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The Diabetic Foot
Plantar forefoot ulcer, heel ulcer and minor amputation
Hedvig Örneholm
DOCTORAL DISSERTATION
by due permission of the Faculty of Medicine, Lund University, Sweden.
To be defended at Clinical Research Center Aula
Skåne University Hospital Malmö
April 6, 2017 at 9.00.
Faculty opponent
Professor Michael Edmonds
King’s College, London
1
Organization
LUND UNIVERSITY
Document name
DOCTORAL DISSERTATION
Department of Orthopaedics
Clinical Sciences Malmö
Date of issue
2017-04-06
Author Hedvig Örneholm
Sponsoring organization
Title and subtitle
The Diabetic Foot: Plantar forefoot ulcer, heel ulcer and minor amputation
Abstract
Diabetes mellitus is increasing worldwide and is one of the most challenging healthcare dilemmas of the 21st century. Diabetes
is associated with both micro- and macrovascular complications. These include neuropathy, retinopathy, nephropathy,
cardiovascular and cerebrovascular complications, and peripheral vascular disease. These complications all contribute to an
increased risk of foot ulcer, infection, delayed ulcer healing and amputation.
This thesis is based on four papers: Paper I on minor amputations, Paper II on plantar forefoot ulcers, Paper III on heel ulcers,
and Paper IV on new foot ulcer development following healing of a plantar forefoot ulcer.
In Paper I 64% of all minor amputations healed at a level below the ankle. Re-amputation rate was 37% and almost one third of
these healed below the ankle. The median healing time was 26 weeks. Vascular intervention (including endovascular and open
methods) and pain as an indication for amputation were related to a lower healing rate below the ankle. Wagner grades 0–3 and
age below 73 years at time of amputation were associated with a higher healing rate below the ankle.
In Paper II 79% of patients healed their plantar forefoot ulcer without amputation. Severe peripheral vascular disease (SPVD)
was present in 26% of patients. Nine per cent healed after amputation (either minor or major) and 12% died unhealed. The
median healing time was 17 weeks. Wagner grade 1 or 2 at inclusion, independent living and age below 67 years at inclusion
were factors related to primary healing.
In Paper III 66% of patients healed their heel ulcer without amputation. SPVD was present in 31% of patients. The median
healing time was 17 weeks. Vascular surgery after inclusion, nephropathy and oedema were factors related to primary healing.
In Paper IV 47% of patients developed a new foot ulcer within two years following healing of a plantar forefoot ulcer. Only
eight per cent developed a recurrent foot ulcer (on the same foot and at the same site as the previously healed ulcer).
In summary, the major conclusions from this thesis are the following. Despite long healing time, it is possible for minor
amputations to heal in a large proportion of patients with diabetes, although patients are elderly, with extensive co-morbidity
and with severe foot ulcers including infection and/or gangrene in many cases. Four out of five patients with diabetes and a
plantar forefoot ulcer heal without the need for an amputation. SPVD was present in one out of four patients with plantar
forefoot ulcer, indicating the importance of vascular assessment in these patients. Two-thirds of patients with diabetes and a
heel ulcer healed without amputation. Following a healed plantar forefoot ulcer the risk of developing a new foot ulcer is high.
There is a lack of uniform terminology regarding new foot ulcer development. A concise definition for recurrent and other new
foot ulcers is suggested. This may facilitate comparison and enhance scientific discussions.
Key words: diabetes, plantar forefoot ulcer, heel ulcer, minor amputation, outcome, recurrent ulcer
Classification system and/or index terms (if any)
Supplementary bibliographical information
Language English
ISSN and key title 1652-8220
ISBN 978-91-7619-336-5
Recipient’s notes
Number of pages 86
Price
Security classification
I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference
sources permission to publish and disseminate the abstract of the above-mentioned dissertation.
Signature
2
Date
The Diabetic Foot
Plantar forefoot ulcer, heel ulcer and minor amputation
Hedvig Örneholm
3
Copyright Hedvig Örneholm
Faculty of Medicine, Lund University, Sweden
Department of Orthopaedics and Clinical Sciences
ISBN 978-91-7619-336-5
ISSN 1652-8220
Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:40
Printed in Sweden by Media-Tryck, Lund University
Lund 2017
4
To Peter, Idun, Tor and Sigrid
“For an obstinate ulcer, sweet wine and a lot of patience should be enough”
Hippocrates
5
Contents
Contents ....................................................................................................................6
List of original papers ...............................................................................................8
Definitions ................................................................................................................9
Abstract ..................................................................................................................13
Introduction ............................................................................................................15
Diabetes Mellitus..........................................................................................15
Macrovascular complications ..............................................................15
Microvascular complications ...............................................................16
The diabetic foot...........................................................................................17
Diabetic foot ulcer ........................................................................................18
Prevalence and incidence ....................................................................18
Aetiology .............................................................................................18
Classification .......................................................................................18
Infection...............................................................................................20
Treatment .............................................................................................21
Complications and outcome ................................................................22
Factors related to healing.....................................................................23
Peripheral vascular disease ..................................................................25
Plantar forefoot ulcer ....................................................................................26
Prevalence, incidence and aetiology ....................................................26
Treatment .............................................................................................26
Outcome ..............................................................................................27
Factors related to outcome ...................................................................27
Plantar ulcer recurrence .......................................................................28
Heel ulcer .....................................................................................................28
Prevalence, incidence and aetiology ....................................................28
Treatment .............................................................................................28
Complications and outcome ................................................................29
Factors related to healing.....................................................................32
Lower limb amputations...............................................................................33
Prevalence and incidence ....................................................................33
Indications ...........................................................................................33
6
Complications and outcome ................................................................34
Factors related to healing.....................................................................34
Aims of the studies .................................................................................................41
Patients ...................................................................................................................42
Paper I ..........................................................................................................42
Paper II .........................................................................................................42
Paper III ........................................................................................................42
Paper IV .......................................................................................................43
Method....................................................................................................................45
Setting ..........................................................................................................45
Treatment .....................................................................................................45
Statistical analysis ........................................................................................46
Results ....................................................................................................................49
Paper I ..........................................................................................................49
Paper II .........................................................................................................50
Paper III ........................................................................................................51
Paper IV .......................................................................................................51
Discussion...............................................................................................................53
Minor amputation .........................................................................................53
Plantar forefoot ulcer ....................................................................................56
Heel ulcer .....................................................................................................58
Risk of new foot ulcers and lack of definitions ............................................59
General and methodological considerations.................................................62
Strengths and limitations ..............................................................................63
Future perspectives .......................................................................................65
Conclusions ............................................................................................................67
Svensk sammanfattning ..........................................................................................69
Acknowledgements ................................................................................................71
References ..............................................................................................................73
7
List of original papers
This thesis is based on the following papers, which are referred to in the text by
their Roman numbers.
I. Svensson H, Apelqvist J, Larsson J, Lindholm E, Eneroth M. Minor amputation
in patients with diabetes mellitus and severe foot ulcers achieves good outcomes. J
Wound Care 2011; 20(6): 261–2, 264, 266 passim
II. Örneholm H, Apelqvist J, Larsson J, Eneroth M. High probability of healing
without amputation of plantar forefoot ulcers in patients with diabetes. Wound
Repair Regen 2015; 23(6): 922–31
III. Örneholm H, Apelqvist J, Larsson J, Eneroth M. Heel ulcers do heal in
patients with diabetes. Int Wound J 2016 Aug 4. [Epub ahead of print]
IV. Örneholm H, Apelqvist J, Larsson J, Eneroth M. Recurrent and other new
foot ulcers after healed plantar forefoot diabetic ulcer (submitted)
8
Definitions
Amputation
Surgical removal of the whole or a
part of the limb including its distal
end
Assisted living
Any institutional living outside the
patient’s own home
Cerebrovascular co-morbidity
History of neurological deficit
Concordance
The ability to keep 50% or more of
appointments with the
multidisciplinary foot care team
Critical limb ischaemia (CLI)
Toe pressure <30 mmHg and/or ankle
pressure <50 mmHg
Deep ulcer
Full thickness lesion of the skin
penetrating below the dermis to
subcutaneous structures, such as
fascia, muscle, tendon, or bone
Duration of diabetes
Calculated from the year of diagnosis
until presentation with an ulcer at the
foot clinic
End-stage renal disease (ESRD)
Uraemia (creatinine level >300
µmol/l), treatment in dialysis, or a
previous renal transplantation
Foot
The structure below the malleoli
Foot ulcer
Full thickness lesion of the skin of the
foot
Gangrene
Death of tissue in all tissue layers
(cutis, tendon, fascia, muscle)
Healing
Macroscopically complete
epithelialization which has to be
reconfirmed after 6 months
9
Healing time
Number of weeks from arrival at the
foot clinic until healing
Home care
Any assistance the patient had in
his/her own home
Hypertension
Blood pressure over 140/90 mmHg or
treatment with antihypertensive
agents
Index ulcer
The first ulcer in the studied time
period
Infection
A pathological state caused by
invasion and multiplication of
microorganisms in tissues
accompanied by tissue destruction or
a host inflammatory response
Ischaemic heart disease
Angina pectoris or myocardial
infarction
Minor amputation
Any amputation through or distal to
the ankle joint
Minor debridement
Removal of callosities and debris that
can be performed in the outpatient
clinic without anaesthesia
Major amputation
Any amputation proximal to the ankle
joint
Major debridement
Surgical revision or resection of soft
tissues and/or bone that requires
anaesthesia and/or the use of an
operating theatre
Necrosis
Devitalized (dead) tissue
Nephropathy
Persistent urine albumin > 300 mg/L
Neuropathy (diabetic)
The presence of symptoms or signs of
peripheral nerve dysfunction in people
with diabetes, after exclusion of other
causes
Non-ischaemic heart disease
Other causes such as atrial fibrillation
or valvular heart disease
10
Osteomyelitis
Infection of the bone, with
involvement of the bone marrow
Other new foot ulcer
A foot ulcer developing after healing
of a previous foot ulcer, located at any
site on the contralateral foot, or on the
same foot at any other site than the
previously healed foot ulcer
Pain
Rest pain localized in the foot
Partial forefoot amputation
Resection of two, three or four rays.
The partial forefoot amputations were
divided into two groups: one group in
which the first ray was included and
one in which it was not.
Peripheral vascular disease (PVD)
Obstructive atherosclerotic vascular
disease, outside the heart and brain,
with clinical symptoms, signs or
abnormalities on non-invasive
vascular assessment, resulting in
disturbed or impaired circulation in
one or more extremities
Previous amputation
Amputation performed before the
patient entered the study
Previous vascular surgery
Vascular surgery performed before
the patient entered the study
Primary amputation
The first amputation in a sequence
until a final outcome (healing or
death)
Primary healing
Healing without major debridement or
amputation
Re-amputation
An amputation performed on a
previously amputated limb, due to
non-healing of the previous
amputation
Recurrent foot ulcer
An ulcer appearing on the same foot
and at the same site as a previously
healed ulcer
11
Retinopathy
Classified as pre-proliferative or
proliferative based on retinal
photographs by an ophthalmologist
Severe peripheral vascular disease (SPVD) Toe pressure <45 mmHg or ankle
pressure <80 mmHg
Single ray amputation
Resection of one toe including part of
the metatarsal bone. This group was
subdivided in two: single first ray
amputations and single ray
amputations of any other toe (II, III,
IV or V).
Smoker
Currently smoking or having stopped
smoking for less than one year
Superficial ulcer
Full thickness lesion of the skin not
penetrating any structure deeper than
the dermis
Toe amputation
Resection of the toe through or distal
to the metatarsophalangeal joint
Trans-metatarsal amputation
Resection of all toes through the
metatarsal bones
Ulcer
A full thickness lesion through all the
layers of the skin
Ulcer duration
Defined as number of weeks from
onset until arrival at the foot clinic.
When time of onset could not be
established, ulcer duration was
categorized as unknown.
12
Abstract
Diabetes mellitus is increasing worldwide and is one of the most challenging
healthcare dilemmas of the 21st century. Diabetes is associated with both microand macrovascular complications. These include neuropathy, retinopathy,
nephropathy, cardiovascular and cerebrovascular complications, and peripheral
vascular disease. These complications all contribute to an increased risk of foot
ulcer, infection, delayed ulcer healing and amputation.
This thesis is based on four papers: Paper I on minor amputations, Paper II on
plantar forefoot ulcers, Paper III on heel ulcers, and Paper IV on new foot ulcer
development following healing of a plantar forefoot ulcer.
In Paper I 64% of all minor amputations healed at a level below the ankle. Reamputation rate was 37% and almost one third of these healed below the ankle.
The median healing time was 26 weeks. Vascular intervention (including
endovascular and open methods) and pain as an indication for amputation were
related to a lower healing rate below the ankle. Wagner grades 0–3 and age below
73 years at time of amputation were associated with a higher healing rate below
the ankle.
In Paper II 79% of patients healed their plantar forefoot ulcer without amputation.
Severe peripheral vascular disease (SPVD) was present in 26% of patients. Nine
per cent healed after amputation (either minor or major) and 12% died unhealed.
The median healing time was 17 weeks. Wagner grade 1 or 2 at inclusion,
independent living and age below 67 years at inclusion were factors related to
primary healing.
In Paper III 66% of patients healed their heel ulcer without amputation. SPVD was
present in 31% of patients. The median healing time was 17 weeks. Vascular
surgery after inclusion, nephropathy and oedema were factors related to primary
healing.
In Paper IV 47% of patients developed a new foot ulcer within two years
following healing of a plantar forefoot ulcer. Only eight per cent developed a
recurrent foot ulcer (on the same foot and at the same site as the previously healed
ulcer).
13
In summary, the major conclusions from this thesis are the following. Despite long
healing time, it is possible for minor amputations to heal in a large proportion of
patients with diabetes, although patients are elderly, with extensive co-morbidity
and with severe foot ulcers including infection and/or gangrene in many cases.
Four out of five patients with diabetes and a plantar forefoot ulcer heal without the
need for an amputation. SPVD was present in one out of four patients with plantar
forefoot ulcer, indicating the importance of vascular assessment in these patients.
Two-thirds of patients with diabetes and a heel ulcer healed without amputation.
Following a healed plantar forefoot ulcer the risk of developing a new foot ulcer is
high. There is a lack of uniform terminology regarding new foot ulcer
development. A concise definition for recurrent and other new foot ulcers is
suggested. This may facilitate comparison and enhance scientific discussions.
14
Introduction
Diabetes Mellitus
Diabetes mellitus is increasing worldwide and it is one of the most challenging
health care dilemmas in the 21st century.1,2 In 2015 415 million people over the
world were estimated to have diabetes, and this number is projected to rise to 642
million by the year 2040.3 Two of the main types of diabetes are type 1 and type 2.
Type 1 diabetes is caused by an autoimmune reaction, in which the body’s defence
system attacks the insulin-producing beta cells in the pancreas. Type 1 diabetes
accounts for a small percentage of the total burden of diabetes in the population.
Type 2 diabetes is the most common type of diabetes. In type 2 diabetes, the body
is able to produce insulin but becomes resistant so that the insulin is ineffective.
Over time, insulin levels may subsequently become insufficient. Type 2 diabetes
constitutes about 85–90% of all diabetes in developed countries and accounts for
an even higher percentage in developing countries.3 The economic consequences,
for both patient and society, are very large and every effort to improve care of
these patients is worthwhile. Diabetes mellitus is characterized by hyperglycaemia
due to defects in insulin secretion, insulin action, or both.4 Diabetes-related
complications are frequently grouped into micro- and macrovascular diseases.
Macrovascular complications
Cardiovascular disease
Cardiovascular disease is the leading cause of morbidity and mortality in patients
with diabetes5 and risk factors for cardiovascular disease, such as hypertension,
dyslipidaemia, smoking, albuminuria, and a family history of cardiovascular
events, should be assessed once a year in patients with diabetes.5 Prevention
strategies, as well as treatment of manifest complications, can be beneficial6 and
elimination of risk factors to prevent cardiovascular events is an important part of
treatment. Both lifestyle changes and pharmacological agents may be used to treat
risk factors.5
In a 30-year follow-up of the Diabetes Control and Complications Trial (DCCT),
the cumulative incidence of cardiovascular disease was 14% in the conventional
15
therapy group and 9% in the intensive therapy group.7 In the follow-up of the same
study, intensive treatment of blood glucose levels in patients with type 1 diabetes
was shown to reduce the risk of long-term complications.8
Cerebrovascular disease
The risk of death due to cerebrovascular disease is increased in patients with
diabetes (both type 1 and type 2). Hyperglycaemia at hospital admission for a
stroke has been shown to be a predictor of worse neurological outcome.9 In a large
study on more than 13,000 patients, the presence of diabetes led to a two- to
threefold increase in the risk of stroke. The same study also showed that women
had a higher risk of stroke than men.10 In patients with diabetes there is also an
increased risk and rate of dementia and cognitive decline.5 Cerebrovascular
disease has been shown to be more common in patients with diabetes and a foot
ulcer than in patients without a foot ulcer.11
Microvascular complications
Diabetic peripheral neuropathy
Diabetic peripheral neuropathy affects up to 30–50% of patients with diabetes and
is a serious complication in patients with diabetes.12-15 Diabetic neuropathy is one
major risk factor for development of diabetic foot ulcer.16-18
The nervous system is divided into three main parts: sensory, motor and
autonomic. The sensory nerves are important to feel the surroundings, and loss of
the sensory nerves leads to a loss of protective sensation. A sensory neuropathy is
associated with the loss of pain, pressure awareness, temperature sensation and
proprioception.19 The ability to feel pain, for example stepping on a pin and
feeling it, is an important protective sensation. It was first described by the late Dr
Paul Brand and summarized by Dr Andrew Boulton.18 The motor nerves are
responsible for maintaining posture and balance. Loss of function in these nerves
affects the muscles in the leg and foot, altering the biomechanics and foot
anatomy, leading to foot deformities and increased pressure within the foot in an
effort to maintain balance. The autonomic nerves work to maintain normal organ
function and homeostasis, and are subdivided into the sympathetic and
parasympathetic system. Loss of the autonomic nerves in the lower limb leads to
loss of normal sweating leading to dry skin which may crack, and loss of the
ability to control vascular blood flow which may play a part in impaired wound
healing.20
16
Diabetic retinopathy
Diabetic retinopathy is a specific vascular complication to diabetes, is related to
the duration of diabetes, and is the leading cause of new blindness in patients
under 75 years.5 After 15 years’ diabetes duration almost all patients with type 1
diabetes will have diabetic retinopathy. In patients with type 2 diabetes and
duration of diabetes of more than 15 years the corresponding number is 85% of
patients receiving insulin treatment and 58% in patients not receiving insulin
treatment.21 Presence of retinopathy and loss of vision have been associated with
an increased risk of foot ulcers.22
Diabetic nephropathy
Diabetic nephropathy is present in 20–40% of patients with diabetes and is the
leading cause of end-stage renal disease (ESRD), dialysis and/or renal
transplantation.23 Nephropathy has been described as a marker for worse outcome
in diabetic foot ulcers.24,25 ESRD seems to have a stronger negative impact in
patients who also have peripheral artery disease.24
The diabetic foot
The definition of the diabetic foot has been described as infection, ulceration
and/or destruction of deep tissues associated with neurological abnormalities and
various degrees of peripheral vascular disease.1,2 As indicated by this description,
one or more of these conditions may coincide, and they often do. A diabetic foot
ulcer is the general term to describe a full-thickness wound below the ankle in a
patient with diabetes.1 The major adverse outcomes of diabetic foot problems are
foot ulcers and amputations, and foot problems account for more hospital
admissions than any other long-term complications of diabetes, and also result in
increasing morbidity and mortality.26
17
Diabetic foot ulcer
Prevalence and incidence
The prevalence of diabetic foot ulcers is described to be between 4% and 10% of
the diabetic population, with a lifetime risk of up to 25%.27 The incidence of foot
ulcers in diabetic patients varies between 2 and 6% in Western Europe and North
America, and between 19% and 29% in the Middle East.26 The EURODIALE
study showed that there are marked regional differences throughout Europe
regarding diabetic foot ulcer and amputation incidence.28,29
Aetiology
Peripheral neuropathy and PVD are the two factors most commonly attributed to
diabetic foot ulcer. Diabetic foot ulcers are therefore often described as of
neuropathic, ischaemic, or neuro-ischaemic origin.1 The cause of diabetic foot
ulcers is often multifactorial. Sensory loss, foot deformities, repetitive pressures
and skin breakdown are considered to be the key aetiopathogenetic pathways to
neuropathic foot ulcers in diabetes, as first described by Paul Brand in the mid20th century, and addressing these issues is today a cornerstone in the
management of plantar diabetic foot ulcers.18,30 Visual impairment, reduced joint
mobility, callosities, present or previous foot ulceration, and previous amputation
have also been described as factors contributing to the development of diabetic
foot ulcers.1,31,32
Classification
There are several classification systems for diabetic foot ulcers, three being the
most commonly used33-35, each with their advantages and limitations. The Wagner
classification system33 for foot ulcers is widely used, and was the only one of these
three that was available when the study databases were started. It includes the
following grades.
18
Wagner grade 0
No ulcer
Wagner grade 1
Superficial ulcer (up to but not through dermis)
Wagner grade 2
Ulcer extension involving ligament, tendon, joint
capsule or fascia (no abscess or osteomyelitis)
Wagner grade 3
Deep ulcer with abscess and/or osteomyelitis
Wagner grade 4
Gangrene of portion of the foot
Wagner grade 5
Extensive gangrene of the foot
The first three grades (grades 0–2) are based on the physical depth of the lesion
only, grade 3 on the physical depth and infection and grades 4–5 on the extent of
gangrene in the foot. Shown below are examples of ulcers in different Wagner
stages.
Wagner grade 1
Wagner grade 3
Wagner grade 2
Wagner grade 4
19
Wagner grade 5
Figure 1.
Foot ulcer classification according to Wagner
The Texas Diabetic Wound Classification System34 includes wound depth, the
presence of infection and PVD in every category of the wound assessment.
The PEDIS classification system35 includes the categories: Perfusion, Extent/size,
Depth/tissue loss, Infection and Sensation, with a grading system for each
category. These two classifications are mainly used for research purposes. In 2010
a review of scoring systems for diabetic foot ulcer was published.36 In summary,
this review showed that many scoring systems exist for classification of diabetic
foot ulcer, but few of these have been validated. Detailed scoring systems may be
useful in comparing data from different centres, while simpler scoring systems
may be more easily used in clinical practice.
Infection
Although infection is seldom the direct cause of a diabetic foot ulcer, in the
EURODIALE study, 25–75% of patients at various centres were considered to
have a wound infection at the time of admission.37 Infection in the diabetic foot
increases the risk of hospitalization and of a subsequent amputation, especially in
combination with PVD.25,37-39
20
Treatment
Prevention of diabetic foot ulcers includes regular inspection and examination of
feet at risk, education of patients and relatives, and off-loading with custom-made
insoles and individually adjusted footwear.1,40
The basis for management of the diabetic foot ulcer is the multidisciplinary team,
which includes medical and surgical treatment, podiatry, nursing and orthotic
support.1,19 The multidisciplinary team treatment of diabetic patients with foot
ulcer has been shown to be cost-effective, improves healing rate, and reduces
amputation rate and ulcer recurrence.41-47 Treatment of metabolic disturbances,
malnutrition, peripheral vascular disease, infection, pain, and oedema as well as
topical treatment with ulcer dressings, off-loading, vascular assessment and
surgery, and orthopaedic surgery (major debridement, minor and major
amputation) are all important parts of the multidisciplinary team approach.19
Excision of the ulcer, metatarsal head resection, Achilles tendon lengthening, and
local skin flap have all been described as surgical treatment of diabetic foot ulcers.
The results seem good but adequate perfusion of the foot is needed.19 Amputations
(both minor and major) are also part of the surgical procedures used for treatment
of diabetic foot ulcers. Indication for amputation is often multifactorial. A nonhealing ulcer should not be used as an indication for amputation.19
21
Table 1. Multifactorial treatment of diabetic foot ulcers (adapted from Apelqvist 201219).
ESR = erythrocyte sedimentation rate, CRP = C-reactive protein, CT = computer tomography, MRI = magnetic resonance
imaging, HbA1c = glycosylated Haemoglobin A1c.
Goal
Investigation/evaluation
Treatment
Improve circulation
Non-invasive vascular testing:
Systolic toe/ankle blood pressure,
transcutaneous oxygen pressure, duplex
(ultrasound)
Invasive vascular testing:
Angiography, MR angiography, CT
angiography, CO2 angiography
Percutaneous angiography (PTA)
Sub intimal angioplasty
Reconstructive vascular surgery
Vascular agents
Remove oedema
Hyperbaric oxygen
Treat infection
Superficial or deep infection, osteomyelitis,
abscess
ESR, CRP, white blood cell count, bacterial
culture, bone biopsy, X-ray, CT-bone scan,
MRI
Antibiotics (oral/parenteral)
Incision/drainage
Resection
Amputation
Remove oedema
Evaluate the cause of oedema
Pain control
Cause/type of pain
Pain evaluation protocol/diary
External compression therapy
Intermittent compression (pumps)
Diuretics
Analgesic agents
Immobilization/off-loading
Improve metabolic control
HbA1c self-monitoring of glucose
Insulin treatment often necessary
Nutritional support
Off-loading
Type and site of ulcer, biomechanical
evaluation, walking capacity
Therapeutic/protective footwear, insoles,
orthosis, total contact cast, crutches,
wheelchair, bed rest
Wound bed preparation
Type, site, and condition of the ulcer,
necrosis, exudation, peri-ulcer maceration,
signs of inflammation, granulation
Topical treatment and dressings
Debridement
Control of exudation
Moist wound healing
Infection control
NWPT
Removal of dead tissue
Extent of tissue destruction, infection,
ischaemia
Minor debridement
Incision
Drainage
Amputation
Correction of foot
deformities
Evaluation of foot deformities
Corrective foot surgery
Improve general condition
Dehydration, malnutrition, intercurrent
disease, congestive heart failure, nephropathy,
metabolic syndrome, smoking habits
Fluid and nutrition replacement therapy
Aggressive treatment of intercurrent
disease
Antiplatelet drugs, antihypertensive
agents, lipid decreasing agents
Cessation of smoking
Physiotherapy
Complications and outcome
Occasionally, a diabetic foot ulcer may be considered an underlying, even if not an
immediate, cause of death, and not infrequently it may be a contributing factor by
starting a deteriorating chain of events. Diabetic foot ulcer patients have a greater
than twofold increase in mortality compared with non-ulcerated diabetic patients,
and Chammas et al concluded that ischaemic heart disease is the major cause of
premature mortality.48 Up to 70% mortality after 5 to 10 years has been
22
reported.49,50 Evaluating outcome for more than five years, around half of the
patients will have died, making analysis more difficult due to small numbers.49,51-53
The high mortality rate among these patients deserves attention and further
underlines the general morbidity of this patient group. Mortality, specifically
related to foot ulcer location, is rarely reported on. A report from 2012 showed
that patients with depressive symptoms and a new diabetic foot ulcer had a higher
mortality than patients who did not exhibit signs of depression.54
Apart from increased mortality, the most serious immediate adverse outcome is a
lower limb amputation. It has been claimed that every 30 seconds a lower limb is
amputated due to diabetes.1 Up to 70% of all lower extremity amputations are
performed in people with diabetes and 85% of these amputations are preceded by a
foot ulcer.1,2,55
Factors related to healing
The main outcomes of a diabetic foot ulcer are primary healing, healing after
debridement, healing after amputation (either minor or major), and death unhealed.
Most seem to agree that neuropathy, PVD, minor foot trauma and foot deformity
contribute to the development of diabetic foot ulcers.1,42 When it comes to factors
which influence outcome of foot ulcers and minor amputations there are no
unanimous results. This is mostly due to confounding factors such as differences
in study design, patients included, follow-up time, definitions (or lack thereof),
and treatment strategies.
The number of large cohort studies with factors related to healing of foot ulcers is
limited. In most mixed cohort studies primary healing rates of 60 to 74% and
amputation rates of 8 to 23% have been reported.24,25,56-59 Multiple factors have
been described to be predictors of non-healing of various types of diabetic foot
ulcers, such as PVD25,60, infection24, cardiovascular disease25,61, end-stage renal
disease25,62, severe retinopathy63, tissue involvement24,25,57,64, peripheral
oedema24,25, ulcer location65, male gender63,66, age67, diabetes duration, metabolic
control63,66, and socio-economic status.66,67 Depression has been found to be
associated with amputation.68 Most of these studies have small numbers of patients
and there are differences in study design, patient selection, definitions and followup, making comparisons difficult. In a prospective study of 575 patients with an
infected diabetic foot ulcer presenting to 14 different diabetic foot clinics in ten
European countries, periwound oedema, foul smell, (non-)purulent exudate, deep
ulcer, positive probe-to-bone test, pretibial oedema, fever, and elevated C-reactive
protein were all found to be independent risk factors for amputation.69 However,
there does not seem to be any consensus with regard to factors related to outcome.
23
Table 2. Factors related to outcome
Factors related to
outcome (non-healing)
Factors related to
amputation
Patient
Extremity
Ulcer
Cardiovascular disease25,61,
ESRD25,62, retinopathy63, male
gender63,66, age67, diabetes
duration25, metabolic control63,66,
socio-economic status66,67
Fever69, elevated CRP69 (Creactive protein), depression68
PVD25,60
Infection24, tissue
involvement24,25,57,64, peripheral
oedema24,25, ulcer location65
PVD60
Periwound oedema69, foul
smell69, (non) purulent exudate69,
deep ulcer69, positive probe-tobone test69, pretibial oedema69,
ulcer severity68
Healing time after a diabetic foot ulcer or a minor amputation is not always
reported. Reported healing times in the literature for plantar ulcers range from 6 to
12 weeks.56,57,70,71 Most data in the literature are from randomized controlled trials
with less than 20 weeks’ follow-up, which means that many ulcers are not given
enough time to heal. To further complicate scientific discussion and comparison,
healing is not always defined. In the studies which make up this thesis, healing
was defined as intact skin for 6 months or intact skin at time of death.
The long healing times and costs attributed to minor amputations have been
mentioned as reasons to perform a major amputation instead. However, the
functional outcome of a major amputation is worse even if it heals better.
Furthermore, the costs of a major amputation by far exceed the cost of a minor
amputation, even with the long healing times.2,72
24
Peripheral vascular disease
Peripheral vascular disease (PVD) refers to diseases of blood vessels outside the
heart and brain, with a narrowing of the vessels that carry blood to the extremities,
stomach or kidneys. Symptoms or signs of PVD can be observed in up to 50% of
the patients with a diabetic foot ulcer and is a risk factor for poor healing and
amputation.25,37,56,60,73 Identifying PVD is important because its presence is
associated with worse outcomes.24,74 In a systematic review of which measures of
PVD predict healing of diabetic foot ulcers, skin perfusion pressure ≥40 mmHg,
toe pressure ≥30 mmHg and transcutaneous pressure of oxygen (TcPO2 ) ≥25
mmHg were associated with at least a 25% higher chance of healing.60 Among
patients with diabetic foot ulceration, the measurement of skin perfusion pressures,
toe pressures and TcPO2 appears to be more useful in predicting ulcer healing than
ankle pressures or the ABI.60 An ankle pressure of <50 mmHg or an ABI <0.5 is
associated with a significant increase in the incidence of major amputation.60 In a
systematic review on the effectiveness of therapies to revascularize the ulcerated
foot in patients with diabetes and PVD, improved rates of limb salvage were found
associated with revascularization compared with the results of conservatively
treated patients.73
The most important factors related to development of foot ulcers in individuals
with diabetes are peripheral neuropathy, minor foot trauma, foot deformity and
decreased tissue perfusion.1,75 Diabetic foot ulcers are frequently presented as
neuropathic or neuroischaemic/ischaemic, according to above-mentioned
classification system, related to its aetiology or pathogenesis, or to site of ulcer.
Diabetic foot ulcers are frequently seen in patients with a combination of two or
more risk factors occurring together.24,25 With regard to the aetiology of foot
ulceration, peripheral vascular disease and neuropathy are frequently present in the
same patient. Although traditionally it is stated that the majority of foot ulcers are
purely neuropathic an increase has been found in the incidence of neuroischaemic
and/or ischaemic foot ulcers. Ulcers frequently result from external trauma to the
insensitive foot, such as ill-fitting shoes, burns, walking barefoot and foreign
objects in shoes.25,42 However, an ulcer caused by increased mechanical stress due
to disturbed biomechanics is usually localized in the metatarsal heads or the
plantar area of the first digit, whereas decubitus ulcers are located in the heel.
25
Plantar forefoot ulcer
Prevalence, incidence and aetiology
Plantar ulcers are usually localized under the metatarsal heads or plantar surface of
the first digit, and constitute 22–25% of all diabetic foot ulcers in large Western
cohort studies.25,37 These ulcers are usually considered purely neuropathic and
caused by mechanical stress, but a large share of these patients also have
PVD.25,26,37
Treatment
The main aim of treatment is to achieve healing of the wound and avoid minor and
major amputation as well as ulcer recurrence. The basis for treatment of plantar
forefoot ulcers is the same as for all diabetic foot ulcers, and described in Table 1.
Off-loading
Off-loading is the most important treatment strategy in plantar forefoot ulcers,
especially Wagner grades 1–2. It can be achieved by non-surgical or surgical
methods. Total contact casting is currently considered the gold standard to off-load
plantar foot ulcers.40 By using the total contact cast, healing rates of 90% in
neuropathic and 69% in non-infected ulcers with PVD can be achieved.76-78 Bus
and colleagues showed in a systematic review that there is sufficient evidence in
the literature to support the recommendation of non-removable off-loading devices
to heal a plantar forefoot ulcer.79
Surgical treatment
The most important part of the treatment for control of a deep infection with or
without minor gangrene in the diabetic foot (Wagner grades 3–4), is urgent
incision and drainage and radical debridement of all infected, non-viable tissue.
Various elective surgical procedures have been described to off-load plantar
forefoot ulcers, such as flexor tenotomy80, Achilles tendon lengthening81, plantar
fascia release82 and multiple metatarsal head resections83, to name some. A review
by Scott and colleagues80 discusses the evidence that flexor tenotomy can heal and
prevent toe ulcers in diabetic patients. This review concludes that while most
studies report high healing rates (92–100%) and low recurrence rates (0–18%),
these are case series studies, which undermines the validity of the procedure
studied. Colen et al investigated whether Achilles tendon lengthening in
combination with total contact cast and wound surgery would be effective in
26
healing midfoot and forefoot ulcers in 287 diabetic patients.81 The results of this
study showed that patients with Achilles tendon lengthening had a lower ulcer
recurrence rate and fewer transfer lesions than patients receiving total contact cast
and wound surgery alone.81 Kim et al82 showed that 60 diabetic patients who had a
selective plantar fascia release healed their neuropathic forefoot ulcer in 56% of
cases. Armstrong and colleagues83 evaluated 92 diabetic patients with a plantar
forefoot ulcer treated with multiple metatarsal head resection. The authors
concluded that patients with surgery healed faster and had fewer recurrent ulcers
than patients not having surgery. Since the evidence of the effect of surgical
procedures on off-loading is weak, and since surgical procedures were not
specifically evaluated in the present thesis, no detailed description of surgical
procedures is given.
Outcome
There are few studies on larger cohorts who specifically discuss the characteristics
and outcome of plantar forefoot ulcers in diabetic patients, and in most studies
there is a combination of various types of ulcer and ulcer locations.84,85 In mixed
cohort studies regarding short-term outcome, primary healing rates of 64–85%,
amputation rates of 8–23% (irrespective of level), and mortality rates of 10–20%,
have been described. In randomized controlled trials of neuropathic diabetic foot
ulcers (mostly, but not exclusively, plantar) healing rates over 12–20 weeks of 36–
60% have been reported.29,52,56,70,71,86-88
Factors related to outcome
There are not many published studies specifically focusing on long-term outcome
of plantar forefoot ulcer. In reports on cohorts with mixed ulcer locations, extent
of tissue involvement, PVD, neuropathy, age, male gender, and co-morbidity have
been reported as factors influencing outcome.24,57,89,90
In studies with plantar and mixed ulcer location, poor glycaemic control,
neuropathy, poor compliance with footwear and foot care, non-attendance, delay
in reporting new symptoms, PVD, insulin treatment, plantar ulcer location,
osteomyelitis, and cumulative duration of past foot ulcers have been reported as
factors negatively influencing long-term outcome.51,91-96 A Cochrane review from
2013 found that non-removable off-loading devices were more effective in healing
plantar foot ulcers than removable ones.97
27
Plantar ulcer recurrence
There are very few large cohort studies about the risk of new foot ulcers following
healing of a diabetic foot ulcer, particularly after healing of a plantar forefoot
ulcer. In available reports, rates of new foot ulceration following healing of a foot
ulcer of various aetiologies in subjects with diabetes vary widely50,51,80,81,91,94,95,98100
, from 8% in a study on percutaneous Achilles tendon lengthening in 52
patients98 to 70% in a study of all types of diabetic foot ulcers.50
Bus et al found evidence to support the claim that therapeutic footwear worn by
the patient can prevent foot ulcer recurrence, while there is not enough evidence
regarding the efficacy of surgical off-loading to prevent and heal plantar forefoot
ulcers.79
There is no consensus regarding the terminology of foot ulcers appearing after an
initial foot ulcer has healed. In the literature these foot ulcers are termed recurrent
ulcer51,91,94,98,99, reulceration94,99,100, new ulcer95, and transfer ulcer80,81. Often the
term ulcer recurrence is used without any definition.101-104 To be able to compare
treatment strategies and to identify risk factors and prevent new foot ulcers, there
is a need for more uniform definitions of new foot ulcers.
Heel ulcer
Prevalence, incidence and aetiology
In the EURODIALE study heel ulcers were reported as 10% of all diabetic foot
ulcers37, and Gershater et al found heel ulcers to be 15% of diabetic foot ulcers.25
Most studies with regard to ulcers located in the heel in patients with diabetes have
small numbers or a selected category of patients.1,105-113 An ulcer located to the
heel often has decubitus origin26, but it may also be caused by repetitive trauma
and mechanical stress.
Treatment
The main aim of treatment of a diabetic heel ulcer is to heal the ulcer, to avoid
major amputation as well as new ulcer development. The basis for treatment of
heel ulcers is the same as for all diabetic foot ulcers, and is described in Table 1.
28
Off-loading
Irremovable off-loading devices have been shown to be effective in healing plantar
foot ulcers79 and off-loading is thought to be an important part of the treatment
strategy in heel ulcers although there are no published studies on heel ulcers.
Jeffcoate and colleagues114 have published a study protocol for investigating a
removable device to off-load and heal heel ulcers. As yet there are no published
results available on PubMed.
Surgical treatment
As in all other ulcer localizations in the diabetic foot, the most important treatment
for control of a deep infection of heel ulcers is drainage and radical debridement of
all infected, non-viable tissue.115 Other surgical procedures, such as partial
calcanectomy116, distal bypass surgery and partial calcanectomy combined108, and
free flap transfer and revascularization combined115,117, have been described as
improving the healing of heel ulcers. There are no large studies evaluating
different surgical procedures to improve the healing of diabetic heel ulcers.
Surgical procedures were not specifically evaluated in the present thesis and thus
no detailed description of these procedures is given.
Complications and outcome
Avoiding major amputation is the main goal in treating a heel ulcer. However,
studies focusing specifically on heel ulcers in patients with diabetes are scarce in
the literature. In sixteen studies on heel ulcers65,107-113,115-122, seven include a
mixture of diabetic and non-diabetic subjects107,110,112,118-121, Table 3. The
remaining nine studies on diabetic patients with heel ulcers comprise in total 508
patients. The median age spans from 53 to 73 years and reported healing rates vary
from 51 to 95% .65,108,109,111,111,113,115-117,122
29
Table 3.
Overview of studies of heel ulcers and factors related to outcome
Author/year
Number
of
patients
Age
Patient
selection
Definition
of healing
Healing
rate
Healing
time
Follow-up
Factors related to outcome
Mortality
Comments
Baumhauer et
al 1998118
8
52 (33-71)
Diabetes +
non diabetes
No
88%
Not reported
27 (6-57)
months
Not reported
25%
Primary closure in 5 cases.
Retrospective review of total
calcanectomy.
1/8 amputation.
Baravarian et
al 1999109
12
65 (39-89)
Diabetes
Yes
83%
6 (2-20)
weeks
13 months
Not reported
17%
Long surgical description.
No amputation during follow-up.
Treiman et al
2000112
91
67 (38-88)
Diabetes +
non diabetes
No
73%
3.2 (1-6)
months
21 (1-60)
months
Normal renal function,
palpable pedal pulse, patent
posterior tibial artery had
positive influence on outcome
15%
11% major amputation.
Bollinger et
al 2002119
22
57 (32-83)
Diabetes +
non diabetes
No
100%
Not reported
27 (2-80)
months
Not reported
18%
Primary wound closure. No major
amputation.
Chipchase et
al 2005111
97 (157
heel
ulcers)
69±13
Diabetes
Yes
61%
200 (241225) days
minimum 4
months
Larger ulcer, PVD showed
worse outcome
20%
7% major amputation
Bakheit et al
2012113
100
55±14
Diabetes
No
51%
180 (90204) days
3 years
Shorter DM duration,
adequate lower limb
perfusion, superficial ulcer
associated with better healing
8%
22% lower extremity amputation
Fraccalvieri
et al 2012110
7
74 (60-87)
Diabetes +
non diabetes
No
100%
Not reported
22 (6-36)
Not reported
14%
No amputation
Goudie et al
2012108
21
61 (39-84)
Diabetes
No
95%
99 (79-133)
days
24-48
months
Small sample, no conclusive
factors found
5%
4/21 (19%) major amputation
Van Riet
2012107
24
54 (20-81)
Diabetes +
non diabetes
Yes
92%
129 (67321) days
37 (3-91)
months
Not reported
21%
4% major amputation (1/24)
Pickwell et al
201365
116
(cohort of
>1000
patients)
65±14
Diabetes
Yes
65%
237 (205269) days
1 year
Longer duration of DM and
ulcer, heart failure, PVD
predicted time to healing
11%
Subgroup analysis of the
EURODIALE cohort
30
Author/year
Number
of
patients
Age
Patient
selection
Definition
of healing
Healing
rate
Healing
time
Follow-up
Factors related to outcome
Mortality
Comments
Walsh et al
2013120
10
64 (50-83)
(DM)
77 (50-87)
(non DM)
Diabetes +
non diabetes
Yes
8/10
(5/7 in
DM
patients)
64 days
(mean)
3 years
Not reported
0%
Case series of efficacy of
calcanectomy. Small patient sample.
Shojaiefard et
al 2013115
37
62 ±14
Diabetes
No
89%
6 (4-7)
months
Minimum 1
year
Not reported
0%
11% major amputation
Oliver et al
2015121
42
61±16.6
64±16
Diabetes +
non diabetes
No
Not
reported
Not reported
41±26
months
Not reported
12%
Study on partial calcanectomy for
heel ulcers. Question is whether
resection of more or less than 50%
of calcaneus has an influence on
outcome. It does not.
29% major amputation.
Yosuf et al
2015122
50
(cohort
100
patients)
52.9±11
Diabetes
Yes
54%
20 weeks
Not
specified
Not reported
0%
Study from Sudan. Compares
outcome of forefoot ulcers vs heel
ulcers.
Kallio et al
2015117
63
56 (range
21)
Diabetes
Yes
84%
56%
33%
1991-2003
6 years
Smoking, heel ulcer,
nephropathy, ulcer diameter
>10 cm associated with
increased amputation risk
3% (30 day
mortality)
Studies free flap transfer for heel
ulcers.
Amputation rate 11% (30 day amp
rate).
30% major amputation during
follow-up.
Lin et al
2016116
12
73 (65-79)
Diabetes
No
75%
Not reported
2 weeks to 3
years
Not reported
8%
Included patients with near total
occlusive PVD.
Primary wound closure in all cases.
Örneholm et
al 2016Paper III
768
73 (17-98)
Diabetes
Yes
66%
17 (1-416)
weeks
Until
healing or
death
Vascular surgery,
nephropathy, oedema,
creatinine <91 µmol/L
25%
12% major amputation
31
Chipchase et al were the first to describe a large number of diabetic patients with
heel ulcers.111 They found a healing rate of 61%. In studies where healing time is
reported the healing time was 6–33 weeks.65,108,109,111,113,122
In available reports on heel ulcers, in mixed cohorts of diabetic and non-diabetic
subjects, the major amputation rate is reported to be between 0% and 30%.107113,115,117,121,122
In more than half of these studies there are less than 50 study
participants.
For heel ulcers in diabetic patients reports of mortality range from 0% to
20%.65,108,109111,113,115-117,122
Factors related to healing
Due to the small number of studies on diabetic patients with heel ulcers it is not
easy to find definitive evidence of factors related to outcome of heel ulcers, Table
3. A study of 91 diabetic and non-diabetic patients showed that normal renal
function, a palpable pedal pulse, and adequate perfusion to the foot had a positive
influence on outcome.112 Chipchase and colleagues, in a study on 97 diabetic
patients, showed that a larger ulcer and the presence of PVD led to worse
outcome.111 Bakheit and colleagues, in a study on 100 diabetic patients, showed
that shorter diabetes duration, adequate lower limb perfusion, and a superficial
ulcer were factors associated with better healing.113 In a study on a subgroup from
the EURODIALE study, Pickwell and colleagues showed that longer duration of
diabetes and ulcer, heart failure, and PVD predicted time to healing.65 Yosuf and
colleagues, in a study comprising 50 heel ulcers, showed that a larger ulcer had a
longer healing time.122 Kallio and colleagues, in a study on 63 diabetic patients
with free flap transfer for heel ulcer, showed that smoking, nephropathy, and ulcer
diameter >10 cm were factors associated with increased risk of major
amputation.117
32
Lower limb amputations
Prevalence and incidence
The prevalence of amputation in patients with diabetes varies globally (1/1,000
inhabitants in Madrid and Japan to up to 20/1,000 in some Indian tribes in North
America).123,124
For many years the incidence of minor amputation was unknown and little was
known about the outcome.125,126 In recent years several studies have described the
incidence and/or prevalence of minor amputations.55,127-130 Both Larsson and
Krishnan described a fall in incidence of major amputations, but described an
increase in minor amputations.127,128 Spanish national data show a decrease in the
incidence of both minor and major amputations in patients with diabetes.129
Ahmad found that the prevalence of major amputations in diabetics in England
2003–2013 was reduced, whereas minor amputations increased.55 Wang et al
described a decrease in both major and minor amputations between the years 2004
and 2013 although minor amputations increased during the last two years of the
period.130
Indications
The most common indications for amputation described in the literature are
gangrene, infection, and a non-healing ulcer.1,86,131-147 Although frequently reported
as such, a non-healing ulcer should not necessarily be considered an indication for
amputation since the duration of an ulcer is not an unfavourable factor with regard
to amputation.42
The immediate objective of a minor amputation is often to control infection and
halt the progression of gangrene, thereby minimizing the risk of major amputation
and thus optimizing ambulatory function. Infection is often present when a minor
amputation becomes necessary in patients with diabetes and the blood supply to a
smaller or larger extent compromised. This may often require open treatment in
order to preserve all viable tissue, and this means long healing times.
There is no randomized controlled study regarding amputation level selection in
diabetic foot ulcer. The basic consideration is to choose the lowest amputation
level where healing is deemed possible. However, sometimes functional aspect
may modify this, e.g. in the presence of a marked contracture of the knee, which
can make a knee disarticulation more favourable than a transtibial amputation. The
main objectives for major amputation are to relieve pain, to restore ambulation
33
and/or to save the patient’s life. However, non-ambulation and mortality rate after
a major amputation in diabetes are high since many diabetic patients are older and
many have extensive co-morbidity.148,149 Walking with a prosthesis requires more
energy than walking on an intact limb.150 A major amputation therefore often
results in non-ambulation. To improve ambulation is the main reason why it is
important to try to avoid a major amputation in patients with diabetic foot ulcers.
Complications and outcome
Reported healing rates at minor amputation levels, in studies with diabetes patients
and mixed cohorts of diabetes and non-diabetes patients, range from 12% to
100%.52,86,136,141,144,145,151-158 These variations might be explained by differences in
patient selection, definitions, included patients/procedures, and length of followup.
The long healing times after a minor amputation have sometimes been used as an
argument for performing a primary major amputation.42,126 However, the high
complication rate after a major amputation and the long-term costs of a major
amputation by far exceed the negative consequences of a minor amputation.2,72
Furthermore, minor amputation was not associated with a negative impact on
health-related quality of life (HRQoL) in patients with a diabetic foot ulcer and it
may therefore not be considered treatment failure in terms of HRQoL, but rather a
viable treatment option.159
Re-amputation was defined as an amputation at the same or at a more proximal
level after a primary amputation on the same extremity that had not yet healed.126
Reported re-amputation rates for minor amputations in patients with or without
diabetes vary from 8% to 60%.52,86,131-133,137,144,147,151,152,154,162-165 These variations
might also be explained by differences in patient selection, definitions, included
patients/procedures, and length of follow-up.
Factors related to healing
There is limited information from larger studies regarding factors related to
outcome of minor amputation, in patients with diabetes specifically (Table 4).
Peripheral vascular disease144,157,166,167, end-stage renal disease134, transmetatarsal
amputation134, unsuccessful revascularization153, depth of ulcer166, infection166,
renal insufficiency136 and male sex166, less than 100% attendance168, poor
glycaemic control168, hypertension168, insulin-dependent diabetes, and gangrene169
have all been suggested as leading to less healing and increased risk of major
amputation. Hosch et al found that presence of ischaemia and patient less likely to
34
have been prescribed shoes/insoles were risk factors for re-amputation to major
amputation.154 Palpable distal pulses, osteomyelitis, infection limited to the digit,
and higher toe pressure have been suggested as factors having a positive impact on
outcome after a minor amputation.152,155,157
35
Table 4.
Overview of studies on minor amputation and factors related to outcome
Author/year
Number
of
patients
Patient
selection
Outcome
Amputation level
Follow-up
Factors related to outcome
Age
Re-amputation rate
Comments
Sizer et al
1972135
557
Diabetes
94% healing rate
(patients with
emergency
surgery
excluded)
Minor only
1960-1971
Not reported
56.8
Not reported
specifically. Overall
limb salvage 95%.
Chart review of digital
amputations during a 12year period.
Boeckstyns et
al 1984144
63
Diabetes +
non diabetes
17/63 primary
wound healing
Minor only
(transmetatarsal +
transtarsal)
1976-1981
Ankle blood pressure <60
mmHg related to failure.
70 (41-91)
25/63 major reamputation within 1
year
Pinzur et al
1984151
25
Diabetes +
non diabetes
12 % healed in
DM patients.
Minor only (ray
resections)
2 years
Not reported
All patients >
50 years old
9/17 DM patients had
proximal reamputation
Turnbull et al
1988152
68
Diabetes
69% healed
Minor only
(partial foot
amputations)
5 years
Patients with palpable distal
pulses were more likely to
heal.
Mean 69 (range
32-87)
30%
Mortality 7%
Hosch et al
1997154
35
Diabetes
37% healed after
first surgery.
68.6 % healed at
transmetatarsal
level
Minor
(transmetatarsal)
15.1 ±10.1
months
Ischemia, patient less likely to
have been prescribed custom
shoes/insoles, and low
albumin level at admission
were factors related to higher
risk for re-amputation to
major amputation.
54.7 ± 8.3
63% revision and reamputation
28% required major
amputation
Yeager et al
1998153
162
Diabetes +
non diabetes
14% did not heal
forefoot
amputation.
Minor
25 months
Unsuccessful
revascularization predicted
non-healing and major
amputation
Mean age 65
(range 29-90)
Major amputation
rate 18.5% (23 pat
non healing + 7 pat
during follow-up)
Patients not expected to
heal were excluded from
the study.
Mortality at 4 years 51%.
Nehler et al
1999155
92
Diabetes
39% healed
primary
amputation.
25% did not
heal.
Minor (digit
amputations only)
21 months
Osteomyelitis and infection
limited to the digit were
factors associated with higher
probability for healing after
amputation.
53±14
Not reported
Retrospective review of
patient records.
Mortality 35% during
follow-up.
Thomas et al
2001141
41
Diabetes +
non diabetes
11/29 diabetic
patients healed
Minor only
(transmetatarsal
only)
1991-1998
Not reported
Mean age 71
(range 40-91)
15/41 required reamputation to BKA
(14) or Syme (1)
36
Van Damme
et al 200186
146
Diabetes
186 amp
Minor and major
1993-1998
Not reported
66 (mean age)
Neuropathic toe amp:
14% re-amputation
Neuropathic midfoot
amp: 9% reamputation
Neuro-ischaemic toe
amputation: 28% reamputation
Neuro-ischaemic
midfoot amp: 25%
re-amputation
Dalla Paola
et al 2003145
89
Diabetes
65/89 healed by
first intention.
The remaining
24 healed after
dressings.
Minor (first ray
amputations)
16±7
months
Not reported
66±9
17% ulcer recurrence
during follow-up.
8% re-amputation
(no major
amputation).
Sheahan et al
2005134
670
Diabetes +
non diabetes
(all had PVD)
Limb salvage
89.8% at 1 year
Minor only
47.3 months
ESRD, transmetatarsal
amputation (initial
amputation), and subsequent
revascularization were factors
related to limb loss.
Not reported
Not reported
Berceli et al
2006136
165
Diabetes +
non diabetes
208 forefoot
amputations.
Closed
amputation; 86%
healed
Staged
amputation; 91%
healed
Open
amputation; 70%
healed
Minor only
2 years
Renal insufficiency
Not reported
25%
Uzzaman et
al 2011195
126
Diabetes +
non diabetes
Not reported
Minor only
Not reported
Not reported
75±12.9 (DM)
80.5±14.8 (non
DM)
Not reported
Retrospective
5 year mortality 27%
van Battum et
al 2011166
194
Diabetes
18% of
EURODIALE
cohort
underwent minor
amputation.
75% healing rate
in minor
amputations.
Minor
1 year
Depth of ulcer, PVD,
infection, and male sex
predicted minor amputation.
65.2±11.6
Not reported
Analysis of subgroup in the
EURODIALE cohort. The
rate of minor amputations
differed between centres
(2.4-34%). One
explanation is the
difference in disease
severity at presentation.
Mortality 16% at 1 year.
37
Author/year
Number
of
patients
Patient
selection
Outcome
Amputation level
Follow-up
Factors related to outcome
Age
Re-amputation rate
Comments
Kono et al
2012169
116
Diabetes +
non diabetes
Not reported
Minor only
3 years
Insulin dependent diabetes
and gangrene were risk factors
for re-amputation
66.8±11
57/116
Retrospective (single
hospital, veterans)
5 year mortality 46%
Borkosky et
al 2013156
59
Diabetes
100%
Minor only
33.8 months
Not reported
63 (39-97)
42.4% new
amputations on same
site during study
period
Retrospective chart
evaluation. Mortality
47.5% at final chart
review.
Caruana et al
2015157
50
Diabetes
28/50 healed/is
healing (at 6
weeks followup)
Minor only
6 weeks
Toe pressure was higher in
patients healed/healing
67.4 (mean
age)
Not reported
Focus of study is on
whether ankle brachial
pressure index or toe
pressure or ankle
waveforms are better to
predict healing after minor
amputation.
Matsuzaki et
al 2015194
66
Diabetes (all
patients have
nephropathy,
PTA and
amputation)
Main outcome
mortality,
healing rate not
reported
56 minor
10 major
Not reported
Not reported
68±11
Not reported
2 year mortality 41%
(minor amp) 60% (major
amp)
Wiessman et
al 2015196
565
Diabetes
Not reported
All amputation
levels (minor and
major, both above
and below knee)
35 months
Not reported
68±12
Not reported
Primary study focus was
one-year mortality.
1-year mortality 35.8% (all
patients regardless of
amputation level)
Beaney et al
2016168
165
Diabetes
33/165 (20%)
underwent 34
amputations (17
major, 17 minor)
Minor and major
Minimum 1
year
Factors related to amputation:
less than 100% attendance,
poor glycemic control,
hypertension.
Previous vascular surgery and
low comorbidity associated
with lower amputation risk
<50 y: 28
50-54 y: 14
55-64 y: 29
65-74 y: 46
≥75 y: 49
Not reported
Retrospective
Case analysis of patients
referred to diabetic foot
clinic
Chu et al
2016158
245
Diabetes
82.4% healed
Minor
5 years
Not reported
69±9
17.5% (1 year)
22.3% (3 year)
47.1% (5 year)
Study aim was to evaluate
re-ulceration, reamputation and mortality.
Mortality;
5.8% (1 year)
15.1% (3 year)
32.7% (5 year)
Risk factors for reamputation; male
gender, age >70
years, HbA1c >9%.
38
Re-ulceration 76.4% in 5
years. Risk factors;
ischemia, great toe
amputation, HbA1c >9%.
Malyar et al
2016193
40335
DFS 17.3%
PAD + DM
21.5%
PAD 61.2%
Not reported
Minor and major
Maximum 4
years
Not reported
70±12 DFS
72±10
PAD+DM
71±12 PAD
Major re-amputation:
7% (DFS), 12%
(PAD+DM), 9.5%
(PAD).
Minor re-amputation:
19% (DFS), 12%
(PAD+DM), 12%
(PAD).
Study based on German
register of health
insurance.
4 year mortality: 30%
(DFS)
39% (PAD+DM)
52% (PAD)
Mandolfino et
al 2016165
218
Diabetes +
non diabetes
64% healed
Transmetatarsal
2008-2013
Not reported
Mean 67 years
33% re-amputation
1 year mortality 8%
Aim of study was to define
role and timing of vascular
surgery
Wilbek et al
2016197
777
Diabetes
Not reported
1231 minor
amputations
1996-2013
Not reported
56 (27-83) DM
type 1 men
52 (23-93) DM
type 1 women
66 (35-91) DM
type 2 men
71 (35-97) DM
type 2 women
Not reported
Retrospective
5 year mortality:
Type 1 DM 43%,
Type 2 DM 52%
39
40
Aims of the studies
The overall aim of this thesis was to study certain aspects of the diabetic foot in a
large cohort of consecutively presenting patients, and to identify factors related to
outcome and risk of amputation.
Specific aims
Paper I
To analyse the characteristics and outcome of minor amputations in
patients with diabetes and severe foot ulcers threatening the
survival of the foot
Paper II
To analyse the characteristics and outcome of patients with diabetes
and a plantar forefoot ulcer
Paper III
To analyse the characteristics and outcome of patients with diabetes
and a heel ulcer
Paper IV
To evaluate the outcome in a two-year follow-up study of patients
with diabetes and a healed plantar forefoot ulcer with regard to
development, characteristics, and outcome of recurrent and other
new foot ulcers
41
Patients
Paper I
Paper I is a cohort study of consecutively presenting patients with diabetes,
residing in the Lund/Orup area, who had a minor amputation between January 1,
1982 and December 31, 2006. During this time 309 patients underwent 410
primary minor amputations on 361 extremities (Figure 2). The median age was 73
(32–93) years and 64% of the patients were male. For a detailed description of
clinical characteristics, see Paper I.
Paper II
Paper II is a cohort study of 3,684 consecutively presenting patients with diabetes
and a plantar forefoot ulcer. Patients were included from January 1, 1983 to
December 31, 2012. Inclusion criteria were diabetes and a plantar forefoot ulcer
located in the distal metatarsal area or under the great toe. Patients with multiple
ulcers were not included. During this time period 701 patients (median age 67
[range 22–95]) with a plantar forefoot ulcer were included (Figure 2). For a
detailed description of clinical characteristics, see Paper II.
Paper III
Paper III is a cohort study of 4,273 consecutively presenting patients with diabetes
and a heel ulcer. Patients were included from January 1, 1983 to December 31,
2013. Inclusion criteria were diabetes and a heel ulcer. Patients with multiple
ulcers were not included. During this time period 768 patients (median age 73
[range 17–98]) with a heel ulcer were included (Figure 2). For a detailed
description of clinical characteristics, see Paper III.
42
Paper IV
Of the 701 patients with a plantar forefoot ulcer in Paper II, 385 healed primarily,
173 healed after major debridement, 42 healed after minor amputation, and 18
healed after major amputation. One patient who healed after a major amputation
had had a previous contralateral major amputation and was excluded from the
study. Thus a total of 617 patients were available for analysis (Figure 2). Each
patient is represented by the first recurrent ulcer or, if no recurrent ulcer occurred,
by the first other new ulcer.
The outcome within two years following a healed plantar forefoot ulcer was
investigated with regard to the presence or absence of a new ulcer as well as
mortality and outcome of new ulcers. For a detailed description of clinical
characteristics, see Paper IV.
The consort diagram for the studies is shown in Figure 2.
43
Diabetic foot ulcer
n = patients
Plantar forefoot ulcer
n=770
2
1
3
Other ulcer
location
(not included)
Heel ulcer
n=837
Ongoing
treatment
at final follow up
n=30
Ongoing
treatment
at final follow-up
n=3
Drop out
n=39
Drop out
n=66
Available for analysis
n=701
Paper II
Available for
analysis
n=768
Paper III
Amputations performed in
Deceased
unhealed
n=83
patients with diabetes
n = amputations
Primary healing
Healing after major
debridement
Minor amputation
Major amputation
n=385
Major
n=385
n=173
n=42
n=18
Previous
contralateral
major
amputation n=1
4,5
Minor
n=410
Paper I
1
Database of diabetic foot ulcers
2
Time period 1983-2012
3
Available for
analysis
n=617
Paper IV
Figure 2. Consort diagram
44
Time period 1983-2013
4
Time period 1982-2006
5
Database of amputations
Method
Setting
The multidisciplinary diabetic foot care centre where these studies are performed
is located at a university hospital with a primary care catchment area of
approximately 700,000 people at the end of the studies. The centre is the single
provider of specialized diabetic foot care in this area, from the year 2000 operating
in two geographic locations, and is also a tertiary referral centre for surrounding
regions. The management protocol at the diabetic foot clinic is based on a
multidisciplinary approach and has been previously described.25,61,131,170,171 Briefly,
it consists of inpatient and outpatient visits, regular podiatric care, individually
adjusted footwear, regular ulcer dressings and access to specialists in vascular
surgery, orthopaedics, and infectious diseases when needed.
When presenting with a foot ulcer the patients are seen by the multidisciplinary
foot care team, consisting of a diabetologist, an orthopaedic surgeon, a diabetes
specialist nurse, an orthotist and a chiropodist. The team works in close
cooperation with vascular surgeons, and also has access to specialists in infectious
diseases. Patients were included consecutively. At inclusion all patients were
questioned for medical history and examined, and the findings recorded according
to a pre-set protocol.25,172 The lesions were classified according to Wagner.33 The
patients are followed by the team until final outcome (healing with or without
amputation or deceased unhealed). General, extremity and ulcer related
characteristics were recorded. Systolic toe and ankle blood pressure measurements
were obtained using strain gauge and Doppler techniques as previously
described.172
Treatment
The basic management at the diabetic foot clinic is in accordance with a
multidisciplinary approach, as described above and in Table 1. Treatment was
performed in close cooperation with primary care and home care.
45
Non-surgical treatment
Individually adjusted off-loading equipment (total contact cast, individually fitted
shoes and/or insoles, orthosis, and/or half shoes) was offered to all patients. Type,
duration, and utilization of off-loading were not recorded.
Infection, metabolic control, peripheral vascular disease, oedema, and comorbidity were managed in close cooperation with the specialists
concerned.1,25,131,170,171 When clinical signs of infection were present, oral
antibiotics were given. Patients with deep abscess or osteomyelitis were
hospitalized and intravenous antibiotics were administered.39 Analgesia was used
related to cause and intensity of pain. Hospitalization was used in case of need for
acute surgical treatment, parenteral antibiotics, or when there was a deterioration
of infection despite non-operative treatment. The treatment chosen in each case
was based on written guidelines at our institution (in cooperation with the
department of infectious diseases) including antibiotic treatment, and changed
when decided necessary by the responsible physician.39
Topical treatment was prescribed by the multidisciplinary foot care team
according to the individual wound bed condition. Dressing changes were
supervised by a registered nurse in primary health care and/or home nursing
services. Telephone support during daytime was provided by the team.
Surgical treatment
Minor debridement was performed as required at the outpatient clinic by a
chiropodist without anaesthesia. Major debridement and amputation were
performed at the discretion of, and by, an orthopaedic surgeon. No Achilles tendon
tenotomy or any kind of osteotomy was performed. A non-healing ulcer was not
per se considered an indication for amputation.171 Vascular surgery (including
endovascular and open methods) was performed at the discretion of, and by, a
vascular surgeon. Resection of less than the distal phalanx was not considered as
an amputation.
Statistical analysis
Values are given as numbers or median (range) unless otherwise stated. Statistical
analysis (chi2) was performed for those who healed primarily versus those who
healed after major debridement or amputation. A stepwise multiple logistic
regression model with backward selection, including variables with p<0.1, was
performed to determine factors related to outcome. Statistical analysis in Paper I
was performed using NCSS 2004 (NCSS statistical software, Kaysville, Utah,
46
USA). All statistical analysis in Papers II–IV was performed using IBM SPSS
Statistics 21 (SPSS, Chicago, Ill, USA).
47
48
Results
Paper I
In 309 patients undergoing 410 primary minor amputations, the median age at
inclusion was 73 (range 32–93) years and 64% of the patients were male. With
regard to patient-related data, results are given relating to the first amputation in
each patient (n=309) after entering the study. With regard to amputation-related
data, results are given relating to all primary amputations (n=410) in this study.
Sixty-four percent of the minor amputations (261/410) healed at a level below the
ankle, and 80% (329/410) healed at the primary or at a more proximal level. In
surviving patients the healing rate below the ankle was 79% (261/330). The total
number of major amputations before healing or death was 84 (20%).
Patients younger than the median age of 73 years displayed a higher healing rate
below the ankle (78%) compared to patients at or above the median age (50%), p <
0.001. Healing rate was related to the severity of tissue involvement at inclusion.
A higher healing rate below the ankle (75%) was seen in amputations with an
ulcer classified as Wagner grade 0-3 as compared to those with Wagner grades 4–
5 (54%; p < 0.001).
In 81% of minor amputations there was presence of SVPD and/or general vascular
disease. If SPVD was present there was a lower healing rate below the ankle
(56%) than if SPVD was not present (75%), p < 0.001. Minor amputations in
patients who had vascular surgery had a lower healing rate below the ankle
compared to amputations in those who had not (51% and 70%, respectively) p <
0.001.
Of primary minor amputations, 150/410 (37%) subsequently required one or more
than one re-amputation, either at the same or at a more proximal level. One third
of these (49/150) healed at a level below the ankle. Seventy-nine percent
(118/150) healed after re-amputation irrespective of level.
Median healing time from primary amputation to wound healing was 26 (range 2–
250) weeks for those amputations that healed below the ankle, and 15 (range 4–
190) weeks for those amputations that healed above the ankle. The longest healing
time (median 42 weeks) was seen for partial forefoot amputations not including
49
the first ray. Toe amputations had the shortest healing time in this study, 18 (range
2–200) weeks.
In a multivariate analysis including the first minor amputation in each patient
(n=309) vascular intervention (before and after amputation) and the presence of
intractable pain (as one indication for amputation) were found to be associated
with a lower healing rate below the ankle. A low Wagner grade and a low age at
amputation were found to be associated with a higher healing rate below the ankle.
In a multivariate analysis including all minor amputations in all patients (n=410),
the presence of CLI or SPVD, and vascular intervention (before or after
amputation) were found to be associated with a lower healing rate below the ankle.
A low Wagner grade was found to be associated with a higher healing rate below
the ankle.
In summary, despite long healing time, it is possible for minor amputations to heal
in a large proportion of patients with diabetes, although patients are elderly, with
extensive co-morbidity and with severe foot ulcers including infection and/or
gangrene in many cases.
Paper II
In 701 patients with a plantar forefoot ulcer, the median age at inclusion was 67
(range 22–95) years, the median duration of diabetes at inclusion was 13 (range 0–
62) years, and 66% of the patients were male. SPVD was present in 26% of
patients.
Seventy-nine per cent (558/701) of patients achieved healing; of these 385 healed
without and 173 healed after major debridement. Nine per cent healed after an
amputation either below or above the ankle, and 12% died unhealed. Progress of
Wagner grade was seen in 20% of patients.
Median healing time from inclusion was 17 (range 1–252) weeks.
In multivariate analysis Wagner grades 1 or 2 at inclusion (p<0.0001), no progress
in Wagner grade (p<0.0001), independent living (p=0.02), and age at inclusion
≥67 years (p=0.02) were factors found to be related to healing without major
debridement or amputation.
In summary, most of surviving patients with a plantar forefoot ulcer heal without
an amputation within an average 4 months but frequently after a major
debridement. One out of four of these patients have signs of SVPD, although in
the literature this is often described as purely neuropathic.
50
Paper III
In 768 patients with a heel ulcer, the median age at inclusion was 73 (range 17–98)
years, the median duration of diabetes at inclusion was 17 (range 0–72) years and
56% of the patients were male. SPVD was present in 31% of patients.
Sixty-six per cent of patients (504/768) achieved healing without (n=447) or with
(n=57) major debridement, nine per cent (72/768) healed after an amputation, and
25% (192/768) died unhealed. Primary healing in surviving patients was 78%
(447/576). Median healing time from inclusion was 17 (range 1–416) weeks.
In a multivariate analysis vascular surgery (p<0.0001), nephropathy (p=0.007),
and oedema (p=0.007) were factors related to a lower probability of healing
without major debridement or amputation, and a creatinine level below 91 µmol/L
(p=0.03) was found to be related to a higher probability of healing without major
debridement or amputation.
In summary, despite long healing time, two-thirds of patients with diabetes and a
heel ulcer healed without amputation treated in a multidisciplinary setting.
Paper IV
Out of 617 patients in paper II who had healed a plantar forefoot ulcer, 250 (41%)
did not develop any new ulcer, 262 (42%) developed a new ulcer, 87 (14%) died
and 18 (3%) were lost to follow-up. Fifty-one patients (8%) developed a recurrent
ulcer. The remaining 211 patients developed ulcers only at other sites than the
previously healed ulcer (112 on the same foot and 99 on the contralateral foot). Of
the 87 patients who died within two years, 57 had not developed any new ulcer, no
one had a recurrent ulcer, and 30 patients had developed other new ulcers.
In those 262 patients who developed a new ulcer within 24 months, primary
healing was achieved in 137 (52%) and the ulcer healed after major debridement
in 51 patients (19%). Healing was achieved after minor amputation in 10 patients
(4%), and after major amputation in 12 patients (5%). Thirteen patients (5%) died
with the ulcer still unhealed, 24 patients (9%) had ongoing treatment at last
follow-up and 15 (6%) were lost to follow-up.
Ninety-two patients developed more than one new ulcer during the two-year
follow-up. The total number of recurrent or other new ulcers was 384.
There were no differences between men and women, or between patients with or
without SPVD, regarding development of new ulcers. Major debridement or
51
amputation prior to healing of index ulcer did not affect the risk of developing new
ulcers, nor did the location of the index ulcer.
In summary, patients with diabetes who have healed a plantar forefoot ulcer have a
high risk of developing new ulcers irrespective of site and side. Few patients
developed a recurrent ulcer on the same side and site. A concise definition of new
ulcers is suggested, since there seems to be general confusion regarding definitions
in the literature.
52
Discussion
Diabetes mellitus is increasing worldwide and is one of the most challenging
healthcare dilemmas of the 21st century. Diabetes is associated with both microand macrovascular complications. These complications all contribute to an
increased risk of foot ulcer and amputation. The St Vincent Declaration (1989) set
a goal of a 50% reduction in amputations in patients with diabetes.173 A
multidisciplinary team approach has been shown to be important to lower the
incidence of major amputation in diabetic patients.1,127,128,130,174-181 In 2005, The
Lancet had on its front cover “Every 30 seconds a lower limb is lost somewhere in
the world as a consequence of diabetes”.2 Dr Andrew Boulton concluded that
through research we have the power to help thousands of people with diabetic
complications.2 The reduced rates of major amputations nationwide in diabetics in
England, despite a rising prevalence of diabetes, suggest improvements in the
process of diabetes care delivery.55 The overall aim of this thesis was to study
certain aspects of the diabetic foot in a large cohort of consecutively presenting
patients, and to identify factors related to outcome and risk of amputation.
Minor amputation
In patients with diabetes, the immediate objective of a minor amputation is often
to control infection and halt the progression of gangrene, thereby minimizing the
risk of major amputation and thus optimizing ambulatory function. Paper I is, to
my knowledge, the first large population-based study of consecutively presenting
patients with diabetes undergoing minor amputation. All patients are consecutively
included and almost all followed to healing or death. Although the vast majority of
patients had severe lesions that threatened the survival of the foot, two thirds of
patients healed at a level below the ankle and thus had a retained limb for
ambulation, but at the price of long healing times. During part of the same study
period the number of major amputations in the same defined area decreased.127
This strongly indicates that minor amputations in diabetic patients with infections
and/or gangrene, treated in a multidisciplinary setting, are worthwhile. The fact
that over 400 amputations were included, and all but four followed until healing or
death, further strengthens the value of this study.
53
Most studies/reports regarding the incidence of lower limb amputations are
focused on major amputations. These studies tend to underestimate the total
number of diabetes-related amputations performed. There is still some controversy
concerning the benefit of a primary minor amputation versus primary major
amputation (below knee).42,75 The objective of a minor amputation is often to
control infection and halt the progression of gangrene, thereby minimizing the risk
of major amputation and thus optimizing ambulatory function. Minor amputations
are associated with higher re-amputation rate and as a consequence longer wound
healing time. The advantage of primary major amputation is a lower re-amputation
rate and shorter healing time. However, the energy expenditure of walking with a
prosthesis, necessary for ambulation after a major amputation, is greater than that
of walking with an intact limb.150 Since many patients are older and have extensive
co-morbidity, retaining a limb for support is therefore important.
There is limited information in the literature describing indications for minor
amputation. No randomized controlled studies on amputation versus nonamputation exist. The indications for amputation in patients with diabetes suggest
the indications are often multifactorial, of which progressive gangrene and
infection are most common, frequently in combination.1,126 Most studies regarding
particularly minor amputation either do not mention indication or use the term at
the discretion of the surgeon. In Paper I, multiple indications (more than one) for
amputation were present in 52%. In the presence of pain and/or progressive
gangrene there was a significantly lower healing rate below the ankle than if pain
and/or progressive gangrene were not present. In contrast, if deep infection was
present as one indication for amputation, more amputations healed below the ankle
than if no deep infection was present. However, even in the presence of pain or
progressive gangrene as one indication, healing below the ankle was seen in
almost half of amputations. Thus, no indication excludes the possibility of healing
below the ankle.
Table 4 above shows an overview of studies on minor amputations, including
factors related to outcome and re-amputation rate. Many studies have a mixture of
diabetic and non-diabetic patients, or a selection of specific amputations. There are
various difficulties in comparing the results of Paper I with those of the literature,
due to variations in definitions regarding patient selection, ulcer classification,
indications, minor amputation, re-amputation, and healing. Sometimes there is
even a lack of definitions.132-134,141-143,182,183
In paper I, the healing rate below the ankle was 79% in surviving patients.
Reported healing rates at minor amputation levels, in studies with diabetes patients
and mixed cohorts of diabetes and non-diabetes patients, range from 12% to
100%.52,86,136,141,144,145,151-158 These variations might be explained by differences in
54
patient selection, definitions, included patients/procedures, and length of followup.
In paper I, SVPD and/or general vascular disease was present in 81%. If SPVD
was present there was a lower healing rate below the ankle than if SPVD was not
present. Despite various limitations SVPD seems to be a risk factor that needs to
be evaluated, and if possible, treated in patients with minor amputations pending
or recently performed, although no consensus exists as to which measure of PVD
best can predict outcomes.60
In paper I, more than one in three patients subsequently required one or more than
one re-amputation, either at the same or at a more proximal level and 21% of the
amputations had a re-amputation to a level above the ankle. The latter patients
constitute the group where the primary treatment strategy failed. The rate of reamputation when reported for various minor amputations, in patients with and
without diabetes, varies between 8% and 63%.86,132,136-138,141,142,145,151-154,162,164,184,185
Comparison of re-amputation rates suffers from the same biases mentioned above.
The aim for the future is to achieve even better identification of patients who will
most likely heal below the ankle and those where a primary major amputation
should be performed instead.
The long healing times and costs attributed to minor amputations has been
mentioned as a reason to perform a major amputation instead. In paper I, the
median healing time in patients undergoing primary amputation to wound healing
varied between 18 and 42 weeks depending on primary minor amputation level.
With regard to the long healing time in patients who underwent amputation, two
circumstances should be pointed out. First, these do not reflect the time from
amputation to healing, but from the time of arrival at the foot clinic to healing.
Second, in most minor amputations the operation wound had to be left open for
secondary healing. Assessing healing time, and comparing results in this regard,
presents great difficulties. There is often a delay from onset of ulcer until it is seen
by a healthcare practitioner, and then there is a further delay until the patient
arrives at a specialized clinic. We count the healing time from the day the patient
is seen at our clinic until the day the ulcer is healed. The time from surgical
treatment (major debridement or amputation) to healing is not presented.
In 2016 Pickwell and colleagues159 published a report on the EURODIALE cohort
regarding minor amputation and quality of life. This report showed that minor
amputation did not reduce the quality of life in patients with diabetic foot ulcer.
This further underlines the importance of using minor amputation whenever
possible to avoid a major amputation. Furthermore, the functional outcome of a
major amputation is worse and the cost of a major amputee by far exceeds the cost
of a minor amputation.2,72
55
In summary, the findings of paper I support the use of minor amputation in
patients with diabetes and severe foot ulcers. The price to pay may be long healing
times and the risk of repeated surgical interventions.
Plantar forefoot ulcer
In Paper II, studying consecutively presenting patients with diabetes and a plantar
forefoot ulcer during a 30-year period, 80% healed without an amputation, 6%
healed after minor amputation, 3% healed after major amputation, and 12% died
unhealed. In mixed cohort studies regarding short-term outcome, primary healing
rates of 64–85%, amputation rates of 8–23% (irrespective of level) and mortality
rates of 10–20% have been described from centres of excellence. In randomized
controlled trials of neuropathic diabetic foot ulcers (mostly plantar) healing rates
over 12–20 weeks of 36–60% have been reported.29,52,56,70,71,86-88
In all papers in this thesis, the definition of healing was set at the start of the
inclusion in 1983. The time of healing of the index ulcer was defined as the date
when the wound was considered healed with macroscopically complete
epithelialization, and healing had to be confirmed at a 6-month check-up. If the
ulcer was still present at that time, the original assessment of healing was revised.
Many studies in the literature do not have a definition of healing, and in those
which do report a definition of healing, it is often reported as a single
observation51,53,64,91,93,186,188 which makes comparisons uncertain.
Median healing time from inclusion in Paper II was 17 (range 1–252) weeks. The
shortest healing time was seen in patients with healing without major debridement
or amputation (median 13 weeks) and the longest for patients who healed after
amputation (median 36 weeks). There are not many studies on healing time and
since healing is not always defined, comparing results is not easy. Reported
healing times range from 6 to 12 weeks56,57,70,71 indicating other selection of
patients than in Paper II. Most data in the literature are from trials with less than
20 weeks follow-up, which means that many ulcers are not given enough time to
heal.
When assessing healing time it is important to know from when the time is
counted. Is the starting point when the patient says the ulcer first appeared, is it
from the first visit to the diabetic foot centre or is it the time from surgical
intervention? Assessing healing time, and comparing results in this regard,
presents great difficulties. There is often a delay from onset of ulcer until it is seen
by a health care practitioner, and then there is a further delay until the patient
arrives at a specialized clinic. In the studies of this thesis, healing time is counted
56
from the day the patient is seen at the centre until the day the ulcer is healed. The
time from surgical treatment (major debridement or amputation) to healing is not
presented.
Wagner grade and age at inclusion, and independent living were factors found to
be related to healing without amputation in Paper II. Comparing these results with
those in the literature is not easy since there is a lack of studies focusing solely on
plantar forefoot ulcers. In the EURODIALE study, which has a mixed cohort of
ulcer location, older age, male sex, larger ulcer size, heart failure, inability to stand
or walk without help, ESRD, neuropathy and PVD were factors predicting failure
to heal a diabetic foot ulcer.24 Patients exhibiting PVD had a worse healing rate,
more major amputations and higher mortality than patients without PVD.24,29 In
addition, if a patient with PVD also presented with infection of the ulcer, a worse
healing rate was seen.24,29 Margolis and colleagues found that initial ulcer area,
duration of ulcer and patient ethnicity were factors related to healing of
neuropathic foot ulcers.87 Renal impairment and smoking have also been reported
as predictors of failure to heal a diabetic foot ulcer.51 A recently published
retrospective review of patients with diabetic foot ulcer admitted through
emergency department showed that elevated CRP (C-reactive protein) at arrival
indicated a higher risk of major amputation.187
As regards factors related to outcome of diabetic foot ulcers, and plantar forefoot
ulcers specifically, there is a lack of uniformity in the literature. Some general
factors, for example the presence of neuropathy and PVD, are generally agreed to
influence outcome negatively. But when it comes to determining certain specific
factors for outcome, it seems difficult to come to a consensus. One explanation for
this could be the differences in patient selection between studies. It would seem as
if diabetic foot ulcers are a heterogeneous group, and it might be that there is no
single specific factor, or specific factors, responsible for determining outcome.
This is an interesting area of research to pursue for the future.
In the literature PVD is reported to be around 50% in patients with diabetic foot
ulcer.37 These studies are mostly on mixed cohorts. In the literature plantar
forefoot ulcers are frequently regarded as neuropathic and there are no studies
detailing the frequency of PVD in patients with plantar forefoot ulcer. Paper II
shows that a quarter of patients with plantar forefoot ulcer also have SPVD.
Although not related to outcome in multivariate analysis, it is important that
patients presenting with a plantar forefoot ulcer should be subject to evaluation of
lower limb circulation as a substantial portion of these patients also have SPVD.
57
Heel ulcer
An ulcer located in the heel in patients with diabetes is a serious complication. In a
larger cohort of foot ulcers, regardless of ulcer location, heel ulcers made up ten
per cent of all foot ulcers.37 To my knowledge Paper III with its 768 patients is to
date the largest study on heel ulcers in patients with diabetes, with a number of
patients included that is equal to all the other presented studies together, Table 3.
Most studies with regard to ulcers located in the heel in patients with diabetes thus
have small numbers or a selected category of patients.105-113
Reported healing rates of heel ulcers in patients with diabetes vary between 51%
and 95%, Table 3. In clinical practice heel ulcers are often referred to as difficult
and hopeless cases, in many cases ending up with a major amputation. The results
of Paper III, and of other reports in the literature, show a more favourable
outcome. A team approach to this group of patients, early referral to a centre with
expertise in caring for diabetic foot ulcers, and adequate pressure relief are key
elements in the treatment strategy at the centre, and might have played a role in the
favourable outcome. The price to pay is often a long healing time.
The patients in Paper III had a median age of 73 years. Many studies in the
literature combine both diabetic and non-diabetic patients. In studies reporting
only on diabetic patients the median age is often 10 years younger than in Paper
III.65,108,109,111,113,122 In Paper III, despite being elderly and having co-morbidities,
two thirds of patients with a heel ulcer still healed without an amputation. From
both patient and society perspective this can be considered a good outcome. The
subgroup of patients who had a pressure heel ulcer had a higher mortality than
patients with other precipitating factors. This could be due to these patients having
more co-morbidity. The findings in Paper III indicate that ulcers located in the
heel in patients with diabetes overall do not have a poor outcome. However,
pressure heel ulcers may be considered a separate entity with a potentially poorer
prognosis. It is important to identify different subgroups of patients with a
potentially poorer prognosis at an early stage, before there has been too much
tissue damage to facilitate healing.
The median healing time among patients in Paper III was 17 weeks. A longer
healing time was seen in patients who had an amputation or major debridement
than for those who healed primarily. In studies where healing time is reported the
healing time was 10–33 weeks.57,65,107,108111,113 Comparing healing times between
studies is not easy since there are no clear definitions and healing is not always
defined. In Paper III all patients are followed to final outcome, and unlike in many
other studies there is no set time limit to follow-up. Another important difference
from most other studies is that time to heal is registered from date of arrival at the
foot clinic, not from date of surgery.
58
In the literature there are some studies which look at factors related to outcome of
heel ulcers. Treiman and colleagues112 found, in 91 patients (both diabetic and
non-diabetic), that normal renal function, a palpable foot pulse, functioning
posterior tibial artery, and the number of functioning tibial arteries predicted
healing of heel ulcers. Bakheit and colleagues113 found, in 100 patients with
diabetes, that short duration of diabetes, adequate circulation, and a superficial
wound were factors associated with healing, while Chipchase and colleagues111, in
97 patients with diabetes, found that a larger ulcer and presence of peripheral
vascular disease predicted a worse outcome. In a report from the EURODIALE
study of diabetic foot ulcers co-morbidity, SVPD, infection and extent of tissue
involvement were factors associated with outcome.1,24
Multivariate analysis in Paper III showed that vascular surgery, nephropathy, and
oedema were factors related to poor outcome, whereas a creatinine level below 91
µmol/L was the only factor related to a higher probability for healing without
major debridement or amputation. Further studies on factors related to outcome
are needed. Reported factors in the literature vary widely, indicating different
selection of patients in different studies. It is possible that no single factor has the
power to influence outcome by itself. Rather, it is a combination of factors, both
patient and environmental, which contribute to outcome.
Risk of new foot ulcers and lack of definitions
In Paper IV the results show that 47% of patients with a healed plantar forefoot
ulcer develop one or more new foot ulcers within two years following healing.
This stresses the importance of an active follow-up and intense preventive
measures following healing of plantar forefoot ulcers in diabetic patients.
However, in only 8% of the patients did a new ulcer develop on the same foot and
at the same site as the previously healed ulcer, thus fulfilling the definition of
recurrent ulcer. This marked difference between recurrent ulcers and other new
ulcers highlights the importance of making a clear distinction between these two
groups. Of all new ulcers, 17% were recurrent ulcers.
There are few large cohort studies regarding the risk of new foot ulcers,
particularly in individuals with diabetes and plantar forefoot ulcers. In available
reports, new ulceration rates following healing of a foot ulcer of various
aetiologies in subjects with diabetes vary widely.50,51,80,81,91,94,95,98-100 The lowest
rate (8% at a mean follow-up time of 24 months) is reported by Batista et al98, in a
study on percutaneous Achilles tendon lengthening in 52 patients, and the highest
rate (34%, 61%, and 70% after 1, 3, and 5 years, respectively) is reported by
Apelqvist et al50 in a study of 558 patients with all types of diabetic foot ulcers.
59
These differences could be explained by differences in patient selection, types of
ulcers included, definitions used, as well as length of follow-up. Whether the low
rate of recurrent ulcer in Paper IV is a true low rate compared to other centres is
difficult to say, since there is no uniformity regarding definitions. To be able to
compare results there is a need for more uniform definitions and more specified
methodological descriptions.
In Paper IV, 8% of patients developed a new ulcer on the same side and site as the
previously healed ulcer. There are few studies which differentiate between new
ulcer locations. Only two other studies reporting outcome with regard to new ulcer
location100,188 have been found. Galea and colleagues100 report recurrence rates
similar to the results in Paper IV, albeit in a small study population (32 patients).
In a study by Piaggesi and colleagues188, who evaluate the outcome after
conservative surgery versus a non-surgical approach to plantar foot ulceration (in
41 patients), patients in the non-surgery group re-ulcerated at the same site, while
patients receiving surgery developed a new ulcer at another site. In Paper IV there
was no difference in development of new ulcers with regard to location of index
ulcer or whether the index ulcer healed primarily or after major debridement or
amputation. Identifying subgroups of ulcer sites is an important tool to improve
preventive strategies.
There is no consensus regarding the terminology of ulcers appearing after an
initial ulcer has healed. In the literature these ulcers are termed recurrent
ulcer51,91,94,98,99, reulceration94,99,100, new ulcer95, and transfer ulcer80,81. Often there
is no definition of ulcer recurrence at all.101-104 Since there is a lack of uniformity
in defining new ulcers, comparing results from the literature is not possible. A
concise definition is a prerequisite for meaningful comparisons of treatment
strategies and for identifying risk factors and preventing new foot ulcers. The
findings in Paper IV indicate the need for a more precise description and
terminology. As a first step, a new terminology is suggested, differentiating
recurrent foot ulcers (on the same foot and at the same site) from other new foot
ulcers (at any other site on the same foot, or at any site on the contralateral foot).
In Paper IV, the time of healing of the index ulcer was defined as the date when
the wound was considered healed with macroscopically complete epithelialization,
and healing had to be confirmed at a 6-month check-up. If the ulcer was still
present at that time, the original assessment of healing was revised. This strict
definition of healing could be one explanation for the low rate of recurrent ulcers.
Many studies in the literature do not have a definition of healing, and in those
which do report a definition of healing, it is often reported as a single
observation.51,53,64,91,93,186,188
In 2010, the European Wound Management Association Patient Outcome Group
published a report on recommendations for reporting on wound management. In
60
this report it is suggested that a healed wound be reconfirmed at two consecutive
visits two weeks apart.189 The FDA states in a document from 2006 that a followup evaluation of at least 3 months following complete wound closure is
recommended to help distinguish actual wound healing from transient wound
coverage.190
A wide variety of factors have been reported as related to ulcer recurrence
following healing of a foot ulcer. Most studies have mixed ulcer locations and in
some studies patients with PVD or previous foot ulcers have been excluded.
Mantey and colleagues91 were the first to report on factors related to the risk of
new ulcers, and in a study on 51 diabetic patients with foot ulcer they found poor
glycaemic control, neuropathy, delay in reporting symptoms and increased alcohol
intake to be related to the risk of new ulcers. Both Connor et al 92 and Dubsky et
al95 also found glycaemic control to be relevant in risk assessment for new ulcer
development, with Connor et al also reporting on alcohol as a contributing factor.
Neither of these studies specified the location of the index ulcer.
PVD, plantar location of index ulcer, insulin treatment, osteomyelitis, a low
maximal Wagner grade, and vascular surgery have also been reported as factors
related to development of new ulcers.51,94,95,191 Interestingly Faglia et al, in a study
on 115 patients, could not find any factor significantly determining the risk of new
ulcers.52
A study on plantar foot ulcers reported minor lesions, day-to-day variation in
stride count, and cumulative duration of previous foot ulcers as factors related to
ulcer recurrence.96 Another study on 35 patients with plantar foot ulcer, which
evaluated ulcer recurrence after metatarsal head resection, reported that resection
of less than 25% of the metatarsal led to a higher rate of ulcer recurrence.99
So far, it is not possible to point out any one specific factor, or specific factors,
which can predict the risk of future new foot ulcers. The rate of new ulcers is
relatively high and many factors have been reported to be related to the risk of new
ulcer development. Perhaps diabetic patients are such a heterogeneous group that
it is not possible to define a specific factor. Rather, it is important to be aware of
the risk of new ulcer development, to take preventative measures, and be vigilant
regarding foot inspection.
61
General and methodological considerations
Some methodological considerations need to be borne in mind when evaluating
the studies. Potential negative selection bias always has to be considered, since the
patients were admitted to a university-based foot centre. It cannot be excluded that
more superficial ulcers of neuropathic origin were treated in primary healthcare,
nursing homes, or home care without the knowledge of the centre. There was
general agreement at the hospital that irrespective of where patients were admitted,
they would be passed on to the foot centre.
Definition of healing varies between studies, and 6 months was considered
necessary to prove that patients remained healed. Definitions of outcome can be
very complex, an issue that has been previously analysed.56 Comparisons between
studies are difficult due to differences in design, setting, patient selection,
definitions, follow-up time, and other confounding factors. Healing was defined as
intact skin for 6 months or intact skin at time of death, whereas other studies
provided no definition or failed to report follow-up. The patients were followed
until healing or death, whereas most other studies report on healing within a
specified time, usually 6 to 12 months.87,88,192
In Paper IV 92 patients had more than one new ulcer and the total number of new
ulcers was 384. A pitfall in reporting on new ulcers in patients with diabetes is that
more than one new ulcer on either side might develop simultaneously or
subsequently. In the literature there are no unanimous reports on how to handle
this. When evaluating patient outcome it is important to differentiate between
number of patients and number of ulcers. Reporting clearly on this will render the
scientific discussion more complete and reduce the risk of misinterpretations. The
finding in Paper IV also highlights that not only the number of patients suffering
new ulcers needs be taken into account, but also the number of ulcer episodes.
Patients in these studies were divided into groups according to outcome: primary
healing, minor amputation, major amputation, and patients deceased unhealed. In
some studies minor amputations are included in primary healed and also the
definition of amputation varies. Comparisons between centres are difficult, due to
the heterogeneity of patients and complexity of the disease. In many health care
systems there are limited possibilities for following up patients until healing is
achieved. The Swedish health care system, due to its geographical responsibilities
and reimbursement system, enables patients to be followed up until a specific
endpoint, irrespective of who the caregiver is.
A large amount of missing data on retinopathy was mainly due to patients being
unable to attend fundoscopy. Duration of diabetes is in most cases an uncertain
variable, since the disease may have gone unrecognized for a shorter or longer
62
time, maybe for years. This is particularly true for type 2 diabetes. The duration of
diabetes is based on the year the diagnosis was set until the year the patient was
seen at the foot care centre. Duration of diabetes unknown refers to the fact that
the diagnosis of diabetes was previously known but that time of diagnosis could
not be established and verified through medical records. Duration of ulcer when
presenting at the foot centre is the most uncertain variable, due to a combination of
patients’ unawareness of the need to seek healthcare and healthcare providers’
choice of treatment and willingness to refer patients. It is uncertain how the ulcer
was treated before referral to the foot centre, due to lack of proper documentation
from the primary care or home nursing services. The clinical characteristics and
variables included in the study such HbA1c and serum creatinine levels, were
registered at baseline without further follow-up during the study period.
Ulcers in this study were classified according to Wagner. This classification has a
weakness; it does not describe ulcer area or extent of infection. Unfortunately, it is
not possible to reclassify the ulcers to more recent systems retrospectively as the
older records lack information on, for example, ulcer size and classification of
infection.
Strengths and limitations
The strength of the studies in this thesis is the size of the consecutively included
and followed patient cohort, followed by a protocol and specific pre-set criteria
and definitions, as well as the length of follow-up. There is no set time limit to
follow-up and patients are followed to healing or death. Since the
multidisciplinary foot care team is the single provider of specialized diabetic foot
care in the region there is little risk of selection bias. All diabetic patients with foot
ulcers needing specialist care are referred to the centre.
The studies have a long inclusion time, from 1983. During that time, new
treatments in foot ulcer care were introduced, including local treatments,
antibiotics, anticoagulants, radiological examinations, endovascular techniques,
surgery, off-loading, and drug treatment. This database spans over three decades.
There has undoubtedly been progress in both medical and surgical care during this
time. However, the long-time follow-up which this database provides gives us
important insights into the course of these ulcers. In the studies of this thesis, no
attempt to analyse these changes over time has been made.
In Papers II–IV each patient is represented by one ulcer per patient. This ulcer is
the first or worst ulcer appearing during the study period. If a patient presented
with more than one ulcer at the same time, the worst ulcer was included. In Paper
63
III patients with an ulcer located in the heel were included. Patients classified as
having multiple ulcers were not included. Among the patients admitted to the
centre 671 were classified as having multiple ulcers. In this group of patients there
could be a number of heel ulcers as well. Discerning which of these patients had a
heel ulcer as well is not possible. Analysis of patients with multiple ulcers
admitted to the centre showed that these patients had a higher mortality rate (33%)
and a lower primary healing rate (21%) than patients with ulcers located in the
heel. One possible reason for this is that patients with multiple ulcers can have
more severe disease and co-morbidity.25
In patients with multiple ulcers on the same foot it was not possible to verify
which of the ulcers determined outcome. This issue illustrates the challenge to
differentiate factors related to outcome whether they are related to the individual,
the extremity, the foot or the ulcer(s).
A systematic review by Bus and colleagues79 showed that therapeutic footwear
worn by the patient can prevent ulcer recurrence. Adherence to prescribed
footwear is unfortunately not part of the protocol in the studies of this thesis. All
patients at the multidisciplinary diabetic foot care centre are prescribed therapeutic
footwear for indoor and outdoor use as well as a recommendation for regular
chiropody.
Plantar forefoot ulcers are classified as located in the plantar surface of the foot.
Classification of ulcers with a medial part on the first metatarsophalangeal joint or
a lateral part on the fifth metatarsophalangeal joint is at the discretion of the
physician.
The difficulty in reporting on patients and ulcers is that each patient may have one
or more simultaneous ulcers, and/or one or more subsequent ulcers. Each patient
also has two legs, thus further complicating the situation.
In Paper I amputations are presented both as one amputation per patient (the first
amputation during the study period) and as all amputations. It is clearly stated
what is presented to minimize the risk of misunderstanding. Failure to clearly
report how the data has been analysed may contribute to misunderstanding and
wrongful comparisons.
The findings from these studies indicate the heterogeneity and complexity with
regard to aetiology, treatment, and outcome among individuals with diabetes.
Future studies with regard to treatment and/or preventive strategies and “high-risk
feet” might need to be more focused on specific lesions considering aetiology and
locations such as ulcers located in the heel, ulcers related to disturbed
biomechanics, or neuro-ischaemic/ischaemic ulcers.
64
Future perspectives
Ideally a patient with a diabetic foot ulcer should never progress as far as to need
to see an orthopaedic surgeon. In the perfect setting diabetic foot ulcers would be
preventable, and if an ulcer appears, it can be healed without surgical intervention.
But if an ulcer appears which cannot be healed primarily, then I want the
orthopaedic surgeon to be aware of the fact that a major amputation is usually not
necessary and that these ulcers can heal with a minimal amount of surgery and a
large amount of time and patience.
My dream when I started this research project was to develop a clinical guideline
for diabetic foot ulcer patients and when and where it is best to perform major
debridement or minor amputation, and when it is best to perform major
amputation. Along the way I have realized that this is probably not possible, these
patients are complex and multifactorial, and every patient is unique.
An evaluation of the effects of vascular surgery over time, and the effect of the
shift towards endovascular procedures, is something which would be interesting to
study.
Studying the difference in quality of life in patients with diabetes only, diabetes
and an ulcer, and diabetes and an amputation (both minor and major) is interesting
and something to plan for future studies.
A study on amputation level selection would be interesting, albeit difficult to
design.
65
66
Conclusions
Despite long healing time, it is possible for minor amputations to heal in a large
proportion of patients with diabetes, although patients are elderly, with extensive
co-morbidity and with severe foot ulcers including infection and/or gangrene in
many cases. This indicates that healing is possible even in these difficult
circumstances and warrants a liberal approach to minor amputation to avoid a
major amputation. However, when applying this approach, it must be borne in
mind that a protracted healing process, particularly if jeopardizing mobilization,
might not always be in the patient’s best interest. For the orthopaedic surgeon, this
clinical situation represents a delicate balance between recommending a major
amputation too early or too late.
Four out of five patients with diabetes and a plantar forefoot ulcer heal without the
need for an amputation. SPVD was present in one out of four patients with plantar
forefoot ulcer, indicating the importance of vascular assessment in these patients.
Two-thirds of patients with diabetes and a heel ulcer healed without amputation.
In patients with diabetes and a plantar forefoot ulcer almost half of all patients
develop a new foot ulcer within two years, although the risk of recurrent ulcers (on
the same foot and at the same site as the index ulcer) is small. It is important that
both patients and health care professionals recognize the high risk of future foot
ulceration.
There is a lack of uniform terminology regarding new foot ulcer development. A
concise definition of new foot ulcers is suggested, since there seems to be general
confusion regarding definitions in the literature. This may facilitate comparison
and enhance scientific discussions.
67
68
Svensk sammanfattning
Diabetes är en växande folksjukdom och 2015 beräknades 415 miljoner människor
ha diabetes. Denna siffra förväntas stiga till 642 miljoner fram till år 2040.
Komplikationer till följd av diabetes är till exempel neuropati (försämrad
nervfunktion i framför allt nedre extremiteter), kärlsjukdom (bland annat
hjärtsjukdom och försämrad blodcirkulation till nedre extremiteter), retinopati
(ögonsjukdom) och nefropati (njursjukdom). Till följd av nedsatt känsel och
försämrad blodcirkulation till fötterna finns det risk att patienter med diabetes
utvecklar fotsår. Uppkomsten av fotsår hos diabetiker är en allvarlig komplikation
som är förenad med risk för amputation och död.
Syftet med denna avhandling är att undersöka förutsättningarna för att rädda foten
hos patienter med diabetes och fotsår med olika lokalisation.
I delarbete I studeras patienter med diabetes som genomgått amputation nedom
fotleden. Totalt 309 patienter genomgick 410 amputationer. Medianåldern var 73
år och durationen av diabetes var i genomsnitt 16 år. Av alla amputationer läkte 64
% nedom fotleden, trots att patienterna var gamla, multisjuka och hade allvarliga
fotsår. Reamputation innan läkning behövdes hos 37 %.
I delarbete II studeras 701 patienter med ett sår på framfotens trampdyna.
Medianålder var 67 år och durationen av diabetes var i genomsnitt 13 år.
Försämrad blodcirkulation till foten noterades hos 26 % av patienterna. Av alla
patienter läkte 79 % sitt sår. Av dessa läkte 69 % utan operation och 31 % efter
kirurgisk revision av såret.
I delarbete III studeras 768 patienter med ett sår på hälen. Medianålder var 73 år
och durationen av diabetes i genomsnitt 17 år. Av alla patienter läkte 66 % sitt
hälsår utan amputation.
Av de 701 patienterna i delarbete II med ett sår på framfotens trampdyna läkte
618. En patient hade tidigare genomgått underbensamputation på det andra benet.
Således studerades 617 patienter i delarbete IV med avseende på risken för att
utveckla nya sår. Av dessa utvecklade 47 % nya sår inom 2 år efter läkning av det
ursprungliga såret. Endast 8 % utvecklade sår på samma ställe som det tidigare
läkta såret. Både patient och sjukvårdspersonal bör vara uppmärksamma på denna
risk för nya sår.
69
Sammanfattningsvis visar denna avhandling att det är möjligt att rädda foten hos
en stor andel patienter med diabetes som genomgår amputation nedom fotled, samt
att det finns goda förutsättningar att läka både plantara sår på framfoten och sår på
hälen utan att patienten behöver genomgå amputation. Det är viktigt att undersöka
om patienter med plantara sår på framfoten och patienter med hälsår har samtidig
perifer kärlsjukdom. Det är också viktigt med förebyggande åtgärder och
information till patienter att vara uppmärksamma på sina fötter.
70
Acknowledgements
I would like to express my gratitude to all who have supported me along the way
to this dissertation and especially to:
Magnus Eneroth, my supervisor, for support, encouragement and for always
taking time to answer my questions.
Jan Apelqvist, my co-supervisor, for all interesting discussions, encouragement
and for sharing your deep knowledge of the world of the diabetic foot. I look
forward to our future collaborations on the diabetic foot.
Jan Larsson, my co-supervisor, for guidance, inspiration and support during my
writing. Your knowledge and enthusiasm for the diabetic foot is one of the reasons
why I wanted to be an orthopaedic surgeon.
Eero Lindholm, for helping me to understand the world of statistics.
Magdalena Annersten Gershater for interesting discussions and assistance with
the database.
Maj-Britt Johansson for sharing knowledge of the database.
Friends and co-workers for laughs and interesting discussions on many topics.
The staff at the Diabetic Foot Team for sharing knowledge of patients and for
never-ending care, enthusiasm, and support to all patients with diabetic foot
disease.
My parents, Björn and Carina, for endless love and support.
My brother and sister, Hjalmar and Ulrika, for always being there.
Last and first to my husband Peter, without whose love and support this thesis
would not be possible, and our children Idun, Tor and Sigrid. You are my
everything.
71
72
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