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Clinical effectiveness of hemoglobin spray (Granulox ® ) as adjunctive therapy in the treatment of chronic diabetic foot ulcers

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Introduction Hemoglobin spray (Granulox®) comprises purified hemoglobin and is a novel approach for increasing oxygen availability in the wound bed in diabetic foot ulcer patients. Its mode of action is to bind oxygen from the atmosphere and diffuse it into the wound bed to accelerate wound healing in slow-healing wounds. Patients and methods Wound healing outcomes, that is, wound size, pain, percentage of slough, and exudate levels, were compared retrospectively to a similar cohort of patients treated over the same period the previous year. The same inclusion and exclusion criteria applied to both groups. Results All 20 (100%) hemoglobin spray-treated patients and 15 (75%) control patients experienced some wound healing by week 4, with 5 (25%) and 1 (5%), respectively, achieving complete wound closure. At week 4, mean wound size reduction was 63% in the hemoglobin spray group versus 26% for controls, increasing to 95% reduction at week 28 in the hemoglobin spray group versus 63% for controls (p<0.05 at all timepoints). Hemoglobin spray was associated with substantially lower pain scores using a 10-cm visual analogue scale, with 19/19 patients (100%) being pain-free from week 12 onwards, compared to 6/18 patients (33%) in the control group. At week 28, 2/18 patients (11%) in the control group still had pain. Both groups had similar baseline slough levels, but hemoglobin spray-treated wounds had slough completely eliminated after 4 weeks versus 10% mean reduction in the control group (p<0.001). Hemoglobin spray was associated with markedly reduced exudate levels; within 4 weeks, no patients had high exudate levels in the hemoglobin spray group versus 5 in the control group. Conclusion Standard wound care plus hemoglobin spray results in improvements in wound closure, wound size reduction, pain, slough, and exudate levels compared to control patients for chronic diabetic foot ulcer treatment.
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CLINICAL RESEARCH ARTICLE
Clinical effectiveness of hemoglobin spray (Granulox)
as adjunctive therapy in the treatment of chronic diabetic
foot ulcers
Sharon D. Hunt, RGN, Dip, BSc Hons, MA
1
* and
Fredrik Elg, PhLic, MSSc, MBA, BA, Dip Eng
2
1
Wellway Medical Group Northumberland, Berwick Upon Tweed, United Kingdom;
2
Pracipio Ltd, London,
United Kingdom
Introduction: Hemoglobin spray (Granulox) comprises purified hemoglobin and is a novel approach for
increasing oxygen availability in the wound bed in diabetic foot ulcer patients. Its mode of action is to bind
oxygen from the atmosphere and diffuse it into the wound bed to accelerate wound healing in slow-healing
wounds.
Patients and methods: Wound healing outcomes, that is, wound size, pain, percentage of slough, and exudate
levels, were compared retrospectively to a similar cohort of patients treated over the same period the previous
year. The same inclusion and exclusion criteria applied to both groups.
Results: All 20 (100%) hemoglobin spray-treated patients and 15 (75%) control patients experienced some
wound healing by week 4, with 5 (25%) and 1 (5%), respectively, achieving complete wound closure. At week
4, mean wound size reduction was 63% in the hemoglobin spraygroup versus 26% for controls, increasing to 95%
reduction at week 28 in the hemoglobin spray group versus 63% for controls (pB0.05 at all timepoints).
Hemoglobin spray was associatedwith substantially lower pain scores using a 10-cm visual analogue scale, with
19/19 patients (100%) being pain-free from week 12 onwards, compared to 6/18 patients (33%) in the control
group. At week 28, 2/18 patients (11%) in the control group still had pain. Both groups had similar baseline
slough levels, but hemoglobin spray-treatedwounds had slough completely eliminated after 4 weeks versus 10%
mean reduction in the control group (pB0.001). Hemoglobin spray was associated with markedly reduced
exudate levels; within 4 weeks, no patients had high exudate levels in the hemoglobin spray group versus 5 in the
control group.
Conclusion: Standard wound care plus hemoglobin spray results in improvements in wound closure, wound size
reduction, pain, slough, and exudate levels compared to control patients for chronic diabetic foot ulcer
treatment.
Keywords: diabetes-related complications;diabetic foot ulcer;hemoglobin;topical oxygen therapy;wound healing
*Correspondence to: Sharon D. Hunt, Wellway Medical Group Northumberland, Independent Specialist
Wound Care, 71 Ravensdowne, Berwick Upon Tweed, TD15 1DQ, United Kingdom, Email: Sharon.hunt
10@nhs.net
Received: 9 August 2016; Accepted: 8 October 2016; Published: 7 November 2016
It was estimated in 2000 that 2.8% of the worldwide
population had diabetes, and this is projected to
reach 4.4% of the population by 2030 (1). Diabetes is
a life-long condition, and sufferers may have to deal with
a range of associated short- or long-term complications
(2); furthermore, diabetic patients are at higher risk of
overall mortality (3). In an 11-year retrospective audit by
Chammas et al., results showed that patients with a
diabetic foot ulcer (DFU) have a greater than two-fold
increase in mortality compared with non-DFU diabetic
patients (3).
DFU is multifactorial and notoriously difficult to heal.
If left untreated, it can result in infection, extensive tissue
damage, amputation, and long-term disability (4). It is
estimated that around 10% of people with diabetes will
develop at least one DFU over their lifetime (5), and it
represents one of the most common reasons for admission
of a diabetic patient to a healthcare setting in the United
Kingdom (6). A report published by the NHS Diabetes
states that £650 million is spent in the United Kingdom
alone on treatment of DFU and associated amputations
each year (7).
DIABETIC
FOOT & ANKLE
Diabetic Foot & Ankle 2016. #2016 Sharon D. Hunt and Fredrik Elg. This is an Open Access article distributed under the termsof the Creative Commons Attribution-
NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
1
Citation: Diabetic Foot & Ankle 2016, 7: 33101 - http://dx.doi.org/10.3402/dfa.v7.33101
(page number not for citation purpose)
Oxygen is an essential component in the wound healing
process (8) and without it, wounds fail to heal. There is an
increased demand for oxygen in the healing of damaged
tissue, thereby enabling wound healing to progress effec-
tively; however, in patients with diabetes, the capacity for
vascular supply of oxygen is often greatly reduced due to
macro- and micro-angiopathy. Temporary hypoxia after
injury triggers wound healing by stimulating the release of
growth factors and angiogenesis, but persistent hypoxia
delays wound healing by increasing the levels of oxygen
free-radicals (9, 10). The resulting chronically oxygen-
depleted cells in these patients have devastating effects on
vulnerable tissue, often resulting in infection, wound
deterioration, disfigurement, and disability (11).
A topical hemoglobin contact spray (Granulox, infirst
Healthcare Ltd, London, UK) is a novel treatment that
accelerates healing in slow-healing wounds, including
DFU, and it was first approved for use in chronic wounds
in 2012. The active ingredient is purified hemoglobin, and
its mode of action is to bind oxygen from the atmosphere
and then release it into the wound bed by facilitating
diffusion (1216).
The safety and efficacy of this hemoglobin spray added
to standard wound care was initially evaluated in a wound
care clinic in a group of 20 patients presenting with chronic
(12 weeks) DFU. Patients received the standard wound
care regimen that they had received prior to entering the
evaluation, with the only variable being the addition of
hemoglobin spray. A preliminary analysis that was pub-
lished after 4 weeks showed that all wounds had positive
wound reduction, 25% had complete wound closure, and
no adverse events were reported (17). We now present the
wound healing outcomes for the same 20 DFU patients
after an extended 28-week period for the first time, and the
results have also been compared with a retrospective
patient cohort treated the previous year with standard
wound care alone, that is, before the introduction of
hemoglobin spray into the clinic.
Patients and methods
This evaluation was conducted in a single wound care
clinic in a large UK general hospital, with patients
recruited in February 2015 and followed for a 6-month
period (i.e. 28 weeks); control patients were retrospectively
selected from the same clinic and period in February 2014.
The evaluation was not conducted as a formal clinical
study, but data on the use of the hemoglobin spray and the
outcome of the wounds were collected by the wound care
nursing team as part of standard care and then compared
retrospectively to a similar cohort of patients, using the
same inclusion and exclusion criteria, over the same period
the previous year before the introduction of the hemoglo-
bin spray in the clinic. Ethics committee approval was not
required in line with the NHS Trust’s policy on clinical
evaluations of CE marked products used within their
licensed indications without randomisation. Patients were
required to give verbal consent following an explanation
and review of the product and information leaflet prior
to receiving the hemoglobin spray. This procedure was
documented by the clinician in the patient notes.
The same inclusion and exclusion criteria applied to
both patient cohorts. Inclusion criteria comprised patients
aged 18 years with DFU that had failed to heal sub-
stantially, defined as B40% reduction, in the last 12 weeks.
The DFU had to be located below the ankle and have a
Site, Ischemia, Neuropathy, Bacterial Infection, Area and
Depth (SINBAD) score of a maximum of 2 (Table 1).
The SINBAD classification system encompasses variables
that are recognised to contribute to ulcer outcome.
The maximum SINBAD score of 2 was selected for this
evaluation since patients scoring ]3 usually have vascular
insufficiency and other wound healing issues that would
impair the effectiveness of any wound healing product.
Patients were excluded if they presented with infected
ulcers, were receiving systemic antibiotic therapy or
corticosteroids, were pregnant or lactating, had an ankle-
brachial pressure index B0.5 or toe pressure B70 mmHg,
or a hemoglobin A1c (HbA1c) measurement 10% (13.3
mmol/L), in line with the recommendations for use in the
product label where underlying conditions should be
treated and all alternative options for revascularisation
of arterial insufficiency should have been exhausted.
A total of 20 patients who presented at the department
with chronic DFU for ]12 weeks who met the inclusion
criteria and who verbally consented to participation were
Tab l e 1 . The SINBAD system for classifying and scoring foot
ulcers
Category Definition
SINBAD
score
Site Forefoot 0
Midfoot and hindfoot 1
Ischemia Pedal blood flow intact, one
pulse palpable
0
Clinical evidence reduced
pedal blood flow
1
Neuropathy Protective sensation intact 0
Protective sensation lost 1
Bacterial infection None 0
Present 1
Area Ulcer B1cm
2
0
Ulcer 1cm
2
1
Depth Ulcer confined to skin and
subcutaneous tissue
0
Ulcer reaching muscle,
tendon, or deeper
1
Total possible score 06
Source: Adapted from Ince et al. (31).
Sharon D. Hunt and Fredrik Elg
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treated with standard wound care plus hemoglobin spray
and were monitored over 28 weeks. Each patient group
(i.e. both the hemoglobin spray group and the retro-
spective control group) was cared for in the same clinical
setting by the same medical team. The patients in the
hemoglobin spray group were also maintained on the
same dressing type they were using prior to the evalua-
tion. Patients were permitted to continue using off-
loading devices, such as surgical shoes or foam boots.
Debridement was carried out in both groups based on
medical need. The hemoglobin spray was applied in the
clinic by the wound care nurse twice a week until complete
wound closure, with dressings changed each time the
hemoglobin spray was applied. If required for appropriate
wound management, additional dressing changes and
spray applications were permitted.
Data regarding wound size and wound healing attri-
butes, including exudate levels, percentage of slough, and
pain levels, were collected by the same wound care team at
each dressing change using a standard data collection sheet
based on the applied wound management assessment
documentation, which is the standard wound care doc-
umentation used in the NHS Trust (18). Wound size was
measured using a disposable paper ruler. Pain levels were
evaluated using the McGill Pain Index for all patients who
reported suffering pain at baseline, with the pain levels
scored on a 10-cm visual analogue scale from 0 ‘No pain’
to 10‘Pain as bad as possible’. Data for the control
cohort were collected retrospectively from patient notes
from the same clinic during the same period the previous
year using the same inclusion and exclusion criteria and
using the same data collection form. The control group
were selected sequentially over the same time period the
previous year to ensure minimisation of sampling bias.
Statistical analysis
Statistics are reported using chi-square test for group-level
(nominal) data and unpaired two-tailed t-test for numeric
(parametric) values. Statistical significance was defined as
pB0.05. No adjustment for multiple statistical analyses
was made. The primary outcome was defined as wound
healing over 28 weeks.
Results
Patient disposition
A total of 40 patients were included in this evaluation: 20
patients in the hemoglobin spray group, and 20 in the
retrospective control group. Preliminary data up to week 4
from the 20 patients in the hemoglobin spray group were
reported previously (17). Small deviations from the pre-
viously published information are possible as all analyses
were re-conducted from current patient notes.
The mean age of the patients was 55.0 years in the
hemoglobin spray group and 54.4 years in the control
group (range from 18 to 89 years overall). In the hemo-
globin spray group, 50% of the patients were male, and in
the control group, 55% were male. The mean HbA1c was
7.0%/8.6 mmol/L in the hemoglobin spraygroup and 6.9%/
8.4 mmol/L in the control group (Table 2). Anatomical
sites for the DFU represented the common sites (19) for
these ulcers to occur, with the most common location being
plantar (hemoglobin spraygroup 40%; control group 50%)
(Table 3). The mean time for wounds being present prior to
the application of hemoglobin spray was 5.8 months com-
pared with 5.4 months in the control group. The mean
baseline wound size was slightly larger in the control group
at 6.6 cm
2
versus 5.1 cm
2
in the hemoglobin spray group
(p0.45) (Table 2). Eleven patients (55%) in each
group used a variety of off-loading devices to aid pressure
reduction, with the most common being a surgical shoe
(hemoglobin spraygroup 30%; control group 35%) (Table 3).
Overall there were no statistically significant differences
between the two groups at baseline for any of these
parameters (Table 2).
Tab l e 2 . Baseline data
Hemoglobin spray group
(N20)
Control group
(N20) p
a
Mean age (range), years 55.0 (1889) 54.4 (2685) 0.92
Gender (male/female), n10/10 11/9 0.75
Mean hemoglobin A1c at week 0,%/mmol/L 7.0%/8.6 mmol/L 6.9%/8.4 mmol/L 0.84
Mean wound size at week 0, cm
2b
5.1 6.6 0.45
SINBAD score (score 1/score 2) 8/12 8/12 1.0
Duration of wound at week 0 (range), months
b
5.8 (318) 5.4 (312) 0.72
Neuropathy present (Yes/No) 10/10 9/11 0.75
Ischemia
c
present (Yes/No) 9/11 8/12 0.75
a
pvalues for difference between the two groups, using chi-square for group-level data and independent two-tail t-test for numeric
variables.
b
Based on oval of L*W.
c
Vascular deficiency to foot.
Hemoglobin spray treatment for chronic diabetic foot ulcers
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Wound healing
All of the patients in the hemoglobin spraygroup had some
degree of wound healing by week 4, ranging from a
reduction of 18 to 100%, with a mean reduction of 63%,
and five patients (25%) had complete wound healing by
week 4. In the control group, 15 patients (75%) had some
degree of wound healing by week 4, with wound size
reduction ranging from 4 to 100%, with a mean reduction
of 26%, but only one patient achieved complete healing at
this timepoint, and five patients actually had an increase in
wound size (increase ranging from 10 to 108%). All of the
healed wounds in the hemoglobin spray-treated group at
week 4 were of the smallest wound size category (02cm
2
).
These patients also had a shorter duration of wound pre-
evaluation, were in a lower age range (except for one
patient), were free of neuropathy and vascular deficiency,
and had an HbA1c of 8% (10.1 mmol/L) or lower.
Similarly, the patient in the control group whose wound
healed within 4 weeks was non-neuropathic, had no
ischemia, was young (age 28), the wound had been present
for only 3 months and was of the smallest wound size
category (2 cm
2
) at baseline. None of the wounds that were
healed by week 4 recurred over the course of the 28-week
evaluation period.
After 28 weeks’ treatment, a total of 15 patients had
their wounds completely healed in the hemoglobin spray
group. Of the remaining five patients whose wounds had
not healed at this point, one patient had died due to a non-
wound-related cause, and three of the remaining four
patients had stopped the hemoglobin spray treatment
prematurely and then became static or worsening again
after achieving reductions in wound size of 68, 79, and
91%, respectively, with the hemoglobin spray treatment.
The remaining patient, a 76-year old with poorly con-
trolled diabetes, had achieved 95% wound size reduction at
28 weeks despite a relatively large foot ulcer measuring
3.81.5 cm at baseline and suffering from both neuro-
pathy and limb ischemia. In the control group at week 28, a
total of eight patients had their wounds completely healed.
One patient in this group also died due to a non-wound-
related cause, one patient underwent an amputation, six
patients had notably reduced wound sizes (65, 98, 96, 90,
56, and 37%), one patient’s wound had not changed, and
three patients had an increase in wound size (50, 33, and
33%).
A rapid reduction in overall wound size was seen in the
hemoglobin spray group compared with the control group.
By week 4, there was an average wound size reduction of
63% in the hemoglobin spray group versus 26% in the
control group (p0.03). By week 16, this had increased to
91% in the hemoglobin spray group compared with 43% in
the control group (p0.01), and this increased further to a
95% reduction in wound size at week 28 in the hemoglobin
spray group compared with a 63% reduction in the control
group (p0.02) (Fig. 1).
The number of wounds that had not healed by com-
pletion of the evaluation, that is, had not achieved full
epithelialisation by week 28, is shown in Fig. 2. A sig-
nificant difference was seen between the two groups at
week 9 (12 patients in the hemoglobin spray group with a
wound that had not healed (on intent-to-treat basis) com-
pared with 18 patients in the control group) (p0.04), and
by week 16 there was a 50% difference between the groups
in favour of hemoglobin spray (9 patients in the hemoglo-
bin spray group with a wound that had not healed com-
pared with 18 patients in the control group) (pB0.01).
By week 28, only five wounds in patients treated with
hemoglobin spray had not fully healed (one of whom had
died) compared with 12 in the control group (including one
death and one amputation) (p0.04) (Fig. 2).
Tab l e 3 . Wound location and off-loading devices
Hemoglobin spray group
(N20)
n(%)
Control group
(N20)
n(%)
Wound location
Plantar 8 (40) 10 (50)
Calcaneus 4 (20) 4 (20)
Hallux 4 (20) 3 (15)
Pedal 3 (15) 3 (15)
Phalanges 1 (5) 0
Total 20 20
Off-loading device
(number of patients)
None 9 (45) 9 (45)
Surgical shoe 6 (30) 7 (35)
Airboot 3 (15) 4 (20)
Foam boot 1 (5) 0
Heel cast 1 (5) 0
Total 20 20
–10%
–20%
–30%
–40%
–50%
–60%
–70%
–80%
–90%
–100%
0%
–26%
–63%
–39% –37%
–53%
–91%
–58%
–96% –96%
–63%
–95%
–43%
–89%
Control Haemoglobin spray
–78%
0481216202428
Fig. 1. Percent wound size change versus baseline by week.
Sharon D. Hunt and Fredrik Elg
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Pain assessment
Pain levels were evaluated for all patients who reported
suffering pain at baseline (16 patients in hemoglobin
spray group, 14 control patients). As some patients were
unable to feel any pain at all due to loss of sensation in
the feet, patients without any pain at baseline were not
included in the pain evaluation. Mean pain scores were
similar between the two groups at baseline (5.1 for both
groups). Hemoglobin spray treatment was associated
with substantially lower pain scores throughout the
evaluation period. By week 4, mean pain score in the
hemoglobin spray group was 0.3, and all patients were
completely pain-free from week 12 through to week 28.
In the control group, mean pain score was 3.5 at 4 weeks
(pB0.001 compared to the hemoglobin spray group),
at week 12, six patients still suffered from pain and these
six patients had a mean pain score of 3.7, and by week 28,
two patients still had a mean pain score of 4.0 (see Fig. 3
for mean pain scores by group).
Slough levels
All wounds in both groups had a similar degree of slough
present at baseline, with an average level of slough cover-
age of 50% in both groups (p0.99). Wounds in the
hemoglobin spray group rapidly achieved slough elimina-
tion over the course of treatment. After 4 weeks, all
patients treated with hemoglobin spray achieved complete
slough elimination, compared with only a 10% reduction in
the control group (pB0.001). After 24 weeks of treatment,
one patient in the hemoglobin spray group had recurrence
of slough in the wound, however this patient had stopped
using hemoglobin spray prematurely which may have
contributed to the slough recurrence, while in the control
group, presence of slough was still evident in four wounds,
with an average remaining slough coverage of 43% (see
Fig. 4 for mean slough coverage). As a result of the
superior wound healing, there was no debridement re-
quired in the hemoglobin spray group, with only basic
wound cleaning with saline needed, versus the requirement
for three cases of theatre surgeryand three cases of bedside
debridement in the control group.
Exudate levels
At baseline, 12 patients had a high level, 8 patients had a
moderate level, and 0 patients had a low level of exudate
in the hemoglobin spray group, whereas 9 patients had a
high level, 5 patients had a moderate level, and 6 patients
had a low level of exudate in the control group. By week
4, exudate levels demonstrated a significant reduction
across all patients in the hemoglobin spray group, with all
p=0.04
20
18
16
14
12
10
8
6
4
2
0
048
18 18
12
9
Topical Haemoglobin spray
Control
Max Delta:
Wound closure defined as complete wound epithelialisation
5
12
12 16 20 24 28
p=0.01
p=0.04
Fig. 2. Number of wounds not healed by week.
10
9
8
7
65.1 5.1
4.6
2.3
4.0
0.3
3.6 3.5
0.3 0.3 0.1
1.6
0.0 0.0 0.0 0.0 0.0
0.6
0.9 0.9
1.5
1.9
5
4
3
2
01234
Control Haemoglobin Spray
81216202428
1
0
Fig. 3. Average reported pain scores using a 10-cm visual analogue scale (VAS) by week.
Hemoglobin spray treatment for chronic diabetic foot ulcers
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12 patients with high levels of exudate at baseline being
reduced (100%), versus 4 out of 9 patients (44%) in the
control group. After 28 weeks of treatment, 0 patients
had high levels, 2 patients had moderate levels, 1 patient
had low levels, and 16 patients had no exudate or were
healed in the hemoglobin spray group, whereas in the
control group, 1 patient had persistent high exudate
levels, 5 had moderate and 4 had low levels, and 8
patients had no exudate or were healed (Fig. 5).
Safety
One patient in each group died; however, neither of the
deaths was related to the wounds or to use of hemoglobin
spray. There were an additional nine events in the control
group, but no further events in the hemoglobin spray
group. The events in the control group comprised one
amputation, three unplanned surgeries for wound debri-
dement requiring treatment in a surgical theatre, and five
cases of wounds that were infected and required anti-
biotic treatment (in four of the patients).
Discussion
DFUs are extremely debilitating for patients and are
difficult to treat for clinicians (20). DFUs are a worldwide
problem and a major cause of morbidity in diabetic
patients, in particular, ulcerations and amputations (21,
22). Standard care generally comprises a multidisciplin-
ary approach, but more recently, adjunctive therapies,
such as aided oxygenation, represent new treatment
modalities, although there has been criticism that many
lack significant high-powered studies to support their use
as standard of care (20).
Local oxygen delivery is a crucial element in wound
healing, and it is widely recognised that limited oxygena-
tion can lead to a chronic non-healing ulcer (23). Wound
tissue requires a constant supply of oxygen to meet the
increased metabolic demands of the wound healing
process (24, 25). Hypoxic tissue cannot regenerate and
is unable to move along the wound healing stages of
inflammation, proliferation, and maturation (24), so it
remains in the inflammatory stage, thereby increasing the
risk of bacterial infection and tissue disfiguration (26).
However, the body’s tissues have no capacity for retaining
oxygen molecules and, therefore, require a consistent
oxygen delivery if wound healing is to occur effectively
(27). Topical oxygenation can be delivered as pure
oxygen, either under pressurised or ambient conditions,
through chemical release via an enzymatic reaction, or by
facilitated diffusion using oxygen binding and releasing
molecules, for example, using hemoglobin (12). Topical
hemoglobin treatment permits hemoglobin-mediated
oxygen diffusion within the aqueous medium naturally
present within the wound bed (13).
A novel adjunctive therapy developed to accelerate
healing in slow-healing wounds by improving oxygena-
tion is a topical hemoglobin spray (Granulox) that acts
as an oxygen transporter from surrounding air to
0
0%
10%
20%
30%
40%
50% 50%50%
60%
48%
13%
2%
44%
39%
1% 0%
24%
0%
19%
0% 0%
14%
11%
1%
9%
1%
0%
17%
40%
123481216202428
Control Haemoglobin Spray
Fig. 4. Average percent wound coverage with slough by week.
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Wk0 Wk8 Wk28Wk4
Haemoglobin Spray
High Moderate Low None/Healed
Control
Wk0 Wk8 Wk28Wk4
Fig. 5. Level of wound exudate by week.
Sharon D. Hunt and Fredrik Elg
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improve oxygen availability in the wound bed. However,
the studies to date have not been aimed specifically at
DFUs, and this lack of wound-specific data is considered
by some to be insufficient to evaluate improvements in
wound healing (28). In an attempt to address this point,
this controlled evaluation was conducted to investigate
the use of a topical hemoglobin spray when added to
standard wound care regimens in an acute setting in
patients who presented specifically with chronic DFU,
despite having previously received best practice wound
care according to NICE NG19 guidelines (5). A retro-
spective control group was selected from the same clinical
setting over the same period in the previous year to
provide a comparison. This ensured all other elements of
care remained constant so that the clinician could
observe any difference after the introduction of hemo-
globin spray as an adjunctive therapy to the usual care
regimen. Baseline characteristics were similar between the
two groups, and it is noted that all patients were assessed
at baseline using the SINBAD foot ulcer classification
system, which is considered a valuable universal tool for
predicting ulcer outcome.
Throughout the evaluation, a rapid reduction in wound
size was seen in the hemoglobin spray group compared
with the control group. This was evident as early as the first
week, and by week 4 where there was an average wound size
reduction of 63% in the hemoglobin spray group versus
26% in the control group. This increased further to a mean
95% reduction in wound size at week 28 in the hemoglobin
spray group compared with a mean wound healing
reduction of 63% for control. By week 28, only five wounds
in patients treated with hemoglobin spray had not fully
healed, compared with 12 in the control group (p0.04).
As expected, those patients with a shorter duration of
wound pre-evaluation, small wounds, in the younger age
bracket, and free from neuropathy and vascular deficiency
saw the most rapidwound healing benefits. It is of note that
there were more small wounds B2cm
2
in the hemoglobin
spray group, however, the average size and distribution of
wound sizes at baseline between the two groups were not
statistically significantly different.
Mean pain scores also decreased to a greater extent in
the hemoglobin spray patients compared with the control
patients, and there was also a notable reduction in slough
levels. The number of patients with a significant reduction
in exudate levels was also greater in the hemoglobin spray
group, thus indicating that all measured wound healing
parameters were improved with the use of the topical
hemoglobin spray. The long-term data reported here after
28 weeks follow-up support the initial 4-week data
previously published (17) and indicates substantially
improved healing outcomes with hemoglobin spray
compared to standard care alone. Furthermore, the
results of this evaluation support the findings from other
controlled studies using hemoglobin spray on lower limb
wounds (13, 14). A number of recent UK case series
evaluations investigating chronic ulcers have also shown
the effectiveness of hemoglobin spray in promoting
healing (15, 16, 29). Also in the author’s experience, the
results from this evaluation are representative of the
overall picture seen in the clinic with the continued use of
the hemoglobin spray, with repetitive themes of pain
reduction in approximately 80% of patients, and slough
and exudate reduction in most patients by week 4.
Patients find the hemoglobin spray easy to use, and the
positive effects are seen regardless of the wound pre-
sentation or the type of dressing used.
The results of our evaluation and other investigations
into DFU management, thus, demonstrate that when
hemoglobin spray is added to standard wound care, it
confers significant benefits in terms of wound closure,
wound size reduction, pain reduction, improvements in
visible presence of slough and exudate levels. However, it
is very important that hemoglobin spray treatment is
continued until full wound closure is achieved as
premature discontinuation can result in relapse, as
indicated by the patients in this evaluation who stopped
treatment with hemoglobin spray prematurely and
subsequently stagnated or worsened. Also, despite its
obvious benefits, there are some limiting factors asso-
ciated with the use of hemoglobin spray, and it is
important that best possible conditions should be met
prior to its use (23). For example, it is deemed unsuitable
for use with certain disinfectants, such as octenidine,
as these may impair its effectiveness, and it should not
be used in those patients who are pregnant or lactating.
Also the underlying disease conditions, notably diabetes
and peripheral vascular disease should be treated
appropriately.
In addition, there are a number of limitations that
should be addressed in future research in this field. This
evaluation was not conducted as a formal randomised
clinical study, since data on the use of the hemoglobin
spray and the outcome of the wounds was collected by
the wound care nursing team as part of standard care
and then compared retrospectively to a similar cohort
of patients treated over the same period the previous year.
A formal randomised clinical study may provide more
robust results and may reduce any potential bias caused
by a Hawthorne effect, that is, where the participation in
the evaluation itself has a positive impact on the outcome.
Also the patients included in this evaluation represented
only a small subset of patients who require treatment
for chronic DFU. Furthermore, there was no investiga-
tion into whether these wounds would have healed even
faster if the hemoglobin spray had been applied more
frequently.
In conclusion, the results of this 28-week evaluation of
DFU patients are positive and support the addition of
hemoglobin spray to standard DFU wound care regimens.
Hemoglobin spray treatment for chronic diabetic foot ulcers
Citation: Diabetic Foot & Ankle 2016, 7: 33101 - http://dx.doi.org/10.3402/dfa.v7.33101 7
(page number not for citation purpose)
This conclusion concurs with the consensus recommenda-
tions developed by Chadwick et al. in which a working
group of key opinion leaders met in 2015 to determine the
potential role of topical hemoglobin in non-healing
wounds and to develop a clear decision-making pathway
for clinical practice (30). The guidelines state that topical
hemoglobin should be considered after 24 weeks of
standard care in patients with a non-healing wound, and
potentially earlier for patients at high risk of delayed
wound healing (30). However, it should be recognised that
DFU prevention and management must be individualised
and conducted using a multidisciplinary approach that
includes effective patient education, accurate assessment,
and diagnosis of underlying conditions, as well as effective
management, planning, and re-evaluation (19). Develop-
ment of user-friendly innovative wound management
therapies is important for effective future treatment, and
the results of this investigation could be used to inform the
design of other methodologically robust studies in the
wider field of wound management in real-world practice.
Acknowledgements
The authors would like to acknowledge the help of Dr
Sandip Sarkar for his review of this manuscript and for
his technical advice. Medical writing support was pro-
vided by Debbie Jordan Ltd, with funding from infirst
Healthcare.
Conflict of interest and funding
Sharon Hunt and Fredrik Elg provide advisory and speaking
services to pharmaceutical and other healthcare organisa-
tions, including but not limited to, infirst Healthcare Ltd.
infirst Healthcare provided the hemoglobin spray free of
charge to the study centre but did not haveany influence on the
design of the evaluation or the collection of the data. infirst
Healthcare also provided financial support for data manage-
ment, statistical analysis, and medical writing to help the
authors publish the results of this evaluation.
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... In a wound, there is increased metabolism for healing, and thus an increased need for oxygen. [1,2] Oxygen has multiple roles in the woundhealing process as part of the adenosine triphosphate energy cycle in the mitochondria. A contributing factor towards a failure of acute wounds to heal, and their development into chronic wounds, is decreased oxygen supply to the affected tissue. ...
... [2] Local wound hypoxia can be addressed through several methods: hyperbaric oxygen chambers; local oxygen delivery systems that are either partly or not pressurised; or oxygencontaining dressings or haemoglobin containing spray to increase local oxygen delivery. [1] Currently there is a commercial porcinederived haemoglobincontaining spray on the South African (SA) market called Granulox. Granulox was introduced to the SA market ~2 years ago, but was first approved for use on wounds in 2012. ...
... [2] It has been proven to accelerate wound healing in different chronic wound types: diabetic foot ulcers; pressure ulcers; and chronic venous stasis ulcers. [1] The benefits of Granulox are that it accelerates wound healing, is safe and is associated with reduced pain, slough and exudate. [1] In addition to being effective, it has also been shown to decrease overall cost. ...
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The effect of pressure ulcers on patient quality of life have been recognised as a real problem for many years, and the need for robust and effective management of pressure ulcers is now a prominent national health-care issue. Myriad different interventions exist for the treatment of pressure ulcers, including clinically effective dressings and pressure-relieving devices, yet many pressure ulcers still do not heal and often become a chronic wound. This is the second of a series of articles ( Norris, 2014 ) discussing the clinical evaluation of a topical oxygen therapy in practice. It describes a small evaluation involving 18 patients with pressure ulcers. The study set out to determine the effect of a topical oxygen therapy on wound size. The therapy comprises a canister that sprays pure haemoglobin in a water solution into or onto the wound. The haemoglobin spray needs to be used at least once every 3 days, does not require training on its use and can be used in any care setting. Overall, results identified wound healing progression in all 18 wounds and wound size reduction in 17 of the 18 wounds.
Article
Unlabelled: Chronic wounds are an increasing problem in our ageing population and can arise in many different ways. Over the past decades it has become evident that sufficient oxygen supply is an essential factor of appropriate wound healing. Sustained oxygen deficit has a detrimental impact on wound healing, especially for patients with chronic wounds. This has been proven for wounds associated with peripheral arterial occlusive disease (PAOD) and diabetic foot ulcers (particularly in combination with PAOD). However, this is still under debate for other primary diseases. In the past few years several different new therapeutic approaches for topical oxygen therapies have been developed to support wound healing. These tend to fall into one of four categories: (1) delivery of pure oxygen either under pressurised or (2) ambient condition, (3) chemical release of oxygen via an enzymatic reaction or (4) increase of oxygen by facilitated diffusion using oxygen binding and releasing molecules. In this review article, the available therapeutic topical oxygen-delivering approaches and their impact on wound healing are presented and critically discussed. A summary of clinical data, daily treatment recommendations and practicability is provided. Declaration of interest: J. Dissemond received an honorarium for lectures, advisory boards and/or clinical studies from the following companies: 3M, B. Braun, BSN, Coloplast, Convatec, Draco, Hartmann, KCI, Lohmann&Rauscher, Medoderm, Merz, Sastomed, Systagenix, UCB-Pharma, Urgo. K. Kröger received an honorarium for lectures, advisory boards and/or clinical studies from the following companies: Bayer, Sanofi, GSK, Hartmann, Sastomed, UCB-Pharma, Urgo. M. Storck received an honorarium for lectures for the following companies: KCI, Systagenix, and UCB-Pharma. A. Risse received an honorarium for lectures, advisory boards and/or clinical studies from the following companies: Bracco, Coloplast, Draco, Lilly Deutschland, NovoNordisk, Sastomed, Urgo. P. Engels received an honorarium for lectures, and consulting from the following companies: Sastomed, Oculus.
Article
Acute wounds will generally heal independently of any interventions, whereas chronic wounds are chronic for a reason and are unlikely to successfully heal without intervention. In the treatment of venous leg ulcers, the gold standard will always be compression therapy. However, many wounds still do not heal despite best practice. Therefore, the use of adjunct therapies alongside standard care become the priority for healing. This article describes a small evaluation, involving 17 patients with chronic venous leg ulcers, that set out to determine the effect of a topical oxygen therapy on wound size. The therapy comprises a canister that sprays pure haemoglobin in a water solution into the wound. The haemoglobin spray needs to be used at least once every 3 days, and no training is required on its use. Results showed the device helped promote wound healing in 14 out of 17 wounds treated for more than 2 weeks. These patients had previously been shown to be non-healing during a 4-week run-in period where they received standard care, including compression therapy.