Eur J Vasc Endovasc Surg 27, 201–209 (2004)

doi: 10.1016/j.ejvs.2003.10.003, available online at http://www.sciencedirect.com on

Chronic Transcutaneous Electrical Stimulation of Calf

Muscles Improves Functional Capacity without Inducing
Systemic Inflammation in Claudicants
S. I. Anderson,1* P. Whatling,1,2 O. Hudlicka,1 P. Gosling,2 M. Simms2 and
M. D. Brown3

Departments of 1Physiology, University of Birmingham, 2Vascular Surgery, University Hospital Trust, and
3
School of Sport and Exercise Sciences, University of Birmingham, Birmingham, UK

Objectives. To assess whether electrical stimulation of ischaemic calf muscles in claudicants causes a systemic
inflammatory response and to evaluate effects of its chronic application on muscle function and walking ability.
Design. Prospective randomised controlled trial of calf muscle stimulation.
Materials and methods. Stable claudicants were randomised to receive either active chronic low frequency (6 Hz) motor
stimulation (n ¼ 15) or, as a control treatment, submotor transcutaneous electrical nerve (TENS) stimulation (n ¼ 15) of
calf muscles in one leg, 3 £ 20 min per day for four weeks. Leucocyte activation was quantified by changes in cell
morphology, vascular permeability by urinary albumin:creatinine ratio (ACR), calf muscle function by isometric twitch
contractions and walking ability by treadmill performance pre- and post-intervention.
Results. Acute active muscle stimulation activated leucocytes less (28% increase) than a standard treadmill test (81%
increase) and did not increase ACR. Chronic calf muscle stimulation significantly increased pain-free walking distance by
35 m (95% CI 17, 52, P , 0.001) and maximum walking distance by 39 m (95% CI 7, 70, P , 0.05) while control
treatment had no effect. Active stimulation prevented fatigue of calf muscles during isometric electrically evoked
contractions by abolishing the slowing of relaxation that was responsible for loss of force.
Conclusions. Chronic electrical muscle stimulation is an effective treatment for alleviating intermittent claudication which,
by targeted activation of a small muscle mass, does not engender a significant systemic inflammatory response.

Key Words: Intermittent claudication; Muscle stimulation; Leucocyte activation.

Introduction (CLFES) of fast muscles can mimic many of the effects

of endurance exercise. In healthy animal muscles, it
In patients with peripheral vascular disease (PVD) and rapidly elevates oxidative enzyme capacity and
intermittent claudication, leg muscles display changes capillary supply, thereby improving fatigue resist-
characteristic not only of chronic ischaemia, but also of ance.9 Human muscle, although less amenable to the
muscle disuse, which develops as pain on walking transforming effects of CLFES, can show similar
limits exercise capacity. These changes include responses. Stimulation of healthy human quadriceps
impaired aerobic energy production,1 decreased oxi- for 6 – 8 weeks elevated levels of oxidative enzymes,
dative enzyme capacity and a shift towards less increased capillarity around fast fibres, and improved
oxidative Type II muscle fibres2 – 4 and fibre atrophy.5 resistance to fatigue.10,11 On the basis of studies12
Exercise training of PVD patients is well known to showing that CLFES enhanced capillary supply and
alleviate some of these alterations by elevating activity blood flow and reduced fatigue in chronically ischae-
of oxidative enzymes and improving aerobic metab- mic rat muscles, Tsang et al.13 stimulated the anterior
olism and oxygen extraction, all of which are linked and posterior tibial muscles of claudicants at a low
with significant increases in walking performance and frequency for short periods each day for four weeks.
hence functional status.6 – 8 Muscle performance tested by measuring ankle dorsi-
Chronic low frequency electrical stimulation flexor fatigue was improved after stimulation and
maximum and pain-free walking distances were
*Corresponding author. Dr S. I. Anderson, School of Sport and
Exercise Sciences, University of Birmingham, Birmingham, West significantly greater.
Midlands B15 2TT, UK. For claudicants, one potential disadvantage of

1078–5884/000201 + 09 $35.00/0 q 2003 Published by Elsevier Ltd.

202 S. I. Anderson et al.

training using whole body exercise such as walking or contractions. Blood samples from an antecubital vein
cycling is that the ischaemic muscles experience and mid-stream urine specimens were collected before
repeated episodes of inadequate flow followed by and 1 h after completion of the muscle function test.
reperfusion on cessation of exercise. These may Patients were then randomly assigned, 15 in each
engender a repetitive low-grade inflammatory group, to receive four weeks of either active CLFES
response involving neutrophil activation14 – 17 that treatment or control treatment, the latter provided by
can lead to a systemic increase in vascular per- transcutaneous electrical nerve stimulation (TENS)
meability 18,19 and may be associated with the machines (see below). They returned after two weeks
increased risk of cardiovascular events and mortality for a muscle function test only, and after four weeks,
in this patient group.8 CLFES offers an alternate means all tests (treadmill, ABPIs, muscle function, blood and
of exercising muscles in a targeted manner in urine sampling) were performed as final outcome
comparison with whole body training, but is not measures. Two weeks after cessation of treatment, a
known if it induces neutrophil activation in PVD test of muscle function was performed to evaluate the
patients which could increase cardiovascular risk. persistence of any CLFES effects.
The present study was therefore carried out to
investigate leucocyte activation in response to calf
muscle stimulation in patients with intermittent Testing procedures
claudication, and to see whether application of muscle
stimulation on a chronic basis could improve walking Treadmill performance and ABPI
ability and calf muscle function as endpoints without After 1 h of rest, ABPIs were measured in the supine
adverse effects on leucocytes. The large muscle group position immediately before and after a standardised
of the calf was chosen for treatment because it maximum walking test performed on a Powerjog E10
comprises the major synergists for plantar flexion, treadmill (Sport Engineering Ltd., UK), 10% incline at
plays a prominent role in walking, and is the common a speed of 2.5 km h21. Claudication distance was
site of ischaemic pain limiting exercise performance. defined by the initial onset of claudicating pain and
maximum walking distance by that achieved before
pain became too severe to continue.
Method
Calf muscle function
Patient population Calf muscle function was tested during 5 min of
electrically-evoked twitch contractions. Patients were
With approval from South Birmingham Local seated in a custom-made chair with the lower leg
Research Ethics Committee, 30 patient volunteers under investigation fixed by a knee clamp and the foot
were recruited over a period of 18 months from resting on a plate to which strain gauges were attached
those attending the Vascular Assessment Clinic at for measurement of isometric plantar flexion torque.20
University Hospital Trust, Selly Oak, Birmingham. Calf muscles were contracted at frequencies of 3.5 –
Patients were included in the single blind study if they 5 Hz by transcutaneous electrical motor stimulation
had stable claudication for 3 months or longer, had a (pulse duration 50 ms, 100 V) using a Devices DS7
post-exercise ankle-brachial pressure index (ABPI) of constant voltage stimulator (Devices Instruments,
, 0.8 and were able to walk between 50 and 350 m on a Welwyn Garden City, UK) controlled through a
standard treadmill test. MacLab 4e system (ADInstruments Ltd., Hastings,
UK). To avoid high contraction forces that would not
be tolerable for ischaemic muscles in the patients,
Study protocol initial torque was set by adjusting stimulus intensity to
produce about half the value used in healthy sub-
Patients attended the laboratory at the hospital for five jects,20 i.e. as close to 7.5 Nm as possible. Muscle
visits at fortnightly intervals, the first of these being an torque was recorded throughout 5 min stimulation at a
habituation session the data from which was excluded frequency which gave repeated unfused twitch
from final analysis. At the second visit, patients were contractions.
assessed by treadmill to determine claudication and Torque was averaged from 5 twitches every 10 s
maximal walking distances, and supine resting and throughout the test and muscle function was assessed
post-exercise ABPIs. Calf muscle function of the worse as torque measured 10 s prior to the end of the test as a
affected leg was objectively evaluated by measuring percentage of that measured 10 s after the start, to
fatigue during a test of electrically evoked isometric avoid any movement artefacts. The time course of

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 Electrical Stimulation of Ischaemic Muscles in Claudicants 203

individual twitch contractions was evaluated by placebo treatment that did not induce active muscle
expanding recordings taken throughout the test and contraction.
measuring time to peak contraction (TTP) and time to
half relaxation (1/2RT). Statistical analysis
Comparisons of blood and urine data were made
Blood and urine testing within active or control treatment groups by Wilcoxon
To investigate whether muscle electrical stimulation signed rank test and between patient treatment groups
had any effect on systemic leucocyte activation, mixed by Mann – Whitney U tests for non-parametrically
venous blood samples and urine specimens were distributed data, which is, therefore, presented in the
taken before and 1 h after the calf muscle function results as median (interquartile range (IQR)). Analysis
testing and the treadmill test. Blood was collected into of variance (ANOVA) with Scheffe’s post hoc tests was
EDTA tubes and processed immediately after collec- performed on parametric treadmill, muscle function
tion to extract leucocytes according to the method and ABPI data where two or more samples were
described by McCarthy et al.21 Briefly, 1 ml samples compared. These data are presented as means (stan-
were fixed with paraformaldehyde, lysed and centri- dard deviations (SD)). Analyses were performed using
fuged to remove red cells and platelets to yield a Statview software (Abacus Concepts, USA) with
suspension of leucocytes which were then stained significance in all cases set at the 5% level.
with Toluidine blue. The external morphology of cells
was examined by light microscopy ( £ 400) and the
proportion of activated cells (ruffled or irregular Results
surface appearance) as opposed to quiescent cells
(smooth round surface) was determined in the whole There were no significant differences in baseline
sample.21,22 descriptors of the patients assigned to active or control
Urine samples were stored with sodium azide at treatment groups (Table 1). The most common site of
4 8C until microalbuminurea could be determined by the limiting occlusion was the popliteal artery in 10 of
standard radioimmunoassay (Double Antibody Albu- the active group and nine of the control group, the
min, Euro/D.P.C. Ltd., UK). Creatinine content was remaining occlusions located in the femoral (active 1,
also estimated (kit from Synermed Europe Ltd., UK) so control 2) or tibial (active 4, control 3) arteries. Mean
that urinary albumin:creatinine ratio (ACR) could be (SD) ankle-brachial pressure indices in the worst
calculated.18 affected leg, 0.64(0.14) for all patients, classed them
as having mild claudication and following treadmill
Chronic calf muscle stimulation exercise, ABPIs decreased on average by 30(51)%
Treatment, carried out by patients at home, was ðP , 0:005Þ. Baseline claudication and maximum
applied unilaterally to the calf muscle of the leg walking distances were similar for the groups
which had the lowest ABPI values on baseline testing. (Table 1), with the total duration of treadmill exercise
Active CLFES treatment involved using Compex not exceeding 3 min.
stimulators (MediCompex SA, Ecublens, Switzerland) Significant improvements in treadmill performance
programmed to deliver square wave pulses (250 ms were observed after chronic muscle stimulation
duration, 100 V) at a frequency of 6 Hz for 20 min (Table 2). After active treatment, claudicating and
periods. Patients were instructed in placement of maximum walking distances were 93(37) and
electrodes over the motor point and belly of triceps 150(63) metres, respectively, increases of 82(108)%
surae and in adjusting stimulation intensity to ðP , 0:01Þ and 44(50)% ðP , 0:05Þ from baseline. By
produce visible pain-free calf muscle contractions. contrast, patients receiving the control treatment
They used the stimulators three times per day with an showed no significant change from baseline in either
interval of at least 2 h between sessions, usage being claudicating (64(38) m, NS) or maximum walking
registered by the stimulator programme card. Control (114(100) m, NS) distances. After CLFES, the improve-
treatment involved using TENS machines (SKF Ser- ments in pain-free walking were more marked in
vices Ltd., Kent, UK) which were set to deliver an seven patients with unilateral disease in whom
output at 50 ms, 100 V and 90 Hz. Patients were again treatment was targeted at the affected leg (distance
instructed in positioning of electrodes and were asked increased 102(155)%) than in the remaining eight with
to increase stimulus intensity until a perceived bilateral disease where treatment was only applied to
sensation of tingling without muscle contraction was the worse affected leg (increase of 64(42)%). Better
obtained, and perform three sessions each of 20 min walking ability in the active group was not related to
duration per day. TENS machines were used as a changes in ABPIs, since values in the treated leg were

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204 S. I. Anderson et al.

Table 1. Patient descriptors for active and control treatment groups at the start of the study. Data are given as means (standard deviations).
Ranges are given in parentheses below where appropriate.

Active treatment Control treatment

Number 15 15
Age in years 66(6) 71(5)
(53– 80) (61–80)
Male:female ratio 2:1 4:1
Current smokers 2 2
Duration of symptoms in years 4.9(3.9) 5.1(4.8)
(1– 15) (0.5–20)
Ankle-brachial pressure index at rest 0.64(0.10) 0.63(0.18)
Claudicating distances in metres 58(28) 64(37)
Maximum walking distance in metres 111(42) 115(82)

not different at rest nor was the fall post-treadmill fusion and in consequence, force was maintained
exercise altered (0.60(0.13) and 36(29)%, respectively, throughout the test. By contrast, muscle function in
NS vs. baseline testing). patients receiving the control TENS stimulation
Fig. 1(A) shows a typical example of torque showed the same slowing and fatigue as they had at
recording during the calf muscle function test from baseline testing (Fig. 2(D)). When patients who had
one patient at baseline. At the start of the baseline test received active treatment were tested two weeks after
torque was 7.2(0.9) Nm in the active group and its cessation, muscle force traces showed a reversion to
7.4(1.4) Nm in the control group. Six patients were the baseline pattern (data not shown).
unable to complete the full 5 min test, one ceasing after At baseline testing, median (IQR) values for
1 minute, one after 2 minutes and four between 4 and morphological signs of cell activation under resting
5 min. For all other patients who completed the conditions were 10.5(9.7 – 12.8)% of leucocytes
baseline test, twitch torque had declined to 73(30)% sampled from all patients and this increased to
of initial values by 5 min because the muscles 13.9(12.5 –15.6)% in blood taken 1 h after electrical
progressively fatigued. They were unable to relax stimulation for the calf function test (P , 0:001, Fig. 3).
quickly enough to generate single twitches, and Cell activation was, however, even greater in samples
contractions became partially fused such that basal taken 1 h after a treadmill test where the proportion
torque had risen above zero by 80– 90 s into the test of activated leucocytes was 18.5(16.3 –19.6)% ðP ,
(Figs. 1(A) and 2(A)). The changes in contraction times 0:001Þ even though the duration of treadmill
underlying this effect were a prolongation of half exercise (, 3 min) was shorter than that of the
relaxation time from 78(16) ms at the start of the test to chair test (4 – 5 min) (Fig. 3). Urinary ACRs were
159(133) ms at the end ðP , 0:01Þ, whereas times to 1.27(0.63 – 3.77) mg mmol21 before and 1.38(0.55 –
peak contraction were unaltered (86(14) ms at the start, 2.78) mg mmol21 after calf muscle testing (NS) show-
84(22) ms at the end, NS). ing that acute stimulation did not cause any change in
All patients who received active CLFES treatment systemic microvascular permeability. Ratios were
for 4 weeks were able to complete the full 5 min higher after the treadmill than the chair test
muscle function test. After two weeks, the marked (3.85(1.09 – 8.68) mg mmol21) but the increase was
slowing of relaxation time and rise in basal torque not significant due to large inter-subject variation.
during the electrically evoked contractions were less After chronic active stimulation for 4 weeks, the
(Fig. 2(B)) and after four weeks, they no longer proportion of activated leucocytes at rest (10.1(8.5 –
occurred (Figs. 1(B) and 2(C)). There was no twitch 11.2)%) was not different from baseline and the

Table 2. The effects of 4 weeks of chronic calf muscle motor stimulation (active treatment) versus sub-motor TENS stimulation (control
treatment) on treadmill performance.

Active treatment Control treatment

Change in claudicating distances in metres þ 35(31)* 20.1(5)

(CI þ 17, þ 52) (CI 23, þ 3)
Change in maximum walking distance in metres þ 39(57)** 21(27)
(CI þ 7, þ 70) (CI 217, þ 15)

Data are given as means (standard deviations) with 95% confidence intervals. *P , 0:001, **P , 0:05 active vs. control treatments.

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 Electrical Stimulation of Ischaemic Muscles in Claudicants 205

Fig. 1. Records of electrically-evoked isometric torque (Nm) developed during the test of calf muscle function from one
patient pre (A) and post (B) 4 weeks CLFES. At baseline testing (A), the force of individual twitch contractions declined after
2 min due to slowing of the twitch relaxation and failure of the muscle to relax to zero torque (see inset figures, bar ¼ 1 s).
This no longer happened after CLFES. Any torque shown below zero represents dorsi-flexion rather than plantar flexion,
usually due to small adjustments in body position by the patient.

increase following a treadmill test (17.3(16.4 –19.0)%) Discussion

was also unchanged. Urinary ACRs were not signifi-
cantly altered at rest (0.60(0.42 – 6.21) mg mmol21) or This study shows that low frequency electrical
in response to treadmill exercise (2.61(1.20 – stimulation of calf muscles in PVD patients has
10.47) mg mmol21). minimal effects on leucocyte activation, assessed by

Eur J Vasc Endovasc Surg Vol 27, February 2004

206 S. I. Anderson et al.

Fig. 2. Panels show grouped data for average peak and base torque values for 5 twitch contractions measured every 10 s
during the chair test. (A) For all patients pre treatment, (B) for patients receiving active stimulation after 2 weeks, (C) for
patients receiving active treatment after 4 weeks, (D) for patients receiving 4 weeks of control treatment (D).

their morphology, and does not influence systemic Enhancement of walking was particularly evident
vascular permeability when applied acutely, nor did it in cases of unilateral disease where the affected leg
have any deleterious consequences for leucocyte had been specifically targeted by stimulation and
activation or systemic microvascular permeability its hindrance to walking performance thereby
when used as a chronic treatment. CLFES was, ameliorated.
however, highly effective at inducing improvements These positive effects of calf muscle stimulation
in functional walking capacity of patients. confirm the findings of Tsang et al.13 who stimulated
anterior tibial muscles for four weeks, but the
improvement in pain-free walking was even greater,
82% compared with 26%. This is likely because
treatment was applied to the larger triceps surae
muscle group which makes a more prominent
contribution during the gait cycle.23 The local nature
of the treatment effect is shown by the fact that
maximum walking distances, which would be cur-
tailed by the untreated leg as well as being influenced
by cardiorespiratory and motivational limitations,
increased similarity in the two studies (44 and 34%
respectively). Only one other study has reported
positive effects of gastrocnemius muscle electrical
Fig. 3. Percentage of activated leucocytes, assessed by stimulation in patients with PVD, using it in conjunc-
morphological cell shape change, in venous blood taken tion with an exercise training programme applied to
1 h after either acute calf muscle stimulation (max 5 min) or
treadmill exercise (max 3 min) from all claudicants pre- the leg remaining after amputation.24 It reported that
treatment. †p , 0:001 versus rest, paired t-test. claudication was alleviated by stimulation combined

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 Electrical Stimulation of Ischaemic Muscles in Claudicants 207

with exercise but not by exercise alone but the the magnitude of functional improvements in the
stimulation protocol was more intensive, 2 h per day present study show self-administered chronic stimu-
over 8 weeks, than presently used and the effect of lation to be a very effective treatment for claudicants.
stimulation per se was not evaluated. CLFES can be carried out by patients themselves after
Neutrophil activation in claudicants following minimal tutoring in equipment use, and does not
exercise17,25 is a consequence of ischaemia-reperfusion require attendance at a supervised exercise class, the
and has been considered to present a significant risk usual recommendation for ensuring patient adherence
by contributing to the likelihood of their adherence to to a physical activity programme.
vascular endothelium and to a generalised increase in Stimulation could exert its beneficial effects on
systemic vascular permeability15,16 which has been walking ability by altering metabolic efficiency of the
shown in claudicants by urinary microalbuminuria.18, targeted muscle. Fatigue during electrically evoked
19
In the present patient population, a single bout of twitch contractions in patients prior to treatment was
calf electrical stimulation lasting 4 – 5 min for the evident as an inability to regain baseline between
muscle function test had significantly less effect on contractions due to slowing of muscle relaxation. This
leucocyte activation (28% increase) than did treadmill differed from the response during the chair test of
walking for the shorter period of , 3 min (81%). healthy calf muscle with restricted blood flow in which
Neumann et al.25 observed that total neutrophil force production declined without any slowing of
numbers as well as the proportion of activated contraction times.20 The contractile properties of calf
neutrophils were significantly elevated in venous muscles in the patient group at baseline were
blood leaving the legs compared to arterial blood significantly faster than times to peak contraction
after toe raise exercise to claudication, indicating a (, 170 ms) and half relaxation (130 ms) reported for
release of cells ‘washed out’ from the ischaemic limb plantar flexor muscles in healthy elderly individuals,27
itself by post-exercise reperfusion. Calf stimulation at consistent with the observed increase in fast myosin
submaximal intensity may involve a relatively small heavy chains4 and change in fibre population towards
proportion of the muscle group compared with leg the fast type in ischaemic muscles of PVD patients.2,3
exercise so that any such reperfusion effects are minor. In fatigued muscle, slower relaxation has been
Furthermore, the small increase in leucocyte activation attributed to prolongation of the Ca2þ transient due
during stimulation did not induce systemic vascular in part to the effect of elevated Hþ concentration on the
permeability, based on the lack of change in ACRs, in Ca2þ pump rate of the sarcoplasmic reticulum28 and
contrast to the known effects of treadmill exercise. The during calf exercise, muscle pH falls to a greater extent
increase in ACRs after treadmill was not significant in in claudicants than healthy age-matched controls.1
the present study most likely because of small patient Whether the elimination of slowing of relaxation in
numbers.15 The local nature of electrically-evoked treated muscles implies that CLFES had negated
muscle contractions in comparison with whole body metabolic inefficiency independently of any vascular
exercise therefore, means that CLFES as a treatment effects remains to be investigated.
does not pose any risk to patients of aggravating With regard to the possibility that CLFES has
inflammatory status, neither does it modulate the vascular effects, the fact that ankle-brachial pressure
leucocyte activation response to treadmill exercise. A indices for the stimulated leg were not changed by
further possible benefit of CLFES is that a smaller CLFES either at rest or post-exercise would suggest
degree of leucocyte activation than during exercise that overall perfusion had not been influenced, and
training would have less adverse effects on adhesion indeed, the majority of exercise training studies in
molecule expression which is associated with endo- PVD patients also show that limb blood flow is not
thelial dysfunction in claudicants.26 enhanced.6 However, while ABPI measurements are
The total treatment time with chronic stimulation good at predicting the severity of arterial disease they
(20 min three times daily, 7 days per week, 4 weeks) cannot discriminate redistribution of perfusion within
amounted to 28 h. Compliance was greater than 95% the ischaemic limb. Low frequency electrical stimu-
in both active and control treatment groups, as lation of anterior tibial muscles for several weeks in
registered by stimulator cards or by self-report. PVD patients improved skin oxygen saturation and
Although exercise training programmes may result led to healing of ulcers,29 which implies a cutaneous
in greater improvements in pain-free and maximum vascular effect. In animals with stenosed arteries
walking distances than the present study,7 the mini- supplying the lower limbs, exercise training led to
mum duration required, using sessions of 30 min up to better walking performance which was not associated
1 h which may be repeated daily or several times per with higher limb blood flow but was thought to be
week, is of the order of 3– 6 months.7,14 Set against this, linked with more homogeneous distribution of flow

Eur J Vasc Endovasc Surg Vol 27, February 2004

208 S. I. Anderson et al.

and better oxygen delivery among muscles.30 This Graham JC, Cody DV, Kraemer WJ. Muscle fiber characteristics
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mic rat hindlimb muscles can restore dilator capacity 11 Theriault R, Boulay MR, Theriault G, Simoneau JA. Electrical
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O, Shearman CP. Chronic muscle stimulation improves ischae-
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32 Hillier C, Sayers RD, Watt PAC, Naylor R, Bell PRF, Accepted 30 September 2003

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