DIABETES/METABOLISM RESEARCH AND REVIEWS

SUPPLEMENT
Diabetes Metab Res Rev 2016; 32(Suppl. 1): 232–238.
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2756

ARTICLE

Assessment of foot perfusion in patients with a
diabetic foot ulcer

Rachael O. Forsythe1
Robert J. Hinchliffe2*
1

Centre for Cardiovascular Science,
University of Edinburgh, Edinburgh,
UK

2

St George’s Vascular Institute, St
James Wing, St George’s Hospital,
London, UK
*Correspondence to: Robert J.
Hinchliffe, St George’s Vascular
Institute, St James Wing, St George’s
Hospital, London SW17 0QT, UK.
E-mail: robhinchliffe@gmail.com

Abstract
Assessment of foot perfusion is a vital step in the management of patients with
diabetic foot ulceration, in order to understand the risk of amputation and
likelihood of wound healing. Underlying peripheral artery disease is a common
finding in patients with foot ulceration and is associated with poor outcomes.
Assessment of foot perfusion should therefore focus on identifying the
presence of peripheral artery disease and to subsequently estimate the effect this
may have on wound healing. Assessment of perfusion can be difficult because of
the often complex, diffuse and distal nature of peripheral artery disease in patients with diabetes, as well as poor collateralisation and heavy vascular calcification. Conventional methods of assessing tissue perfusion in the peripheral
circulation may be unreliable in patients with diabetes, and it may therefore
be difficult to determine the extent to which poor perfusion contributes to foot
ulceration. Anatomical data obtained on cross-sectional imaging is important
but must be combined with measurements of tissue perfusion (such as transcutaneous oxygen tension) in order to understand the global and regional perfusion deficit present in a patient with diabetic foot ulceration. Ankle-brachial
pressure index is routinely used to screen for peripheral artery disease, but its
use in patients with diabetes is limited in the presence of neuropathy and medial
arterial calcification. Toe pressure index may be more useful because of the relative sparing of pedal arteries from medial calcification but may not always be
possible in patients with ulceration. Fluorescence angiography is a non-invasive
technique that can provide rapid quantitative information about regional tissue
perfusion; capillaroscopy, iontophoresis and hyperspectral imaging may also be
useful in assessing physiological perfusion but are not widely available.
There may be a future role for specialized perfusion imaging of these patients,
including magnetic resonance imaging techniques, single-photon emission
computed tomography and PET-based molecular imaging; however, these
novel techniques require further validation and are unlikely to become standard practice in the near future. Copyright © 2016 John Wiley & Sons, Ltd.
Keywords

diabetic foot; peripheral arterial disease; foot ulcer

Introduction
The complex pathophysiology of diabetic foot ulceration is the key factor
influencing tissue healing. In patients with ischaemic foot ulceration who do
not have diabetes, the assessment of foot perfusion is relatively straightforward
Copyright © 2016 John Wiley & Sons, Ltd.

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Diabetic Foot Ulcer Perfusion

and the resulting tissue loss may be almost entirely attributed to peripheral artery disease. However, in patients
with diabetes, a similar degree of anatomical arterial
disease can result in a more severe perfusion deficit
because of paucity of collateral vessels as well as the influence of physiological factors associated with diabetes, such
as arteriolar shunting and neuropathy. The fact that some
diabetic foot ulcer wounds (in patients with peripheral
artery disease) may heal without revascularisation [1],
and that up to 40% may experience recurrent ulceration
within 12 months even after technically successful angioplasty or bypass [2], suggests that other factors contribute
to wound non-healing in patients with diabetes.
A thorough physical examination should be carried out
in any patient with diabetic foot ulceration – in particular,
a detailed medical history and assessment of peripheral
pulses – however, clinical examination alone cannot reliably assess the severity of perfusion deficit [3]. In addition, adverse clinical features associated with diabetic
foot ulceration (including infection, oedema and neuropathy) may influence the usefulness of conventional diagnostic tests. Current imaging techniques (such as duplex
and angiography) allow an assessment of the morphological distribution of peripheral artery disease and may provide some information on the global perfusion deficit.
However, in patients with compartmental perfusion deficit,
such as those with ischaemic foot ulceration, these tests
may not reflect the degree of perfusion at the actual area
of tissue loss. Therefore, assessment of foot perfusion in
a patient with a diabetic foot ulcer should also include
the regional tissue perfusion deficit. By understanding
both of these measures, this may go some way towards
assessing the likelihood of wound healing and risk of amputation. However, there is no current consensus as to
the best measure of perfusion in patients with diabetic foot
ulceration; target levels of perfusion remain ill-defined.

low ankle-brachial pressure index (ABI < 0.5), whilst
capillary refill time and foot coolness, colour or hairlessness added no diagnostic value [7] and may be omitted
from routine examination. However, this study used ABI
as the reference diagnostic test; therefore, patients in
whom the ABI was falsely elevated because of medial
arterial calcification will not have been captured in this
series. Whilst a thorough clinical examination by a trained
clinician is imperative, it should be supplemented by other
tests to confirm diagnosis, to assess the morphological
distribution of disease if intervention is being considered
and to understand the regional perfusion deficit.

Ankle-brachial pressure index
Doppler-measured ABI is widely used to screen for the
presence of peripheral artery disease. However, ABI and
other non-invasive bedside tests otherwise useful in the
assessment of peripheral artery disease may be unreliable
in patients with diabetes [7]. Studies have demonstrated
that ABI may be useful in asymptomatic patients with
intact feet [8,9] but is less accurate in those with neuropathy or ulceration. A reduced ABI (<0.9) is indicative of
impaired flow; however, the finding of a normal ABI in a
person with diabetes is not reliable – increased arterial
stiffness may reduce distal flow [10] and medial arterial
calcification, resulting in incompressible vessels, causes
falsely elevated pressures. Automated ABI machines use
software to analyse photoplethysmography signals from
the finger and toe during cuff inflation in order to calculate the ABI. Whilst these automated measurements may
be performed by minimally trained operators, they have
a lower diagnostic performance in patients with diabetes
when compared with Doppler-based (oscillometric) ABI
[9] and may produce falsely elevated results in patients
with borderline or low readings [11].

Assessment of disease severity
Toe pressures
All patients with diabetic foot ulceration should be evaluated for the presence of peripheral artery disease at the
time of presentation and managed in a multi-disciplinary
setting [4–6]. Clinical examination is the first step in the
assessment of patients with foot ulceration. In particular,
a thorough history of symptoms suggestive of peripheral
artery disease and palpation of peripheral pulses are key
components of the examination that may be carried out
by any medical practitioner. One large cross-sectional
study of patients with diabetes and peripheral artery disease demonstrated that diminished peripheral pulses,
age, venous filling time and a history of peripheral artery
disease were independently associated with presence of
Copyright © 2016 John Wiley & Sons, Ltd.

An alternative to ABI, toe pressures and the toe brachial
pressure index (TBI) may be a more useful measurement
of perfusion because of the characteristic sparing of the
pedal arteries from vascular disease in patients with
diabetes.
Toe pressures may be measured by photoplethysmography (detecting pulsatile flow and producing a
pulse wave curve) or laser Doppler (detecting changes in
wavelength when the laser encounters red blood cells).
Results may vary greatly if different machines are used,
but in general, these measurements show good repeatability if the same equipment is used [12].
Diabetes Metab Res Rev 2016; 32(Suppl. 1): 232–238.
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234

In any patient with peripheral artery disease, a toe
pressure of <30 mmHg in the presence of rest pain or
<50 mmHg in the presence of ulceration is generally
accepted as diagnostic of severe limb ischaemia [13];
however, this has not been verified in a selected population of patients with diabetes. A threshold level of TBI
≥0.75 has been shown to reliably exclude the diagnosis
of peripheral artery disease, with little effect from the
presence of neuropathy [8]; however, this study excluded
patients with active foot disease – the presence of digital
ulceration may preclude TBI measurement. Toe pressure
is also not possible in patients with previously amputated
digits, with heavily calcified digital vessels and may not be
reliable when performed on non-hallux toes. Overall,
there is limited data on the thresholds for diagnosing
peripheral artery disease using pressure indices [14],
and wide ranges may be seen in patients with diabetes
and neuropathy [15], even in the absence of peripheral
artery disease.

Continuous Doppler waveform
assessment
Qualitative waveform analysis using Doppler ultrasound
(reported as triphasic, biphasic, monophasic flow and
presence or absence of reverse flow) may be as sensitive
and specific as palpation of pulses or ABI in limbs with
no neuropathy. The presence of a triphasic waveform with
reverse flow in both foot arteries has been demonstrated
to exclude significant peripheral artery disease in >90%
of patients with neuropathy; monophasic or biphasic
waveform with loss of reverse flow is highly suggestive
of significant disease [8]. However, this is subject to inter-observer variability. Quantitative waveform analysis
(using the resistance index) may be useful in patients
without diabetes; however, its accuracy is affected by
low-amplitude or low-intensity signals. One study has
demonstrated that, in a group of patients with diabetes
and peripheral artery disease, the measurements were erroneous in a third of those studied – quantitative analysis
is therefore an unreliable tool in this group of patients [8].

Pulse volume recordings
The measurement of pulse volume may be used to identify
the presence of arterial disease. Pulse wave volume corresponds with the cardiac cycle – a brisk upstroke and sharp
peak occurring in systole and a gradual downslope in
diastole, followed by a reflective wave (the dichrotic
notch). In the presence of arterial disease, the waveform
flattens and the pulse width widens. When used in the
lower limbs, the change in the waveform denotes the
Copyright © 2016 John Wiley & Sons, Ltd.

R. O. Forsythe and R. J. Hinchliffe

general location of significant disease; however, it
assesses the total blood flow through the area and cannot
therefore give accurate information regarding the exact
location of the disease. In addition, low flow states, such
as that observed in patients with congestive cardiac
failure, may be misidentified as inflow disease. Pulse
volume recordings may be useful in patients with diabetes
who have falsely elevated ABI because of calcified vessels
[16], as the effect of calcification on waveform is distinguishable from that because of obstructive arterial
disease.

Assessment of morphological
distribution
Once the diagnosis of peripheral artery disease is
suspected or established and if revascularisation is being
considered, anatomical imaging is required, however
should not replace measurements of perfusion, which
should usually be performed first in patients with diabetic
foot ulceration. The anatomical distribution of disease in a
patient with diabetic foot ulceration will help inform on
whether revascularisation is required and, if so, which
method (endovascular or open surgery) is appropriate
and feasible. The major challenge in imaging the arterial
tree in patients with diabetes is the characteristically
complex anatomical distribution of disease.

Duplex ultrasound
Colour duplex ultrasound is the first line imaging modality to evaluate any patient with peripheral artery disease
if intervention is being considered and is used in some
countries as the only pre-operative imaging required prior
to bypass surgery; however, it may be less useful when
evaluating the infra-arterial tree and the results are operator dependent [17]. Given that patients with diabetes
have characteristically diffuse and distal arterial disease,
many would consider duplex ultrasound alone an insufficient pre-operative investigation when planning
revascularisation – it should therefore be complemented
by more detailed imaging.

Angiography
If revascularisation is being considered, angiography may
provide more detailed morphological information than
duplex ultrasound alone. Traditional digital subtraction
angiography (DSA) remains the gold standard, however
is invasive, costly, involves iodinated contrast and may
not fully identify patent distal vessels. It has therefore
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Diabetic Foot Ulcer Perfusion

been widely replaced by non-invasive angiography (magnetic resonance angiography and computed tomography
angiography) for pre-operative planning.
Magnetic resonance angiography (MRA) is better than
DSA at detecting ‘angiographically occult’ distal vessels,
even in patients with severe occlusive disease and slow
terminal flow [18], and does not require iodinated
contrast. Contrast-enhanced MRA has a high sensitivity
for diagnosing and a high specificity for excluding stenoocclusive disease in patients with peripheral artery
disease (94.7 and 95.6%, respectively), including critical
ischaemia because of distal disease (sensitivity 92.2%,
specificity 93.3% in tibiofibular arteries) [19]. However,
gadolinium-based MRA is not recommended in patients
with severe renal impairment because of the risk of
nephrogenic systemic fibrosis, and MRA is contraindicated in patients with non-compatible metal devices.
The acquisition time of computed tomography angiography (CTA) is much shorter and the resolution superior to
MRA; however, CTA is more vulnerable to artefact, particularly in patients with diabetes who have heavy vascular calcification, which can lead to the over-estimation of the
degree of stenosis. Whilst iodinated contrast carries the risk
of contrast nephropathy, other agents such as carbon dioxide may be used to minimize the risk in patients with renal
impairment or a reduced-dose contrast bolus can be used.

Assessment of regional tissue
perfusion
Assessment of local tissue perfusion may be useful in order
to understand the perfusion deficit at an exact area of tissue loss and, therefore, help estimate the likelihood of
healing. In patients with diabetes, this may be particularly
important, as global measurements of perfusion do not
necessarily reflect the regional deficit, in part because of
the poor collateralisation typically seen in these patients.

Transcutaneous oxygen tension (TcPO2)
Transcutaneous oxygen tension (TcPO2) is an established
method of measuring cutaneous perfusion and may be
more sensitive for the detection of PAD than ABI in patients with diabetes [20]. It measures the transfer of oxygen molecules to the skin surface; a reduction in TcPO2 is
detected in patients with peripheral artery disease [21].
In patients with ulcers or amputation wounds, TcPO2
may be used to assess the healing potential and has also
been used to evaluate response to surgical or
endovascular revascularisation [22,23]. There is a correlation between decreasing TcPO2 values in patients with
Copyright © 2016 John Wiley & Sons, Ltd.

ischaemic wounds and the likelihood of healing – one
study demonstrates that a value of less than 40 mmHg
represents a 24% increase in risk of healing complications
[24]. However, no studies have validated the use of
TcPO2 to determine the level of amputation required in
a patient in whom revascularisation fails.
TcPO2 assesses the area under the probe; therefore, multiple readings may provide more clinically relevant information than a single measurement – the change in values from
flat to elevation may be useful to predict wound healing
[25]. In addition, the regional perfusion index can be calculated by dividing the foot TcPO2 reading by a baseline
TcPO2 value obtained from the patient’s chest [26] and
is more reliable than a single TcPO2 reading.
However, TcPO2 may be paradoxically increased in diabetes because of arteriolar shunting in the microcirculation and is also affected by the metabolic demands of
the tissue being assessed. It is therefore less reliable in patients with active infection, oedema, callus, active
smokers (because of vasoactive effects of nicotine), in a
warm ambient environment (because of vasodilatory effects of heat) or those with autonomic neuropathy or vascular calcification, even in the absence of peripheral
artery disease [15]. However, inhalation of 100% oxygen
during TcPO2 measurement (the ‘oxygen challenge’)
may help distinguish between low values because of oedema or inflammation (causing a barrier to oxygen diffusion) and true values reflecting the presence of arterial
disease. This may also be useful to identify patients who
may benefit from hyperbaric oxygen therapy.

Skin perfusion pressure
Skin perfusion pressure has been used successfully for
assessing the severity of lower limb ischaemia, judging
the likelihood of wound healing and selecting the appropriate level of amputation [27,28]. Skin perfusion pressure may be measured using radioisotope clearance,
photoplethysmography techniques or laser Doppler [29].
An inflation cuff is deployed at the area of interest, and,
by slowly decreasing pressure, the change in the measured parameter (e.g. isotope washout, reappearance of
pulsatile flow or shift in laser waveform) reflects the
severity of perfusion deficit. This technique may be useful
in patients in whom ABI or toe pressure are unreliable
[30], however requires specialist equipment and further
validation.

Fluorescence angiography
Fluorescence angiography, commonly using indocyanine
green dye (ICG), measures fluorescence intensity at
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different areas of the affected limb, allowing a semi-quantitative measurement of regional perfusion and identification of superficial collaterals in patients with arterial
occlusions. ICG is a non-radioactive contrast agent that
is relatively non-toxic and suitable for patients with
impaired renal function.
ICG angiography has been used in patients with critical
limb ischaemia to provide rapid and quantitative information about foot perfusion [31] and may provide information on the specific angiosome affected. It has also been
demonstrated to provide good discriminatory power to
detect critical from non-critical limb ischaemia [32] and
has been used as an intra-operative tool to determine
the demarcation between viable and non-viable ischaemic
tissue [33]. Whilst this technique has the potential to
assess perfusion, response to revascularisation and to
potentially help predict wound healing, it is expensive
and not yet widely available.

Laser Doppler techniques
Laser Doppler flowmetry measures the local microcirculatory blood perfusion, using a beam of laser light that is
partially absorbed as it hits the tissue being evaluated,
to a depth of up to 1 mm. The magnitude and frequency
of change in wavelength can be converted into a measurement representing the relative perfusion, rather than
absolute values. This technique assesses blood flux, rather
than blood flow, and only measures perfusion over a very
small superficial area of tissue. Laser Doppler imaging can
provide similar data by scanning the entire foot and ankle
after induction of ischaemia using a cuff inflated to suprasystolic pressure at the calf and measuring changes
because of reactive hyperaemia after cuff deflation. Laser
Doppler imaging has been used to identify poor perfusion
in lower extremity ulcers [34]; however, these techniques
are vulnerable to motion artefact, ambient temperature
changes and inter-operator variability.

Hyperspectral imaging
Hyperspectral imaging measures the wavelength of light
emitted when a white light is shone at tissues, which
represents the relative oxygenation of haemoglobin in
the tissues at the areas of testing. When used in patients
with diabetic foot ulceration, two groups have shown a
significant association between hyperspectral imaging
readings and wound healing by 24 weeks, suggesting that
this technique could potentially be applied to predict
healing [35,36]. However, a further prospective study
disagreed [37], and the authors suggested that microvascular dysfunction may actually prevent the release of
Copyright © 2016 John Wiley & Sons, Ltd.

R. O. Forsythe and R. J. Hinchliffe

oxygen from the vasculature to the tissues, resulting in a
rise in oxyhaemoglobin at the microvascular level. Whilst
these studies demonstrate a correlation between hyperspectral imaging and wound healing, the nature of this
relationship is yet to be firmly established.

Molecular imaging and novel
techniques
There are many emerging and novel imaging techniques
that are under investigation, including molecular imaging
techniques, contrast-enhanced ultrasound and multi-modal
magnetic resonance imaging (MRI). ‘Molecular imaging’
exploits the known pathobiology of disease, using cell-specific compounds to assess the biological function of molecular events, such as gene transcription, or to identify
surrogate markers for disease activity, such as inflammation. Such techniques have been used in clinical practice
for many years, including PET imaging to detect tumour
metastases and to quantify perfusion to the brain and heart.

PET and SPECT
Nuclear imaging techniques have been used for many
years to assess cardiac perfusion, using highly sensitive
radiolabelled perfusion molecules, to visualize highly
specific cellular events such as perfusion and angiogenesis. These functional data can be combined with high-resolution anatomical data obtained on CT and the images
fused to produce a functional and structural overview of
perfusion. Technetium-based radiotracers have been used
to assess angiogenesis, and the PET radiotracer 15-oxygen
has been used to detect and quantify skeletal blood flow in
patients with critical limb ischaemia [38,39]. PET and single-photon emission computed tomography imaging
could be used to assess distal perfusion in patients with diabetic foot ulceration and may provide a ‘perfusion map’,
allowing evaluation of the regional perfusion according
to an angiosome model. In addition, such techniques
could be used to assess the change in perfusion following
intervention.
There may be huge potential for nuclear imaging to
increase our understanding and knowledge of distal tissue
perfusion; however, this is unlikely to become standard
practice in the near future because of the expense and
expertise required to utilize these techniques.

Contrast-enhanced ultrasound
Contrast-enhanced ultrasound uses microbubble contrast
(injected intravenously in an infusion or bolus) to assess
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Diabetic Foot Ulcer Perfusion

muscle perfusion and reactive hyperaemia after exerciseor cuff-induced ischaemia. This technique successfully
distinguishes between patients with peripheral artery disease and those without; however, it may have poor interobserver reliability and has not been adequately validated
for use in patients with diabetic foot ulceration [40].

Multi-modal MRI
Multi-modal MRI can allow assessment of both the large
vessels and limb perfusion. Arterial spin labelling involves
comparison of a ‘tagged’ image (obtained after placing a
magnetic tag on the water component of blood using radiofrequency pulse sequences) with a non-tagged image
and calculating the difference in perfusion after exercise
or reactive hyperaemia. This allows absolute and objective
quantification of muscle perfusion and has been used to
differentiate between patients with peripheral artery
disease and controls [41].
Blood oxygenation level-dependent MRI makes use of
haemoglobin as an endogenous contrast agent, as its paramagnetic properties alter the signal in T2*-weighted
images. Measurements taken during rest, hyperaemia
and exercise-induced stress may be used to obtain semiquantitative evaluations of relative change in perfusion
in patients with peripheral artery disease [42]. Both of
these MRI techniques involve long acquisition times,
complex interpretation of data and are vulnerable to
motion artefact and variable spatial resolution. They
may show promise but have not been evaluated in a
cohort of patients with diabetes.

Conclusion
In patients with diabetic foot ulceration, it is important to
assess the severity of peripheral artery disease, the
morphological distribution and the regional tissue
perfusion. Comprehensive assessment of foot perfusion
should therefore include anatomical assessments of structural arterial disease (using duplex ultrasonography
complemented by angiography), combined with measurements of functional tissue perfusion such as TcPO2, which
is a widely available technique but may be less reliable in
patients with diabetes and neuropathy. All of the
commonly available techniques have limitations particularly relating to the complexity of diabetes – vascular
calcification and distal arterial disease may make angiographic data difficult to obtain and interpret; measurements of tissue perfusion are affected by changes in
ambient temperature, arteriolar shunting and autonomic
neuropathy and assess only cutaneous perfusion; ABI
and toe pressure indices may be unreliable in patients
with diabetes. Nevertheless, evaluation of perfusion will
direct appropriate treatment and may help predict the
likelihood of wound healing. Novel techniques to assess
muscle and deep tissue perfusion are under development,
however are unlikely to become widely used in the near
future. The assessment of perfusion in patients with
diabetes therefore remains a challenge.

Conflicts of interest
The authors have no conflicts of interest.

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Diabetes Metab Res Rev 2016; 32(Suppl. 1): 232–238.
DOI: 10.1002/dmrr