FINAL VERSION
Clinical Guidelines for
Type 2 Diabetes
Prevention and management of
foot problems
Revised version
The prevention and management of foot problems
157
FINAL VERSION
13. Appendices
(This file contains Appendices 11–23. Appendices 1–10 and the full guideline are available as separate
files)
The prevention and management of foot problems
158
FINAL VERSION
Appendix 11: Human cultured dermis or equivalent: randomised trials
Interventions - skin
Author
(s)
Veves
A et al
2001
see also
Pham
HT et al
1999,
Samms
HH
2002,
individu
al centre
reports
Stud
y
Type of intervention
Setting
and
location
Randomised prospective
trial
T1: Graftskin plus salinemoistened Tegapore
dressing, dry gauze, and
petroleum gauze, reapplied
weekly for up to 4 weeks
(maximum 5 applications).
T2: saline moistened gauze
plus saline-moistened
Tegapore dressing, dry
gauze, and petroleum
gauze reapplied as above.
Both had adjuvant therapy
of surgical debridement
and foot off-loading
24 centres
in USA
Numbers
randomi
sed
T1: 112
T2: 96
Withdraw
n
T1: 22
T2: 22
Inclusion criteria/
Exclusion criteria
Inclusion: Type 1 or Type
2, age 18-80, HBA1c
between 6-12%, full
thickness neuropathic
ulcers ≥2 weeks duration
and between 1-16cm2 postdebridement. Audible
dorsalis pedis and
posterior tibia pulses.
Exclusion: Infection at
ulcer site, lower extremity
ischaemia (ankle/brachial
index<0.65), active
Charcot’s disease, nondiabetic ulcer, medical
conditions impairing
wound healing
Mean age±SD (years)
Male/female ratio
Ethnicity
Follow-up
period
12 weeks
T1: 58±10
T2: 56±10
T1: M88, F24
T2: M74, F22
Main
outcome
measures
Complete
wound healing
(intention to
treat analysis)
T1, T2
Caucasian
77, 67
African-American 20, 14
Hispanic
14, 13
Other? (no details in paper)
1, 2
Results
T1 and T2 similar at baseline for age, sex, type and duration of diabetes, ulcer size and duration.
At 12 weeks, complete wound healing in T1: 63 (56%), T2: 36 (38%) (p=0.0042), odds ratio 2.14 (95% CI 1.23,3.74).
Median time to complete closure T1: 65 days, T2: 90 days (p=0.0026).
Adjusted model for wound closure, also significant (p=0.0001). Average patient in T1 had 1.59-fold better chance for closure than T2 (95% CI 1.26,2.00).
T1 required on average 3.9 applications (range 1-5).
Secondary endpoints T1 also significantly better than T2, for maceration (p<0.05), exudate (p<0.05), eschar p<0.05).
Ulcer re-occurrence at 6 months, T1: 5.9% (3/51), T2: 12.9% (4/31) (ns).
Adverse events, T1: 6, T2 9
Graftskin applied for 4 weeks maximum produces higher healing rate and wound closure than saline-moistened gauze.
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FINAL VERSION
Appendix 11 (contd): Human cultured dermis or equivalent: randomised trials
Trial
Gentzkow et al, 1996
Naughton et al, 1997
Treatment
comparison(s)
T1: Cultured human dermis (1 piece) and dressing once
weekly
T2: Cultured human dermis (2 pieces) and dressing
once fortnightly
T3: Cultured human dermis (1 piece) and dressing once
fortnightly
T4: Saline-moistened gauze dressing
All patients received sharp debridement and pressure
relief including therapeutic shoes.
T1, T2, T3: cultured human dermis was applied weekly
for 8 weeks
T1: Cultured human dermis and dressing
T2: Conventional wound dressing
Other features
Location
Baseline
comparability
at p>0.05
Blinding level
Concealment
of allocation
Inclusion/
exclusion
Numbers
randomised
Length of
follow-up
Loss to
follow-up (%)
Type of
analysis
Outcomes/
endpoints
Multicentre (5 centres), USA
The control group were statistically significantly
younger than the treatment groups and had nonstatistically significantly longer mean ulcer duration;
the importance of these differences is unclear.
Stated single-blind, although none apparent
Yes, assigned by sealed envelope
All patients received conventional care: Debridement,
infection control and special shoes and inserts.
T1: Cultured human dermis application, weekly, for 8
applications in total.
T2: Saline-moistened gauze dressings.
Multi-centre (20 centres), USA
Baseline comparability between groups not reported
Stated single-blind, although none apparent
Not stated
Inclusion: Diabetic patients, with adequate glycaemic
control, with full thickness plantar ulcers, area >1 cm2.
Wound bed free of necrotic tissue or infection, suitable
for skin graft (no exposed tendon, bone or joint).
Adequate circulation.
Exclusion: More than one hospitalisation in the last 6
months for poor glycaemic control. Ulcers of nondiabetic origin. Medication known to interfere with
healing. Pregnancy.
T1: 12; T2: 14; T3: 11; T4: 13
Inclusion: Patients with neuropathic full-thickness
plantar foot ulcers of the forefoot or heel, area = 1.0
cm2.
Exclusion: Ulcers showing rapid healing in a screening
period before randomisation.
12 weeks
At 12 weeks and 32 weeks
None
T1: 30; T2: 16
Intention to treat, last observation carried forward
Endpoint analysis
Wound closure:
T1: 6/12 (50%); T2: 3/14 (21.4%); T3: 2/11 (18.2%);
T4: 1/13 (7.7%)
T1 vs. T4: p=0.03
50% wound closure:
T1: 9/12 (75%); T2: 7/14 (50%); T3: 2/11 (18.2%); T4:
1/13 (7.7%)
T1 vs. T4: p=0.017
No adverse reactions to the cultured human dermis used
were reported or differences in the rate of wound
infection comparing groups.
Ulcer healed:
T1: 42/109 (38.5%); T2: 40/126 (31.7%); p=0.1382
Only 37 T1 (intervention) patients received all
implants: ulcer response appears correlated with the
number of implants received and statistically significant
differences are seen in sub-groups who received all or
most of their implants compared to the control group.
However, patients receiving more implants may be the
ones with the most favourable prognosis and such
analyses are unreliable. Even in the overall comparison,
differential loss to follow-up occurred (22% from
cultured human dermis versus 11% from control)
making interpretation of findings problematic.
No safety problems were reported and no significant
differences were found between cultured human dermis
used and control patients in the occurrence of wound
infections.
T1: 139; T2: 142
Economic data
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160
FINAL VERSION
Appendix 11: Human cultured dermis or equivalent: randomised trials – health economics
Author(s)
Allentet B
et al, 2000
Study
Type of intervention
Markov model, for cost
effectiveness of
Setting
and
location
France
Numbers
randomised
N=100
Inclusion criteria/
Exclusion criteria
Inclusion: diabetic foot
ulcer, Type not stated
Mean age±SD
(years)
Male/female ratio
Ethnicity
Follow-up
period
1 year
Main outcome measures
Ulcers healed, time to
healing, recurrence in
ulcer, cost per patient
T1: Dermagraft (human
dermal replacement)
T2: standard treatment
Results
Costs per treated patient, cost per healed patient given
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Appendix 12: Hyperbaric oxygen: randomised trials
Trial
Leslie et al, 1988
Faglia et al, 1996
Treatment
comparison(s)
T1: Topical hyperbaric oxygen therapy in addition to
normal care
T2: Normal care
All patients received debridement, intravenous
antibiotics, wet-to-dry dressings, glycaemic control
and bed rest.
T1: Patients received hyperbaric oxygen therapy
using a leg chamber and cycled pressure (up to 1.04
atmospheres every 20 seconds) for 90 minutes, twice
daily for 2 weeks.
16 patients were Hispanic, 7 were black, 5 were
white.
None apparent
Yes
T1: Systemic hyperbaric oxygen therapy in addition to
normal care.
T2: Normal care
All patients received standard treatment including
radical debridement, antibiotic therapy and provision of
orthopaedic devices. The treatment group received an
average of 38 sessions and patients were followed until
discharge. Dressing changes happen every 2 days during
granulation period, daily for clean ulcers and twice daily
for necrotic or exuding ulcer.
T1: Patients sat in a hyperbaric chamber breathing pure
oxygen in 90-minute sessions, daily and pressurised at
2.5 atmospheres in the acute phase, reducing to weekly
and 2.2–2.4 atmospheres in the reparative phase.
Milan, Italy
Yes, patient groups appear comparable at baseline,
except that the control group had more claudication
(p=0.07).
None apparent
Not clear
Inclusion: Diabetic patients with well demarcated
foot ulcers.
Exclusion: Visible bone exposure, gangrene,
crepitation, severe ischaemia, persistent fever,
requiring urgent amputation.
T1: 12; T2: 16
Inclusion: Diabetic patients hospitalised for foot ulcer,
having full thickness gangrene (Wagner grade IV),
abscess (Wagner grade III), or persistent large and
infected ulcer (Wagner Grade II) showing defective
healing after 30 days of outpatient therapy.
T1: 36; T2: 34
14 days
T2: 1
Not clear, appears to be until patient discharged from
care
T1: 1 (refused treatment); T2: 1
Endpoint analysis
Endpoint analysis
Ulcers in both groups improved significantly.
However, there were no statistically significant
differences between groups at 2 weeks follow-up. No
significant differences were found in ulcer area or
depth (as a percentage of baseline) between the HBO
group and the control group at two weeks.
Change in ulcer size area (defined as maximum
width x maximum length in mm) measured with
ruler by same observer and depth measured with
sterile probe and photographed.
Ulcer area (% of baseline, ±SD) at day 7:
T1: 67.1±18.3; T2: 69.6±34.5; p=NS
Ulcer area (% of baseline, ±SD) at day 14:
T1: 45.6± 23.4; T2: 35.6±23; p=NS
Changes in ulcer depth, in a sub-group of patients
who could be assessed, revealed no statistically
significant differences between treatment groups.
Transcutaneous oxygen tension (mmHg±SD):
T1: 14.0±11.8; T2: 5.0±5.4; p=0.0002
Major amputation:
T1: 3/35 (8.6%); T2: 11/33 (33.3%); p=0.016
Minor amputation:
T1: 21/35 (60%); T2: 12/33 (36%); p=not stated
No amputation:
T1: 11/35 (31%); T2: 10/33 (30%); p=NS
Two patients showed symptoms of barotraumatic otitis
which did not interrupt treatment.
Other features
Location
Baseline
comparability
at p>0.05
Blinding level
Concealment
of allocation
Inclusion/
exclusion
Numbers
randomised
Length of
follow-up
Loss to
follow-up (%)
Type of
analysis
Outcomes/
endpoints
California, USA
Yes
Economic data
The prevention and management of foot problems
162
FINAL VERSION
Appendix 12 (contd): Hyperbaric oxygen therapy: randomised trials
Author(s)
Heing MCY
et al
2000
Study
Type of intervention
Randomised trial
(randomisation by
drawing lots)
T1: Topical hyperbaric
oxygen therapy T2:
standard wound care
Setting
and
location
Los
Angeles,
USA
Numbers
randomised
T1:13 (7
diabetes, 21
ulcers),
oxygen;
T2: 27 (8
diabetes, 11
ulcers)
standard
care
Inclusion criteria/
Exclusion criteria
Inclusion: nonambulatory,
necrotic/gangrenous
wounds, some
diabetes, type not
stated.
Exclusion: lifethreatening gangrene,
uncontrolled diabetes,
untreated sepsis
Mean age±SD
(years)
Male/female ratio
Ethnicity
T1: 73.8±6.4
T2: 75.5±8.0
T1:M13:F0
T2:M26:F1
Ethnicity: not
stated
T1: Diabetes 7
T2: Diabetes 8
Follow-up
period
4 weeks
Main outcome
measures
Ulcer size (surface area
from tracing taken
weekly)
Ulcer severity
(consensus on staging)
Histology (biopsy at
start and 3 weeks after
treatment)
Costs (nursing,
debridement, dressings,
antibiotics, beds)
Results
Higher number of ulcers in oxygen group at start (p=0.005).
Changes in size of diabetic ulcers in T1 vs T2 reported but no statistical tests done on diabetes subgroups
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Appendix 13: Ketanserin therapy: randomised trials
Trial
Apelqvist et al , 1990
Martinez-de Jesus et al,
1997
Janssen et al,
unpublished
Treatment
comparison(s)
T1: Oral ketanserin
T2: Placebo
Other features
All patients received a 2-week
placebo run in. Check-up visits
occurred at monthly intervals.
Antibiotics were used in response to
infection, footwear was corrected
and surgical debridement provided
where required.
T1: Oral ketanserin (20 mg 3 times
daily for 1 month then 40 mg 3
times daily for 2 months).
Sweden
Yes, except hypertension more
common in ketanserin group p<0.05
and systolic arm pressure lower in
ketanserin group p<0.05
Double blind (patient and
investigator)
Not reported
T1: Topical ketanserin (2%)
ointment
T2: Placebo (unmatched, saline)
All patients were hospitalised for
debridement, systemic antibiotic
treatment, foot rest and correction
of fasting hyperglycaemia caused
by sepsis. Patients received
outpatient care after discharge.
T1: Topical ketanserin (2%)
ointment
T2: Placebo (matched)
T1: Ketanserin (2%) ointment was
administered twice daily.
All patients received conventional
wound care, surgical debridement
of necrotic tissue and mechanical
debridement of necrotic tissue and
exudate with saline impregnated
gauze.
Of 299 patients randomised, only
45 were diabetic patients.
Multicentre, Germany
Yes
Location
Baseline
comparability
at p>0.05
Blinding level
Concealment
of allocation
Inclusion/
exclusion
Numbers
randomised
Length of
follow-up
Loss to
follow-up (%)
Type of
analysis
Outcomes/
endpoints
Mexico
Yes, except smoking: more
common in the ketanserin group
(p=0.043).
Single blinded (patient)
No, sequential allocation
Double blind (patient and
investigator)
Not recorded
Inclusion: Diabetic patients with
deep or superficial foot ulcers, area
≥1 cm2, systolic toe pressure below
45 mmHg.
Exclusion: Severe liver or kidney
insufficiency; myocardial infarction
within 3 months, congestive heart
disease (NYHA III–IV), treatment
with β-Blocker, unable to cooperate.
T1: 20; T2: 20
Inclusion: NIDDM patients with
neurotrophic, non-healing foot
ulcers (Wagner grade II or III).
Exclusion: Metabolic instability at
discharge.
Inclusion: Patients with chronic
skin ulcers: decubitus (80), venous
insufficiency (134), inoperable
arterial and arteriolar ulcers (40)
and diabetic foot ulcers (45).
Exclusion: Patients with a life
expectancy of less than 6 months
Total: 161
T1: 150; T2: 149
3 months
12 weeks
8 weeks
5 lost in run-in period, and not
included in numbers randomised
Endpoint analysis
21 withdrew by 2 weeks and are not
included in analysis
Endpoint analysis
Not recorded
Ulcer healed:
T1: 7/20 (35%); T2: 5/20 (25%)
Improved (wound size decreased by
50% or more):
T1: 4/20 (20%); T2: 2/20 (10%)
No improvement/deterioration:
T1: 6/20 (30%); T2: 6/20 (30%)
Gangrene (*amputated):
T1: 2/20 (10%) (2*); T2: 6/20
(30%) (4*)
Deceased:
T1: 1/20 (5%); T2: 1/20 (5%)
No comparisons gave statistically
significant differences.
Mean reduction in ulcer area(%):
T1: 87%; T2: 62.8%; p<0.001
Average daily reductions in ulcer
area (mm2/day):
T1: 4.5; T2: 2.88
No adverse effects were detected.
Subgroup analysis of 45 diabetic
patients:
Increase in initial healing velocity
relative to placebo:
ketanserin showed 2.96 fold
increase (196% faster) (p<0.001).
Comparability of diabetic patients
at baseline is unknown. Across all
patient groups, ketanserin showed
no increase in side-effects above
placebo treatment.
Endpoint analysis
Economic data
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Appendix 14: Growth factors: randomised trials
Trial
Steed et al, 1992
Holloway et al, 1993
Treatment
comparison(s)
T1: Topical CT-102 solution (0.1 dilution)
T2: Placebo (matched)
Other features
All patients agree to be totally non-weight-bearing,
were provided with a half-shoe, wheelchair, crutches or
walker. Patients were evaluated as outpatients weekly
then fortnightly. Dressings were changed twice daily by
patient or carer. CT-102, platelet-derived wound
healing formula, was applied twice daily with dressing
change or matched placebo (normal saline).
Aggressive debridement was performed at baseline.
Normal saline cotton gauze dressings were used
throughout the study.
USA
In all measures except duration of diabetes (years±sd):
T1: 26±6.6; T2: 10.3±5.9 (p=0.001)
T1: Topical CT-102 solution (0.1 dilution)
T2: Topical CT-102 solution (0.033 dilution)
T3: Topical CT-102 solution (0.01 dilution)
T4: Placebo (matched)
All patients underwent debridement of necrotic,
infected or bony tissue at entry, then subsequent
debridement of callus and necrotic tissue as required,
and were seen weekly for two weeks and then biweekly.
Location
Baseline
comparability
at p>0.05
Blinding level
Concealment
of allocation
Inclusion/
exclusion
Multicentre, USA
Yes
Double blind (patient and investigator)
Not recorded
Double blind
Not clear, a computer-generated list was used
Inclusion: Diabetic patients with neurotrophic ulcers of
lower extremity of at least 8 weeks duration, no wound
infection, ulcer volume 700 mm3 to 50,000 mm3, area
<100 cm2, involving subcutaneous tissue,
transcutaneous oxygen tension >30 mmHg, platelet
count =100,000/mm3
Inclusion: Diabetic patients with at least one nonhealing ulcer (>8 weeks duration), volume 500 mm3 to
50,000 mm3, transcutaneous oxygen tension of ≥30
mmHg, not infected.
Exclusion: If wound malignant, connective tissue
disease, terminal disease. Women: pregnant, nursing or
child-bearing potential.
81 in total (97 initially entered, 16 removed as did not
meet inclusion criteria)
20 weeks
Numbers
randomised
Length of
follow-up
Loss to
follow-up (%)
T1: 7; T2: 6
Type of
analysis
Outcomes/
endpoints
Endpoint analysis
20 weeks
None
Ulcer healing::
T1: 5/7 (71%); T2: 1/6 (17%)
Percentage reduction in ulcer area:
T1: 94%; T2: 73%; p<0.02
Daily reduction in ulcer volume (mean±SE) mm3/day:
T1: 73.8±42.4; T2: 21.8±8.1; p<0.05
Daily reduction in ulcer area (mean±SE) mm2/day:
T1: 6.2±1.8; T2: 1.8±0.4; p<0.05
11 patients were excluded from the analysis due to noncompliance or loss to follow-up
T1: 1; T2: 3; T3: 6; T4: 1
Endpoint analysis
Wound healed:
T1: 11/21 (52%); T2: 8/13 (62%); T3:12/15 (80%); T4:
6/21 (29%), T1 vs. T4: p=0.01
Mean (±sd) area reduction (at 20 weeks or last visit):
T1+T2+T3: 93.0±14.4%; T4: 77.1±25.7%; (p=0.002)
T1: 96.0%; T2: 90.7%; T3: 96.9%
Mean (±sd) volume reduction (at 20 weeks or last
visit):
T1+T2+T3: 94.9±12.0%; T4: 82.7±21.5%; (p=0.005)
T1: 94.3%; T2: 87.8%; T3: 95.7%
No differences in adverse events were reported between
groups.
Economic data
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165
FINAL VERSION
Appendix 14 (contd): Growth factors: randomised trials
Trial
Steed et al, 1995a
Richard et al, 1995
Treatment
comparison(s)
Other features
T1: Topical RGDpm viscous solution
T2: Placebo (not matched for viscosity)
T1: Arginine-glycine-aspartic acid peptide matrix
(RGDpm) was applied topically twice weekly, by
syringe, with dressing change and debridement (if
necessary) at a clinic visit for up to 10 weeks.
T2: Patients received matched care but without
RGDpm.
All patients were given shoes and shoe inserts at the
first visit.
Multi-centre (6 centres), US
Yes
T1: Topical rbFGF solution (as spray)
T2: Placebo (matched)
T1: Topical recombinant basic fibroblast growth factor,
as solution 5 µg/ml, applied once daily on an inpatient
basis for 6 weeks and then twice weekly for 12 weeks
(at home if appropriate). A spray device was used once
or twice for each treatment, delivering 50 µl per use.
Multi-centre (2), France
Yes
Double blind (patient and investigator)
No (pre-arranged randomisation order)
Double blind (treatment and evaluation)
Not reported
Inclusion: Diabetic patients with neurotrophic foot
ulcers (>1 month duration) (penetrating into dermis
without exposure of bone or tendon),: ulcer area >1 cm2
and <15 cm2, >18 years of age, HbA1c<10%, free of
infection and osteomyelitis, adequate transcutaneous
oxygen tension.
Exclusion: Contemporaneous treatment that might
affect healing, and certain medical conditions e.g.
immune system diseases, cancer requiring
chemotherapy
T1: 40; T2: 25
Inclusion: Patients had typical, chronic, non-healing,
neurotrophic foot ulcer (Wagner grade I–III), >0.5 cm
across largest dimension, vibration perception threshold
>30 V, no significant PVD or wound infection, tight
glycaemic control.
10 weeks
18 weeks
Withdrawal: T1: 8/40 (20%); T2: 6/25 (24%)
None
Endpoint analysis
Intention to treat, endpoint analysis
Wound healing
T1: 14/40 (35%); T2: 2/25 (8%); p=0.02
Ulcer: >50% closure by 10 weeks:
T1: 75%; T2: 48%; p=0.03
There was no statistically significant relationship
between treatment and adverse events.
Complete healing:
T1: 3/9 (33%); T2: 5/8 (63%) (p=0.23)
Location
Baseline
comparability
at p>0.05
Blinding level
Concealment
of allocation
Inclusion/
exclusion
Numbers
randomised
Length of
follow-up
Loss to
follow-up (%)
Type of
analysis
Outcomes/
endpoints
T1: 9; T2: 8
Economic data
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FINAL VERSION
Appendix 14 (contd): Growth factors: randomised trials
Trial
Steed et al, 1995b
Wieman, 1998
Treatment
comparison(s)
T1: Topical 30 µg/g rhPDGF gel
T2: Placebo (matched)
Other features
All patients received sharp debridement of ulcers at
baseline and subsequent debridement of callus and
necrotic tissue as required. Treatment occurred at 10
centres although the 5 smallest are pooled together.
T1: Patients received topical recombinant human
platelet-derived growth factor (rhPDGF) gel. Details of
frequency and duration of use are not recorded. Gel
dose is not recorded in the paper but Wieman et al
(1998) report it as 30µg/g
Multi-centre (10 centres), USA
Apparently. The paper states there are no differences in
age, median ulcer area, duration of ulcer or
transcutaneous oxygen tension although no details are
recorded.
Double blind (investigator and patient)
Yes
T1: Topical 100 µg/g or 30 µg/g rhPDGF gel
T2: Topical 30 µg/g rhPDGF gel
T3: Placebo (matched)
All patients received sharp debridement or ulcers at
baseline and subsequent debridement of callus and
necrotic tissue as required..
T1/T2: Patients received topical recombinant human
platelet-derived growth factor (rhPDGF) gel. Gel was
applied once daily at dressing change until healing.
Location
Baseline
comparability
at p>0.05
Blinding level
Concealment
of allocation
Inclusion/
exclusion
Numbers
randomised
Length of
follow-up
Loss to
follow-up (%)
Type of
analysis
Outcomes/
endpoints
Multi-centre (23 centres), USA
Yes
Double blind (investigator and patient)
Yes
T1+T2: 118
Inclusion: Patients had at least one full thickness (IAET
Stage III or IV) chronic ulcer of the lower extremity of
at least 8 weeks' duration, infection under control if
present, adequate arterial blood supply (transcutaneous
oxygen tension ≥ 30 mmHg).
Exclusion: Osteomyelitis affecting target ulcer, ulcers
not due to diabetes, patients with cancer, certain
concomitant diseases or treatment that would interfere
with the protocol. Women: Pregnancy, childbearing
potential, certain contraception.
T3: 127; T2: 132; T1: 123
20 weeks
20 weeks
Not recorded
T3: 24 (19%); T2: 28 (21%); T1: 21 (17%)
Endpoint analysis
Endpoint analysis
Ulcer healing (100% closure of the ulcer, with
epithelialization of the target ulcer):
T1: 48%; T2: 25%; p=0.01
Data are reported as percentages and it is not possible
to assess the validity of the analysis or statistic.
Ulcer healing:
T1: 61/123 (50%); T2: 48/132 (36%); T3: 44/127
(35%)
T1 vs. T3: p=0.007.
Time to healing (35th percentile):
T1: 86 days; T3: 127 days; T1 vs. T3: p=0.013.
No differences in outcome were found between 30 µg/g
rhPDGF and placebo groups. Variation of treatment
effect across centres was not reported. No differences
in adverse events or withdrawals were observed
between groups.
Inclusion: Patients had chronic neuropathic foot ulcers
of at least 8 weeks' duration, free of infection, adequate
arterial blood supply (transcutaneous oxygen tension ≥
30 mmHg).
Exclusion: Poor diabetes control, renal failure,
abnormal liver function.
Economic data
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FINAL VERSION
Appendix 15: G-CSF: randomised trials
Trial
Gough et al, 1997
Treatment
comparison(s)
Other features
T1: IV Granulocyte-Colony Stimulating Factor (G-CSF, filgrastim)
T2: Placebo
T1: G-CSF was administered as a daily subcutaneous injection for 7 days.
The initial dose was 5 µg/kg daily reducing to 2.5 µg/kg if absolute
neutrophil count exceeded 2.5x106/L.
All patients received combination IV antibiotic therapy until cellulitis and
discharge had resolved. Glycaemic control was optimised. Foam dressings
were used throughout. Twelve patients in each group had evidence of
osteomyelitis at randomisation.
London, UK
Yes
Location
Baseline
comparability
at p>0.05
Blinding level
Concealment
of allocation
Inclusion/
exclusion
Numbers
randomised
Length of
follow-up
Loss to
follow-up (%)
Type of
analysis
Outcomes/
endpoints
Double blind (patient and investigator)
Not reported
Inclusion: Diabetic patients, >18 years of age, with feet with spreading
infection involving subcutaneous tissue, characterised by erythema in
association with purulent discharge, with or without lymphangitis.
Exclusion: Absolute neutrophil count <1x106/L or >50x106/L, current or
previous malignant disorders, blood dyscrasia, HIV infection, serum
creatinine >250 µmol/L or renal replacement therapy, hepatic disease,
previous organ transplantation, immunosuppressive therapy, pregnancy,
lactation, multiple organ failure secondary to septicaemia, critical leg
ischaemia.
T1: 20; T2: 20
20 weeks
None
Endpoint analysis
Median time in days:
G-CSF Placebo
p
To hospital discharge:
10
17.5
0.02
To resolution of cellulitis:
7
12
0.03
To cessation of IV antibiotics: 8.5
14.5
0.02
To negative swab culture:
4
8
0.02
Surgery (debridement under general anaesthetic or amputation):
G-CSF: 0/20; placebo: 4/20; p=0.114
Cellulitis resolved at day 7:
G-CSF: 11/20; placebo: 4/20; p=0.05
Ulcer healed at day 7:
G-CSF: 4/19; placebo: 0/20; p=0.09
(1 G-CSF patient had cellulitis but no ulcer.)
Statistically significant improvements in total white cell, neutrophil,
lymphocyte and monocyte counts were achieved in the G-CSF group
compared to placebo, at 7 days.
No patients were withdrawn due to side effects; 3 G-CSF patients
experienced transient bone pain not requiring analgesia.
Economic data
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Appendix 15 (contd): G-CSF: randomised trials
Author
(s)
Yonem
A et al
2001
Study
Type of intervention
Randomised trial
T1: Recombinant
human G-CSF plus
treatment given to T2.
G-CSF, 2.5-5µg/kg,
given subcutaneously
1/day
T2: local wound care
and parenteral
antibiotherapy
Setting
and
location
Hospital,
Turkey
Numbers
randomised
T1:15
T2: 15
Inclusion criteria/
Exclusion criteria
Inclusion: Diabetes
with pedal cellulitis or
Wagner’s grade ≤2
lesion on foot, ```````,
Exclusion: not stated
Mean age±SD
(years)
Male/female ratio
Ethnicity
T1: 60.3±1.3
T2: 61.1±1.4
Follow-up
period
daily until
hospital
discharge
T1: M8, F7
T2: M9, F6
Main outcome
measures
Time to resolution of
infection
Time to hospital
discharge
Ethnicity not stated
Results
No differences in age, sex, duration of diabetes between T1 and T2 at baseline.
Duration of hospital stay T1: 26.9±2 days, T2: 28.3±2.2 (p<0.05 in text but ns on table).
Time to resolution of infection, T1 23.6±1.8 days, T2: 22.3±1.7 (P,<.05 in text but ns on table)
Changes in neutrophic count significantly higher in T1 vs T2 (p<0.001) at 5th and 10th day and post treatment (not a primary outcome)
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Appendix 15 (contd): G-CSF: randomised trials
Author
(s)
de Lalla
F et al
2001
Study
Type of
intervention
Setting and
location
Numbers
randomised
Randomised
controlled, singleblind trial
T1: glycosylated
recombinant
human G-CSF +
conventional
treatment (local
treatment +
systemic
antibiotic therapy)
T2: conventional
treatment
Diabetes
centre,
Vicenza, Italy
T1: 20
T2: 20
Inclusion criteria/
Exclusion criteria
Inclusion: adult, diabetes, with
severe limb-threatening foot
infection, Type not stated.
Exclusion: antibiotics for
infection in past 2 weeks,
infection, non-consent,
immediate risk of major aboveankle amputation for ischaemia,
any critical condition with risk
of death, renal impairment,
history of allergy
Mean age±SD
(years)
Male/female ratio
Ethnicity
T1: 56.6±8.6 (42-74)
T2: 59.8±9.6 (44-85)
T1: M 16, F 4
T2: M14, F 6
Ethnicity not stated
Followup
period
Main outcome measures
6 months,
with major
end points
at 3 and 9
weeks
Average healing time for foot
infection
Cure:
a) complete closure of ulcer, without
underlying signs of bone infection
b) improvement in ulcer (eradication
of pathogens) + reduction in cellulitis,
incomplete wound closure, signs of
bone infection
c) failure, no clinical improvement
Results
No differences in age, sex, duration of diabetes, type of lesion or other general and clinical characteristics at baseline between T1 vs T2.
Week 3
Week 9
T1 (n=20)
T2 (n=20)
T1 (n=20)
T2 (n=20)
Cure n (%)
0
0
7 (35)
7 (35)
Improvement n(%) 12 (60)
9 (45)
8 (40)
4 (20)
Failure n(%)
8 (40)
11 (55)
5 (25)
9 (45)
There were no significant differences between T1 vs T2, at week 3 or week 9, between numbers in the cure/improvement/fail groups (all P>0.05).
At 6 months FU
T1: 13 (81%) were cured or displayed stable conditions, 3 (19%) worsened or had ulterior ulcer infection, 4 lost to FU.
T2: 15 (75%) were cured, 5 (25) worsened, no losses to FU. No differences T1 vs T2 (p>0.05).
Amputation (metatarsals or phalanges)
At 3 weeks, T1: 1, T2: 5 (P=0.08). At 9 weeks (cumulative number of amputations), T1: 3, T2: 9 (p=0.038).
Administration of G-CSF for 3 weeks as adjunctive therapy for limb-threatening diabetic foot infection is associated with a reduction in amputations within 9 weeks after
commencement of treatment.
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Appendix 15 (contd): G-CSF: randomised trials – health economics
Author(s)
Fds M et al,
1999
Study
Type of intervention
Retrospective, cost
minimisation of RCT of
resource use and
treatment cost of
hospitalised diabetic
patients with infected
foot ulcers
T1: filgrastin
(5µg/kg/day) for 7 days
T2: no filgrastin
Setting
and
location
London,
England
Numbers
randomised
N=40
Model based
on T1: 15
T2: 13
Inclusion criteria/
Exclusion criteria
Mean age±SD
(years)
Male/female ratio
Ethnicity
Follow-up
period
Main outcome
measures
Inclusion: Diabetes, Type
not stated, Infected ulcer
Results
ITT cost analysis: mean cost savings £2666 (36% of total cost) in favour of T1.
Cost savings ranged from £3129 (39%) to £155 (4%) when patients with vascular problems and/ or tissue necrosis excluded from analysis.
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Appendix 16: Electrical stimulation: randomised trials
Author(s)
Study
Type of intervention
Setting
and
location
Peters EJ et
al
2001
Pilot
study
Double-blind
randomised, placebocontrolled trial
T1: electrical
stimulation, 50V with
80 twin peak
monophasic pulses, for
10 min + 8 pulses/sec
for 10 min+ 40 min
break, nightly for 8
hour period, delivered
by Micro-Ztm to a
Dacron-mesh sliver
nylon stocking
T2: placebo electrical
unit, no current.
Both T1 and T2 had
standard wound care
(debridement, collagen
wound gel, pressure
reduction)
University
medical
centre,
Texas,
USA
Numbers
randomised
T1: 20
T2: 20
Dropouts
T1: 2
T2: 3
Inclusion criteria/
Exclusion criteria
Inclusion: diabetes,
Type 1 or Type 2,
wounds grade 1A-2A,
transcutaneous oxygen
tension>30mmHg at
dorsum.
Exclusion: soft tissue or
bone infection,
malignancy, cardiac
conductivity disorder
Mean age±SD (years)
Male/female ratio
Ethnicity
T1: 54.4±12.4
T2: 59.9±7.0
T1: M19, F2
T2: M16, F4
Follow-up
period
Every week
until ulcer
healed or 12
weeks
Main outcome
measures
Proportion with
complete wound
healing at 12 weeks
Rate of wound
healing
Complications
Ethnicity: not stated
History of diabetes T1
16.4±11.6yrs; T2
17.0±7.5yrs
Results
Healed: T1: 13 (65%), T2: 7 (35%), p=0.058
Healed stratified by compliance: T1 compliant group 10/14 (71%), noncompliant 3/6 (50%), T2: complaint group 5/13 (39%), noncompliant 2/7 (29%) (p=0.037) (no
difference in compliance between T1: n=14/20 and T2: n=13/20)
Rate of healing: no significant difference
Average time taken to heal: T1: 6.8±3.4 weeks, T2: 6.9±2.8 weeks, no significant difference
Change in ulcer cross-sectional area: T1: 86.2%, T2: 71.4%
Electrical stimulation MAY enhance wound healing when used with standard wound care and pressure reduction.
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Appendix 17: Sulodexide: randomised trials
Interventions - insulin and sulodexide (pilot study)
Author
(s)
Koblik
T et al,
2001
Study
Pilot
Type of intervention
Setting
and
location
Numbers
randomised
Inclusion criteria/
Exclusion criteria
Randomised doubleblind, placebocontrolled trial
T1: Insulin +
sulodexide (600LRV [1
vial] daily for 15 days,
followed by 250LSU [1
cap] for 2 months
T2: Insulin + placebo
(given is same manner
as sulodexide)
Metabolic
disease
clinic,
Poland
T1: 12
T2: 6
(planned
randomisatio
n was 2:1)
Inclusion: persisting
diabetic foot syndrome,
monolateral foot ulcers,
Type 1 or Type 2.
Excluded: poorly
controlled diabetes,
genetic
hyperlipoproteinemias,
systemic diseases and
malignancies, gangrene
of foot
Mean age±SD
(years)
Male/female ratio
Ethnicity
T1: 52.6±8.5
T2: 57.2 (11.1)
Follow-up
period
10 weeks
Main outcome
measures
Ulcer healing rate
T1: M8, F4
T2: M3, F3
Ethnicity not stated
T1: Type 1 2, Type 2
10
T2: Type 1 2, Type 2
4
Results
T1: 92% of foot ulcers healed, mean time to healing 46.4±5.2 days. T283% healed, in 63±8.5 days, 95% CI on difference -36.7, 3.47, p=0.09
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Appendix 18: Charcot osteoarthropathy
Authors
Jude et al 2001
Study
Type of intervention
Double blind
randomised trial
T1: 90mg
pamidronate – single
fusion
T2: saline placebo
All had standard foot
care with scotch cast
boot, pneumatic
walker, or total
contact cast
Setting and
location
4 diabetes
centres:
Manchester,
Nottingham,
Exeter, London
Numbers
randomised
T1: 21
T2: 18
Type 1: 14 Type
2: 25
Inclusion/exclusion
criteria
Inclusion: Type 1 or
2, aged 20-80,
definitive diagnosis of
Charcot
osteoarthropathy and
peripheral neuropathy
Mean age
(years)
Male/female
(M/F) ratio
Ethnicity
T1: 55.9±10.1
T2: 56.5±8.6
M/F
Type 1: 13/1
Type 2: 13/12
T1: 15/6
T2: 11/7
Ethnicity not
stated
Follow-up
period
Main outcome
measures
12 months
2 week FU for 3
months + 3
month FU at 6,
9, 12 months
Foot temperatures
Charcot foot
symptoms
Foot pain, discomfort,
swelling scored
Bone turnover
markers, DPD
crosslinks, bone
specific alkaline
phosphatase
Results
Foot temperatures reduced in T1 and T2 from baseline at 4 weeks (T1 –1.9±0.8, p<0.001; T2, -1.4±0.7, p<0.01) with further falls and non significant differences between T1 and T2.
Pain most common symptom, foot discomfort second most common. Symptom scores fell in T1 and T2 from baseline to 3 months with further fall in T1 (p<0.01) but not in T2. Area under
the curve smaller for T1 (14.3±8.7) than T2 (23.8±8.4) (p<0.01).
Bone turnover markers not different at baseline between T1 and T2, but by 4 weeks, reduced in T1 compared with T2 (alkaline phosphatase p<0.03, DPD crosslinks p<0.01). Both markers
rose towards baseline values by end of FU. Maximum reduction was 32% in DPD and 30% in alkaline phosphatase.
No difference between T1 and T2 in inflammatory markers at baseline of FU.
Pamodronate has an effect on symptoms in acute Charcot’s osteoarthropathy over and above those seen in offloading but limited impact on bone markers (repeated treatments may be more
effective). Larger studies needed to determine optimum treatment regimen.
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Appendix 18 (contd): Charcot osteoarthropathy
Authors
Chantelau and
Schnabel 1997
Study
Type of intervention
Randomised double blind
trial
T1: radiotherapy 300kV,
focus distance 30cm, 3
treatments: single doses
of 0.15Gy, 0.3Gy and 4
of 0.15Gy (max dose
2.45Gy)
T2: sham placebo
radiotherapy, 6 sessions
0Gy
TO CHECK
Setting and
location
Germany
Numbers
randomised
Inclusion/exclusion
criteria
Inclusion: acute
osteoarthropathy of feet,
duration <2 months
T1: 6
T2: 6
Type 1: 3
(T1 1: T2 1)
Type 2: 9
(T1 4, T2: 5)
Mean age
(years)
Male/female
(M/F) ratio
Ethnicity
T1: median 58
(95% CI 24, 64)
T2: 52 (43, 62)
Follow-up
period
Monthly until
healed
Main outcome
measures
Time to healing
M/F
T1: 2/4
T2: 4/2
All had complete relief
of pressure in affected
foot, systematic
treatment with oral
antibiotics, lose-dose
heparin
Results
Healing time was 7 (4-10) months for T1 patients and 9.7 (4-15) months for T2 patients (no statistic test information).
In 6 patients who did not comply with pressure relief (less use of wheelchairs, walking on feet at least once per day) healing time was 10.5 (8-20) months compared with 5.5 (3-7) months in 6 nonwalkers.
Authors conclude non-weightbearing supports healing of acute Charcot’s foot in patients with diabetes (but this was not what they tested in their study) and radiotherapy does not, although they suggest that the dose
could have been too low.
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Appendix 18 (contd): Charcot osteoarthropathy
Authors
Armstrong et al
1997
Study
Type of intervention
Retrospective study
Total contact casts
changed ≤3 weeks, or
weekly in those with
ulceration until
indication to
discontinue (after 18.5
± 10.6 weeks (range 4
– 56) and progress to
removable cast
walkers and then
footwear.
Setting and
location
Texas, USA
Numbers
randomised
55 cases
Inclusion/exclusion
criteria
Inclusion: Diagnosis
of Charcot’s
osteoarthropathy
Exclusion:
Concomitant
osteomyelitis
Mean age
(years)
Male/female
(M/F) ratio
Ethnicity
Follow-up
period
Main outcome
measures
Age 58.6 ± 8.5
years
M/F 27:28
Type 2: 54, Type
1: 1
Minimum 1 year
(mean 92.6 ±
33.7 weeks)
Length of time in cast
Results
All patients returned to permanent footwear at 28.3 ± 14.5 weeks.
All concomitant ulcers healed during total cast regimen.
No significant correlation between location of acute Charcot’s osteoarthropathy and duration cast time or time to footwear.
Men were contact casted for a significantly longer period than women (no difference in age or duration of diabetes between men and women) 21.8 ± 12.4 weeks for men, and 15.2 ± 7.6
weeks for women (p<0.008). Men also took longer to return to footwear at 30.2 ± 14.5 weeks compared with women 26.4 ± 14.8 weeks (not significant).
Significant difference in time to return to permanent footwear between bilateral and unilateral cases (p<0.02).
Surgery performed on 25% of patients, but no difference in surgery or type of surgery between men and women.
Four patients had new-onset neuropathic ulcerations during FU.
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Appendix 19: Economics papers
Author(s)
Ramsey S
et al, 1999
Study
Type of intervention
Gp 1: Retrospective cohort
Gp 2: Those in cohort who
developed foot ulcers (these
were matched to 4 controls
with no foot ulcer,
amputation, osteomyelitis).
Cost analysis
Setting and
location
USA
Numbers
randomised
None
randomised
Gp 1: 8905
Gp 2: 514
Inclusion criteria/
Exclusion criteria
Inclusion: Type 1 or Type 2,
on Health Maintenance
Organisation administrative
data files from 1992-95, ≥18
years age
Mean age±SD (years)
Male/female ratio
Ethnicity
Gp 1: 65.8±12.5
Gp 2: 66.3±12.8
Follow-up
period
3 years
Main outcome measures
development of foot ulcer
attributable cost for new ulcer
Gp 1: M 52%
Gp 2: M 52%
Ethnicity not stated
Results
Cumulative incidence of foot ulcers over 3 years 5.8%
Foot ulcer patients used significantly more inpatient and outpatient resources than age and sex matched controls.
Visits/year (mean±SD)
Controls
Foot ulcer patients
Year 1
Year 2
year 1
Year 2
Emergency dept
0.18±0.03
0.21±0.05
0.42±0.11
0.49±0.23
Outpatient dept
13.05±0.47
13.35±0.52
35.08±9.18
27.92±2.4
Inpatient days
1.46±0.23
1.60±0.60
6.03±2.32
4.06±2.61 Differences between control and foot ulcer patients, all comparisons, all p<0.001
Adjusted model (multivariate analysis) costs: ratio of mean expenditures (95% CI) foot ulcer vs controls
Year from diagnosis
8-39 years age
40-64
≥65
-1
1.96(0.4, 9.65)
2.42 (1.34, 4.38) 1.45 (0.40, 5.36)
1
5.40 (1.20, 4.33)
4.12 (2.35, 7.22)
2.67 (1.65, 4.31)
2
2.59 (0.56, 2.06)
2.83 (1.57, 5.11)
1.56 (0.91, 2.67)
Annual expenditures given, but in US$, relevance?
Currie CJ
et al 1998
Record-linked routine data
on inpatients, 1991/2 and
1994/5
Cardiff,
Wales
None
randomised
N=4245
Inclusion: all inpatients,
those with diabetes Type
not stated
4 years
Costs for diabetic vs
nondiabetic patients for
operation, admission
3 years
Costs of different
treatment strategies
Cost for hospital care,
outpatient care, etc
Long term costs 3 years
after healing
Results
Total costs for diabetics given for chronic ulcer of skin but no costs per 1000 population/year by diabetic: nondiabetic subgroup
Apelqvist
J et al,
1994,
Apelqvist
J et al
1994,
Apelqvist
J et al
1995
Prospective
plus retrospective analysis
of costs
Sweden
None
randomised
Prospective:
N=314 with
foot ulcers
Retrospective
N=274
Inclusion: diabetes, Type
not stated
197 ulcers healed
77 healed after minor
or major amputation
40 died
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Results
Cost for topical treatment $40.3 - £385, dependent upon severity of ulcer and wound healing time. Dominating costs: staff expenses, transportation. Reducing dressing change frequency would reduce costs.
Total care costs SEK 51,000 (3,000-808000) for primary healing, SEK 344,000 (27000-992000) for healing with amputation.
Compared with costs for primary healing: inpatient care costs = 37%; amputation = 82%; topical treatment in outpatients = 45%; ulcer dressings 9%.
Expected total present value cost per patient over 3 years for primarily healed patients = $US26,700 with critical ischaemia, $16,100 without. For healing after amputation, minor amputation $43,100, major
amputation $63,100.
Ollendorf
DA et al,
1998
Results
Model
USA
Hypothetical
cohort
N=10,000
Inclusion: diabetes, Type
not stated
benefits
estimated 3
years
Costs of lower-limb
amputation
Total potential benefits (discounted at 5%), of strategies to reduce amputation risk ranged from $US2.0 - $3.0 million, $2,900 - $4,442 per person with history of foot ulcer, over 3 years. Benefits highest for
educational interventions. Most benefits found to accrue among individuals ≥70 years age.
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Appendix 20 - Guideline development group
Dr Robert Young (Chair)*
Consultant Diabetologist,
Salford Royal Hospital Trust, Hope Hospital, Manchester
Mrs Rose Chiverton
Patient Representative
Mrs Sheila Clarkson*
Diabetes Specialist Nurse
Blackburn Royal Infirmary
Mrs Alethea Foster*
Chief Podiatrist,
Diabetic Foot Clinic, King's College Hospital, London
Dr Roger Gadsby
General Practitioner, Nuneaton and
Senior Lecturer in Primary Care, University of Warwick
Aileen McIntosh*
Deputy Director, Sheffield Evidence Based Guidelines
Programme, Public Health, ScHARR, University of Sheffield
Mr Michael O’Connor
Patient Representative
Dr Jean Peters
Senior Lecturer in Public Health, ScHARR, University of
Sheffield
Dr Gerry Rayman
Consultant Diabetologist,
Diabetes Centre, Ipswich Hospital
Observers
Nancy Turnbull
Chief Executive, National Collaborating Centre for Primary Care
Colette Marshall
National Institute for Clinical Excellence
In attendance
Karen Beck
*
Public Health, ScHARR, University of Sheffield
member of original guideline development group
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Appendix 21 - Scope
Guideline title
Management of type 2 diabetes: prevention and management of foot problems (update)
Short title
Type 2 diabetes – foot care (update)
Background
The National Institute for Clinical Excellence (‘NICE’ or ‘the Institute’) has commissioned the
National Collaborating Centre for Primary Care to review recent evidence on the prevention and
management of foot problems in people with type 2 diabetes, and update the existing guideline
Clinical Guidelines and Evidence Review for Type 2 Diabetes: Prevention and Management of
Foot Problems (Royal College of General Practitioners, 2000) for use in the NHS in England
and Wales. The updated guideline will provide recommendations for good practice that are
based on the best and most recently available evidence of clinical and cost effectiveness. This
guideline will be relevant only to patients with Type 2 diabetes, as the management of foot
problems for patients with Type 1 diabetes will be incorporated into the NICE guideline
currently under development, Type 1 diabetes: diagnosis and management of type 1 diabetes in
primary and secondary care, scheduled for publication in January 2004.
The Institute’s clinical guidelines will support the implementation of National Service
Frameworks (NSFs) in those aspects of care where a Framework has been published. The
statements in each NSF reflect the evidence that was used at the time the Framework was
prepared. The clinical guidelines and technology appraisals published by the Institute after an
NSF has been issued will have the effect of updating the Framework.
Clinical need for the guideline
a) Type 2 diabetes (non-insulin dependent diabetes mellitus) is a common and chronic disease
with a high risk of a number of serious complications. About 1.3 million people are
currently diagnosed with diabetes. This means that in 100,000 people, about 2,000–3,000
will have diabetes. Type 2 diabetes accounts for about 85% of these cases and many more
people may have Type 2 diabetes as yet undiagnosed.1 It has been estimated that diabetes
may be responsible for at least 5% of healthcare expenditure in the UK and up to 10% of
hospital inpatient resources are used for the care of people with diabetes 1,2
b) Foot complications are common in diabetes. Overall, 20–40% of people with diabetes are
estimated to have neuropathy∇ (depending on how it is defined and measured) and about 5%
have a foot ulcer.3,4,5
c) The St Vincent declaration called for a 50% reduction in amputation from diabetic gangrene,
reflecting the belief that much morbidity is preventable by better patient management.6 A
retrospective survey of people with diabetes in Newcastle upon Tyne (UK) undergoing nontraumatic∗ amputation, found that of the patients receiving hospital care, only half had
∇
Nerve damage
∗
These are amputations that are not due to an accident.
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complete foot evaluations in the year preceding initial ulceration or gangrene.7 Another
retrospective study investigated causal pathways to amputation in a series of 80 people with
diabetic lower-extremity amputations. A causal sequence of minor trauma, cutaneous
ulceration and wound-healing failure applied to 72% of amputations.8 The aim of the
guideline will help improve standards of care and outcomes.
The guideline
a) The guideline development process is described in detail in three booklets that are available
from the NICE website (see ‘Further information’). The Guideline Development Process –
Information for Stakeholders describes how organisations can become involved in the
development of a guideline.
b) This document is the scope. It defines exactly what this guideline will (and will not) examine,
and what the guideline developers will consider.
c) The areas that will be addressed by the guideline are described in the following sections.
Population
Groups that will be covered
Adults and children with diagnosed type 2 diabetes.
Groups that will not be covered
a) The guideline will not address identification of undiagnosed diabetes, general management
of people with diabetes (other than aspects that relate to the prevention of foot
complications).
b) The guideline will not cover people with foot problems who do not have Type 2 diabetes.
Healthcare setting
a) The guideline will cover the care received from primary and secondary healthcare
professionals who are involved in the care of people with type 2 diabetes.
b) This is an NHS guideline and although it will also be relevant to practice within residential
and nursing homes, social services and the voluntary sector, it will not make
recommendations regarding services exclusive to these sectors.
Clinical management
The guideline will include recommendations on the following areas.
a) Patient and carer education regarding prevention and management of foot and lower limb
problems associated with diabetes.
b) The definition of increased risk of foot complications, the identification of those at risk and
the management and prevention of foot complications.
c) Diagnosis of the foot with complications
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•
Type of ulceration
•
Infection
•
Charcot neuroarthropathy
•
Critical ischaemia
d) Management of the ulcerated foot including
•
Off-loading ¥.
•
Dressings
•
Debridement
•
Pharmacological interventions including antibiotics and analgesics
•
Skin replacements
•
Physical therapies
•
Growth factors
e) Primary prevention, and prevention of recurrence
f) Indications for referral to specialist services including:
•
Specialist foot teams/clinic
•
Those with responsibility for assessment and provision of (specialist) footwear
•
Podiatry and Orthotics
•
Surgery and Interventional radiology,
•
Mobility assessment.
•
Pain management
g) Aspects of clinical management that will not be covered in the guideline are:
•
surgical procedures and amputation
•
post-amputation rehabilitation
Audit support within guideline
The guideline will be accompanied by audit review criteria and advice.
¥
Offloading is a system that facilitates wound healing by re-distributing plantar foot pressure e.g. bed-
rest, in-shoe orthoses, special footwear, walking casts etc
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References
1.
Department of Health (2001) National Service Framework for Diabetes.
2.
Laing W, Williams R (1989) Diabetes: a model for health care management. London: Office of Health Economics,
No 2.
3.
Kumar S, Ashe HA, Parnell LN et al. (1994) The prevalence of foot ulceration and its correlates in Type 2 diabetic
patients: a population based study. Diabetic Medicine 11:480–4.
4.
Neil HAW, Thompson AV, Thorogood M et al (1989) Diabetes in the elderly: the Oxford community diabetes
study. Diabetic Medicine 6:608–13.
5.
Walters DA, Gatling W, Mullee MA, Hill RD (1992) The distribution and severity of diabetic foot disease: a
community based study with comparison to a non-diabetic group. Diabetic Medicine 9:354–8.
6.
World Health Organization (Europe) and International Diabetes Federation (Europe) (1990) Diabetes care and
research in Europe: the St Vincent Declaration. Diabetic Medicine 7:360.
7.
Deerochanawong C, Home PD, Alberti KGMM (1992) A survey of lower limb amputation in diabetic patients.
Diabetic Medicine 9:942–6.
8.
Pecoraro RE, Reiber GE, Burgess EM (1990) Pathways to diabetic limb amputation: basis for prevention. Diabetes
Care 13:513
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Appendix 22 – Foot care clinical path
(developed for original guideline)
As part of the guideline development process of the original guideline (Hutchinson et al 2000, of
which this is an update), identification of key clinical questions was undertaken. To help this
process a pathway approach was used. The original guideline development group represented this
pathway schematically, with decision nodes and actions identified. From this pathway questions
and issues to be addressed by the guideline were identified. These are presented in Chapter 2,
Guideline development (in section entitled Scope of the foot care guideline).
We present this schematic pathway for completeness of information as part of the development
process rather than as a pathway that is useful in using the guideline or in providing patient care
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footwear
podiatry
metabolic intervention
education
systems of review & care
person with
Type 2
diabetes
identify at
risk foot
in terms of
z
diabetes characteristics
foot characteristics
person characteristics
‘not at risk foot’
f
interventions
z
diagnostic criteria
for ‘at risk foot’
identifying techniques
levels of risk
intervention 2°
e
z
ulceration
(ischaemic)
limb threatening
foot
(early)
z
(neuropathic)
healing
healing
z
late
z
gangrene
a
b
avoid
amputation
ulceration
c
d
infection
set of risk
factors
z
The foot nobody
avoid
amputation
can save
minor
amputation
major
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Appendix 23 – Related NICE guidance
National Institute for Clinical Excellence (2000) Guidance on rosiglitazone for type 2 diabetes
mellitus. NICE Technology Appraisal Guidance No. 9. London: National Institute for Clinical
Excellence.
National Institute for Clinical Excellence (2001) Guidance on the use of pioglitazone for type 2
diabetes mellitus. NICE Technology Appraisal Guidance No. 21. London: National Institute for
Clinical Excellence.
National Institute for Clinical Excellence (2001) Guidance on the use of debriding agents and
specialist wound care clinics for difficult to heal surgical wounds. Technology Appraisal No.24.
London: National Institute for Clinical Excellence.
National Institute for Clinical Excellence (2002) Guidance on the use of long-acting insulin
analogues for the treatment of diabetes – insulin glargine. NICE Technology Appraisal Guidance
No. 53. London: National Institute for Clinical Excellence.
National Institute for Clinical Excellence (2003) Guidance on the use of continuous subcutaneous
insulin infusion for diabetes. NICE Technology Appraisal Guidance No. 57. London: National
Institute for Clinical Excellence.
National Institute for Clinical Excellence (2003) Guidance on the use of patient education models
for diabetes. NICE Technology Appraisal Guidance No. 60. London: National Institute for Clinical
Excellence.
The Institute has also published a series of guidelines on the management of type 2 diabetes.
•
National Institute for Clinical Excellence (2002) Management of type 2 diabetes:
retinopathy – screening and early management. Inherited Clinical Guideline E.
London: National Institute for Clinical Excellence.
•
National Institute for Clinical Excellence (2002) Management of type 2 diabetes: renal
disease – prevention and early management. Inherited Clinical Guideline F. London:
National Institute for Clinical Excellence.
•
National Institute for Clinical Excellence (2002) Management of type 2 diabetes:
management of blood glucose. Inherited Clinical Guideline G. London: National
Institute for Clinical Excellence.
•
National Institute for Clinical Excellence (2002) Management of type 2 diabetes:
management of blood pressure and blood lipids. Inherited Guideline H. London:
National Institute for Clinical Excellence.
The following technology appraisals and clinical guidelines are part of the Institute’s ongoing work
programme.
•
Technology appraisal review on glitazones: expected to be issued August 2003.
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•
Clinical guideline on type 1 diabetes: diagnosis and management of type 1 diabetes in
primary and secondary care: due to be issued early 2004.
•
Clinical guideline on the management of surgical wounds: due to be issued early 2006.
•
Clinical guidelines on woundcare sites: issue date to be confirmed.
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Appendix 24 – Selected glossary
This is not intended as an exhaustive glossary of diabetes terms. It gives limited explanation of
terms used in this guideline that may not be familiar to every reader. For a fuller glossary of terms
the reader is directed to the glossary accompanying the National Service Framework for Diabetes,
which can be accessed from:
http://www.doh.gov.uk/nsf/diabetes/
The glossary that accompanies the Scottish Framework for Diabetes is also suggested:
http://www.diabetesinscotland.org/diabetes/Glossary.asp?index=n%25
≤
less than or equal to
≥
greater than or equal to
<
less than
>
greater than
amputation
surgical removal of limb or part of limb (eg toes), non traumatic
amputation is that undertaken as part of treatment as distinct from
traumatic amputation which results for example from violent
accidents such as road traffic accidents
biothesiometer
equipment used to measure foot sensitivity
buckling strength
measure of how much pressure a piece of plastic can stand before
giving way (buckling)
calibrated tuning fork
specialised tuning fork used to measure foot sensitivity
callus
hard, thick area of skin
cellulitis
infection of the skin
Charcot osteoarthropathy
chronic, progressive, degenerative disease of the foot joints
chiropody
see podiatry
claudication
pain in the legs (especially the calf), due to poor circulation of the
blood to leg muscles
claw toes
deformity of the toes
community diabetes foot care
protection team
multidisciplinary team including diabetologists, nurses, podiatrists,
providing care for people with diabetes
cultured human dermis
treatment consisting of skin tissue that is used in wound management
debridement
the removal of dead skin and tissue
diabetic walker
aircasts to help relieve pressure on foot
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dorsal
pertaining to the back – in the case of the foot, the top of the foot
dyslipidaemia
abnormal lipid (fats, often known as cholesterol) levels
electrical stimulation
the use of electrical current to help increase blood flow, used in
wound management
foot protection programme
programme of care aimed at preventing/reducing foot problems,
includes for example, advice/instruction about hygiene, hosiery,
footwear/shoes and frequent chiropody clinic visits for provision of
chiropody services as well as advice/surveillance
can be provided by different health care professionals in different
settings
granulocyte-colony
stimulating factor (G-CSF)
treatment to help increase the production of a type of white blood cell
that help fight infections
growth factors
treatment to help stimulate and increase cell growth to help wound
healing
hallux
big toe
hammer toes
deformity of the toes (usually the second toe) where toes are bent at
an abnormal angle
hyperbaric oxygen therapy
treatment that uses oxygen to help wound healing, usually involves
person being place in a special room
ischaemia
decreased blood supply to body organ or part
ketanserin
treatment that improves blood supply to a wound which aids healing
macrovascular complications
related to the large blood vessels – complications include stroke and
myocardial infarction
microvascular
related to the small blood vessels – complications include diabetic
retinopathy
monofilaments
instrument used for testing foot sensitivity, a plastic bristle which
lightly touches the skin
multidisciplinary foot care
team
specialist team usually involving diabetologists, podiatrists, specialist
nurses, orthotists, surgeons and radiologists who manage severe foot
problems
neuropathy
damage/degeneration of the nerves, which can lead to loss of
sensation in the feet.
off-loading
the removal or reduction of pressure on the foot (or part of the foot) to
help healing or to prevent damage to the foot, usually involves
immobilisation of affected joint so that it can not bear weight
orthosis
system designed to affect/alter the forces on the foot to control,
correct or compensate for deformities, harmful forces etc – using
specially deigned insoles, shoes, shoe inserts, braces for example
orthotics
specialty concerned with the design, manufacture and fitting of
specialist footwear, leg braces etc
osteomyelitis
infection of the bone
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palpation
physical examination using the hands to feel the texture, size etc of
the part of the body being examined
peripheral vascular disease
the damage caused to large blood vessels supplying lower limbs, this
can result in poor circulation, which can result in pain and also
predispose to the development of foot ulcers
plantar
pertaining to the sole of the foot
plantar callus
callus on the sole of the foot
podiatry/podiatrist
specialty concerned with the foot (used interchangeably with
chiropody). A podiatrist is a health care professional who specialises
in the management of foot problems. In the UK, the terms podiatrist
and chiropodist are interchangeable, but podiatrist is the more modern
term. Following a three or four year degree course, podiatrists are
eligible for State Registration. State Registered podiatrists are
qualified to assess and diagnose, treat or refer onwards all disorders of
the foot or lower limb.
polymicrobial infection
infection with multiple types of bacteria/sources of infection
re-vascularisation
surgical procedure to repair or replace damaged blood vessels
SF-36
a questionnaire used to ask people about the impact any health
problems have on their life, including the way they feel
systemic antibiotic therapy
antibiotics given by injection or pill rather than an antibiotic
lotion/cream just applied to infected area
topical
applied to affected area only
Total contact casting
use of casts (eg plaster cast) to immobilise affected joints/part of foot
valgus
an abnormal bending or twisting outwards of part of a limb
varus
an abnormal bending or twisting inwards of part of a limb
vascular assessment
assessment of blood vessels including condition and blood flow
Veteran (also Veterans
Association, Veterans study)
pertaining to health care system in USA for ex-service personnel,
includes hospitals etc -–studies conducted in this system of
comprising patients in the system
vibration perception threshold
measurement to find out level of foot sensitivity
Wagner system
scale for measuring severity of foot ulcers
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Appendix 25 - Algorithm
The prevention and management of foot problems
191
On diagnosis of type 2 diabetes, and at annual review thereafter
♦
examine patient's feet and lower legs to detect risk factors – include:
♦
testing of foot sensation using 10 g monofilament or vibration
♦
palpation of foot pulses
♦
inspection for any foot deformity
♦
inspection of footwear
Is person at low current risk of foot ulcer?
(normal sensation, palpable pulses)
No
Yes
♦
♦
Does the individual have a foot ulcer?
No
Refer urgently to
multidisciplinary foot care team
Yes
after ulcer heals
Refer to foot protection team for classification
♦
♦
♦
Is person at high risk of foot ulcer?
(risk factor + deformity or skin changes or previous ulcer)
No
♦
♦
Yes
♦
Is person at increased risk of foot ulcer?
(neuropathy or absent pulses or other risk factor)
No
Yes
♦
♦
♦
Agree management plan including foot care education
♦
Arrange recall and annual review as part of ongoing care
Promptly refer patients who may benefit from revascularisation
Wound management:
♦ closely monitor wounds and change dressings regularly
♦ carefully remove dead tissue from foot ulcers (unless
revascularisation is required)
♦ use intensive systemic antibiotic therapy for non-healing or
progressive ulcers with clinical signs of active infection
Consider total contact casting (unless there is severe ischaemia)
Try to achieve optimal glucose levels and control of risk factors
for cardiovascular disease
Manage as ‘at high risk’ when ulcer is healed
Management and frequent review (1–3 monthly) by foot protection team
At each review
♦
inspect patient’s feet
♦
review need for vascular assessment
♦
evaluate provision of and provide appropriate
♦
intensified foot care education
♦
specialist footwear and insoles
♦
skin and nail care
Ensure special arrangements for access to foot protection team for those people
with disabilities or immobility
Management by foot protection team
Inspect patients’ feet 3–6 monthly
review need for vascular assessment
♦
evaluate footwear
♦
enhance foot care education
♦
IF NEW
♦
♦
♦
ulcer (wound)
swelling
discolouration
THEN REFER TO
♦
multidisciplinary foot care team
within 24 hours
IF SUSPECTED CHARCOT
OSTEOPATHY REFER TO:
♦
multidisciplinary foot care team
immediately for immobilisation
of the affected joint and longterm management of offloading
to prevent ulceration
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Appendix 26 – Patient education framework
The Guideline Development Group considered the issues of key points/topics that should be
covered in patient education, particularly from the viewpoint of what people with diabetes need to
know about foot care. The Group members recognised that that it was not possible to give
definitive answers in this area, but they produced a framework of key points that might provide a
useful starting point for healthcare professionals providing or developing education materials on
foot care for people with type 2 diabetes. This was developed from a consensus of the Guideline
Development Group rather than from research literature, which is not available.
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Patient education: key points to address
Education is an essential element in the empowerment of people with diabetes, helping an effective
partnership between healthcare professional and individual develop, which is key in achieving
effective care. Foot care should be considered an important part of self-care in people with
diabetes, and as much part of a self-care routine as blood glucose control or diet.
Patient education/information needs to be tailored to meet each individual’s needs. Some
individuals, because of their personal circumstances or attitudes to their condition, may need
increased levels of education, care and support.
A person with diabetes should expect to be offered information about the following:
♦
♦
♦
♦
♦
what they can expect in terms of care
self-care and self-monitoring
when and where to seek advice
♦ details of the healthcare professional to contact if an individual feels their condition has
changed and they need advice before their next routine appointment
♦ details of an alternative (out of hours) contact if an emergency arises (such as a new ulcer)
and the usual contact professional is not available
the possible consequences of neglecting the feet
management of symptoms (e.g. pain, odour from ulcers)
Other information about foot care and other aspects of diabetes should also be offered as needed.
Key points to be included in patient education
For all people with diabetes, and people at low current risk of foot ulcers
♦
self-care and self monitoring
♦ daily examination of feet for problems (colour change, swelling, breaks in the skin, pain or
numbness)
♦ footwear (the importance of well fitting shoes and hosiery)
♦ hygiene (daily washing and careful drying)
♦ nail care
♦ dangers associated with practices such as skin removal (including corn removal)
♦ methods to help self examination/monitoring (eg the use of mirrors if mobility is limited)
♦
when to seek advice from a healthcare professional
♦ if any colour change, swelling, breaks in the skin, pain or numbness is found
♦ if self-care and monitoring is not possible or difficult (eg because of reduced mobility)
♦
possible consequences of neglecting the feet
♦ foot problems can often be prevented by good diabetes overall management as well as
specific foot care
♦ prompt detection and management of any problems is important, thus the importance of
seeking help as soon as a problem is noticed
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♦
complications of diabetes such as neuropathy and ischaemia can lead to foot problems such
as ulcers, infections, and in extreme cases gangrene and amputation
For people at increased or high risk of foot ulcers
The key points to be addressed for all people with diabetes are still important and should be
addressed in patient education for people at increased/high risk of foot ulcers.
The following should also be addressed.
♦
if neuropathy is present, the resulting numbness means that problems may not be noticed, so
extra care and vigilance is needed and additional precautions to keep feet protected is needed
♦
every break in the skin is potentially serious
♦
not walking barefooted
♦
seeking help to deal with corns and calluses
♦
dangers associated with over the counter preparations for foot problems (eg the dangers of ‘corn
cures’)
♦
potential burning of numb feet
♦ checking bath temperatures
♦ avoiding hot water bottles, electric blankets, foot spas and sitting too close to fires
♦
moisturise areas of dry skin
♦
regular checking of footwear for areas that will cause friction or other problems
♦
seeking help from a healthcare professional if footwear causes difficulties or problems
♦
wearing specialist footwear if it has been prescribed/supplied
♦
additional advice about foot care on holiday
♦ not wearing new shoes
♦ planning adequate rest periods to avoid additional stress on feet
♦ when travelling by air, the importance of walking up and down aisles
♦ use of sun block on feet
♦ have a first aid kit and covering any sore places with a sterile dressing
♦ seeking help if problems develop
♦ holiday insurance issues (does it cover diabetes?)
For people with foot ulcers
The issues to be addressed for all people and those at increased or high risk should again be
covered.
The following issues should also be covered.
♦
every break in the skin is potentially serious
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♦
infection can develop with alarming rapidity
♦
early detection and rapid treatment improve the chances of a good outcome
♦
appropriate resting of foot/leg
♦
signs and symptoms that healthcare professionals involved in the management of a foot ulcer
should be told about
♦
changes in the ulcer
♦ increase in size
♦ colour
♦ redness of the skin round the ulcer
♦ bluish marks like bruises
♦ skin going black
♦ ulcer itself changed colour
♦ discharge
♦ ulcer wet where it was dry before
♦ blood or pus discharging from it
♦
new ulcers or blistering
♦
pain (ulcer becomes painful or uncomfortable or foot is throbbing)
♦
smell (ie foot smells strange/different)
♦
swelling (eg shoe becomes tight)
♦
feeling unwell (fever, ‘flu-like symptoms’ or poorly controlled diabetes)
197