures are to be assessed at baseline and T1-weighted, spin-echo, axial plane sequence will be
upon completion of 3 weeks in-patient rehabilitation. obtained with continuous transverse images from the
Pain response and training load will be recorded over greater trochanter to the lateral condyle of the femur
several time points during the BFR intervention (Fig. 2). with a 1.0 cm slice thickness and no inter-slice gap. If
The authors acknowledge that due to the likely interfer- this distance exceeds 50 cm, two separate sequence
ence effect of a pain response, performing a ‘maximum acquisitions will be required with a triglyceride skin marker
effort’ physical task in a lower-limb injured cohort is used for sequence co-registration. The MRI data will be
unlikely to yield a true measure of MSK performance. It is transferred onto a study laptop computer for analysis
more accurate to describe outcome scores as providing an by a UK Defence Consultant Radiologist, using specially
‘indication’ of participant performance and progression. designed image analysis software (TomoVision Inc.,
We will highlight this as a potential weakness in our study Montreal, Canada) [57]. For each slice on the injured
but feel this is a challenge in the measurement of muscle limb, quadriceps and hamstring muscle compartment
force/strength in all MSK injury research. All outcomes CSA (cm2) will be measured and muscle compartment
measured will be implemented and recorded based upon volumes calculated (cm3). In participants with bilateral
a best effort at the time of assessment. pathology, one leg will be randomly selected for muscle
analysis. The coefficient of variation (CV) for this meas-
Descriptive data urement technique has been demonstrated to be less than
Personal and demographic characteristics including age, 1% [56]. Repeat MRI assessments will be performed 24 h
stature, body mass, body mass index (BMI), gender, after the participant’s final LI-BFR training session.
duration of symptoms, previous injuries, previous treat-
ments, medication use, military occupation, duration of
military service, smoking and drinking habits will be Secondary outcome measure: muscle strength
obtained during the initial participant assessment or Unilateral muscle strength will be assessed using a dynamic
obtained via electronic medical notes using the Defence 5 RM test performed on the knee extension and leg press
Medical Information Compatibility Program (DMICP). machines (Pulse Fitness, Congleton, UK). Following a
general warm-up on a stationary bike for 5 min, sub-
Primary outcome measure: feasibility and acceptability of jects will perform a 10-repetition warm-up on the knee
LI-BFR intervention extension and leg press respectively. An initial resist-
The main focus of this study is feasibility and acceptability ance is set by the supervising ERI based upon the result
for recruitment, retention and measurement of the LI-BFR of a clinical assessment, pain intensity and participant
intervention. Recruitment rates will be measured as the feedback. The resistance is then adjusted and test
rate of eligible participants invited and consenting into repeated until the participant is unable to complete five
the study. Acceptability of allocation/randomisation repetitions. The baseline 5RM is then recorded by the
procedures will be assessed by examining the reasons supervising ERI. Subjects will have 3 min rest between
for drop-out in any discontinuing participants and by each attempt. This procedure follows established and
comparing attrition rates between groups. Session adherence widely used guidelines [58].
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 10 of 14

Secondary outcome measure: functional performance the participant to walk/run on a 20 m track at gradually
assessment increasing speeds until they are unable to continue due
Functional ability will be assessed using the following to an increase in symptoms. Speed is controlled by paced-
standardised outcome measures used in the current auditory cues accompanied by recorded verbal instruc-
best-practice care pathway at DMRC. These tests will be tions. The test will be terminated once a patient fails three
conducted and recorded by an experienced supervising consecutive attempts at reaching the designated marker at
therapist. the sound of the audible cue. Total distance covered in
metres will be recorded.
Isometric muscle strength proximal to the cuff
Unilateral isometric muscle strength will be measured at the Figure of 8 test
start and end of the 3 weeks. Measurements will be taken This test measures the participant’s agility and acceleration/
using a wireless digital microFET2 hand-held dynamometer deceleration ability on a flat surface. Within the limitations
(Hoggan Scientific LLC, Drapper, UT, USA) for hip exten- of their injury, each participant will be required to complete
sion only (see Fig. 4). Isometric hip extension strength will 3 laps of a figure of 8 walk/run at maximal speed, in accord-
measure muscular adaptations proximal to the cuff. Partici- ance with established guidelines [63].
pants will be tested on a clinical examination couch using
procedures often applied in the clinical setting [59]. This test Y-balance test
was chosen as isometric loading induces less stress on the This test developed by Plisky et al., [64] assesses lower-body
musculoskeletal system than eccentric loading (‘break-test’), balance and flexibility using the Y-Balance test kit®. Standing
which is a key consideration when testing individuals with a through a single supporting limb on the test kit, the partici-
physical injury [60]. A long lever arm will be utilised during pant will reach with the free limb as far as possible along
the test to ensure the tester’s strength exceeds the isometric three lines positioned in anterior, posteromedial and pos-
force applied by the participant. The examiner will apply terolateral directions on each leg (see Fig. 5a–c). The test is
resistance in a fixed position whilst the participant exerts a currently used as a measure of postural control in patients
5 s isometric maximal voluntary contraction (MVC) against undergoing UK military lower-limb rehabilitation.
the dynamometer and the examiner. Participants will
perform four consecutive attempts with a 30 s recovery Pain perception
between attempts. Strength measures will be reported It is recognised that BFR training can cause mild muscle
as Newtons (N). The highest value will be used for analysis discomfort. A visual analogue scale (VAS) will be used to
purposes. Good interrater reliability (ICC 0.76–0.79) and measure pain intensity. The VAS uses a 100 mm hori-
low test-retest variation (< 10%) has been demonstrated for zontal line anchored by the terms ‘no pain’ (0) and
the HHD measurement technique in measuring isometric ‘worst possible pain’ (100). The VAS response format
muscle strength [59]. has shown good internal consistency, is easy to under-
stand, is in wide clinical use, and has been sufficiently
Multi-stage locomotion test (MLFT) evaluated in clinical trials [65]. It is useful in this pro-
The objective of this test is to assess the participant’s spective study of twice daily LI-BFR training sessions to
maximal walk/run distance [61, 62]. The test requires record pain scores in the injured limb. This will be

Fig. 4 Hip extension strength measure using microFET-2 hand-held dynamometer (HHD)
Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 11 of 14

recorded immediately prior to starting the exercise, size for a future definitive RCT. All participants will be
during the exercise and then 5 min post-exercise. This included in the analysis. This statistical analysis of the
will be repeated every five BFR training sessions to pilot data will be exploratory only as our sample size will
monitor how pain response changes over time to the not allow for a definitive analysis. We will recommend
BFR intervention. progression to a full study application if minimum criteria
are reached in key feasibility aims and objectives. These
Sample size criteria will include a minimum 80% of target participant
As this is a pilot-feasibility study we will not perform a recruitment over a 6-month period, and a minimum
formal sample size calculation determined by statistical 80% completion of the LI-BFR intervention and outcome
assumptions and tests. Sample size recommendations measurement.
for pilot randomised controlled trials will be followed
[66] and will aim for a minimum of 12 participants in Adverse events
each study arm providing full data. Given the time All clinical and research staff will receive a brief detailing
constraints for data collection, we intend to recruit 14 the procedures for identifying and reporting safety issues
participants into each treatment group (i.e. total sample including the use of project adverse events forms. Informa-
size of 28). We consider this will provide sufficient data tion on any unexpected adverse events deemed to be
to adequately address the aims of this feasibility study related to study participation will be collected and reported
and provide useful information on key issues such as to the chief investigator within 24 h of its occurrence.
recruitment, retention and acceptability of the LI-BFR Reporting of safety incidents will be duplicated using
intervention. This pragmatic preliminary sample will existing DMRC clinical health and safety reporting
inform a power analysis for a full-scale RCT. procedures and in accordance with the principles of
good clinical practice (GCP). It is not anticipated that
Statistical analyses there will be any risk to study participants.
Data generated from this pilot study will help inform a
future fully-powered RCT by testing the study procedures. Discussion
We will not use feasibility trial data to formally test for Optimising the recovery of UK Military personnel
between-group differences, and the analysis will be of a suffering MSK injury is of critical importance and has
descriptive nature. Therefore, no statistical analyses will been highlighted as a priority for research by the UK
be performed for the pilot data. Descriptive statistics Defence Medical Services. The premise that the use of
(mean, standard deviation (SD), counts (percentage)) will BFR combined with low-load resistance exercise can
be used to summarise eligibility, consent, randomisation, enhance the strength response in human muscle tissue
adverse events, retention, completion and intervention may have implications for the rate of recovery in patients
adherence rates. Description of participant demographic undergoing injury rehabilitation. We describe the rationale
and baseline characteristics will be compared and simple and design of a feasibility study for the introduction of an
tabulation of this pilot data will be presented. The 95% LI-BFR intervention into a residential, MDT rehabilitation
confidence intervals will be calculated to inform a sample programme for military patients suffering a variety of

Fig. 5 Y Balance test: a anterior, b posteriomedial, c posteriolateral reach direction

Ladlow et al. Pilot and Feasibility Studies (2017) 3:71 Page 12 of 14

lower-limb MSK injuries. To date, this is the first study to Ethics approval and consent to participate
establish the preliminary effects of LI-BFR on the muscle Written informed consent will be obtained from the participant. Ethical
approval was obtained for this study by the Ministry of Defence Research
volume, strength measures and functional capacity of Ethic Committee (MODREC) (protocol number: 442/MODREC/13).
military personnel undergoing intensive, in-patient rehabili-
tation. Furthermore, the recruitment methods, safety, inter- Consent for publication
Written consent was provided for all images taken within the manuscript.
vention adherence and acceptability of a twice daily LI-BFR
intervention are essential feasibility components that need Competing interests
to be understood prior to embarking on a fully powered The authors declare that they have no competing interests.

randomised controlled trial. Therefore, the findings from

this feasibility study will inform a full-scale trial to deter- Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
mine the effectiveness of LI-BFR during in-patient, MDT published maps and institutional affiliations.
rehabilitation. If feasible, military and civilian health
care providers could consider LI-BFR as a cost-effective, Author details
1
Academic Department of Military Rehabilitation, Defence Medical
practical rehabilitation modality to induce muscle adapta- Rehabilitation Centre (DMRC), Headley Court, Epsom, Surrey, UK.
tion in the absence of high mechanical loading of the 2
Department for Health, University of Bath, Bath, UK. 3Imaging Department,
lower-limb. The results of the trial will be published when Oxford University Hospitals, Oxford, UK. 4School of Sport, Health and Applied
Science, St Mary’s University, London, UK. 5National Heart and Lung Institute,
they are available. Faculty of Medicine, Imperial College London, London, UK.

Abbreviations Received: 14 August 2017 Accepted: 1 December 2017

BFR: Blood flow restriction; CECS: Chronic exertional compartment syndrome;
CSA: Cross-sectional area; DMRC: Defence Medical Rehabilitation Centre;
DMS: Defence Medical Services; ERI: Exercise Rehabilitation Instructor; References
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