Hirsh et al., Page 1
Transdermal Oxygen Delivery to Diabetic Wounds: A
Report of 6 Cases
Fred Hirsh, M.D.1, Steven J. Berlin, D.P.M.2, Aliza Holtz, Ph.D.3
1Private
Practice; Associate Clinical Professor of Dermatology, Case Western
Reserve University School of Medicine, Cleveland, OH;
2
Consulting Podiatrist,
President of Podiatric Pathology & Surgical Consulting Services, , Baltimore, MD;
3Biomedical
Consultant., Ogenix Corporation, Beachwood, Ohio; Principal, Holtz
Communications, Inc., New York, NY
Corresponding Author:
Fred Hirsh, M.D.
6551 Wilson Mills Rd, Suite 101
Mayfield Village, OH 44143
Telephone: (440) 460-2884
Fax: (440) 473-6407
e-mail: fshirsh@roadrunner.com
Transdermal Oxygen to Diabetic Wounds: 6 Cases
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Abstract
Objective
To evaluate the use of a transdermal sustained oxygen delivery (TSOT) system
to promote the healing of chronic lower extremity wounds in patients with
diabetes.
Six patients (5M, 1F; 32-77 years old) with diabetes and chronic lower extremity
wounds unresponsive to prior multimodal therapy were treated with transdermal
sustained oxygen. The transdermal sustained oxygen delivery device
(EpiFLOSD; Ogenix Corporation, Cleveland, Ohio) delivered 100% oxygen at 3
mL/hr with ambient humidity, 24 hr/day directly to the wound site which was
covered by an occlusive dressing.
Despite chronicity of wounds (aged 4 months to more than 15 years) and
nonresponsiveness to previous treatments, all wounds in this case series treated
with transdermal sustained oxygen therapy improved within 2 to 20 weeks, within
which time 5 of the 6 wounds had healed completely. In two cases scheduled
amputation were prevented.
The results of the six cases reported here strongly support the use of
transdermal sustained oxygen therapy in promoting the healing of diabetic foot
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and leg ulcers refractory to previous treatments. In addition, amputation was
prevented in two cases, thus reducing prolonged costly patient care!
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Introduction
The National Health Interview Survey (NHIS) of 2003 estimated that the total
prevalence of diabetes in the U.S. for all ages is 20.8 million people (7.0% of the
population as a whole).1 Of these, an estimated 15% will develop foot ulcers
during their lifetimes.2 More than 15% of foot ulcers result in amputation of the
foot or limb,3 and foot ulcers precede approximately 85% of nontraumatic lowerlimb amputations in people with diabetes.4 In 2004, approximately 71,000
nontraumatic lower-limb amputations were performed in people with diabetes.5
In fiscal year 1992 under DRG reimbursement code 271 (skin ulcer) the average
Medicare claim for inpatient care for foot ulcers was $10,171, and Medicare
received 23,352 such claims.4 (These numbers do not include private insurance
claims). In a 3-year (1993-1995) retrospective cohort study of patients with
diabetes in a staff-model health maintenance organization, Ramsey et al.3
observed a cumulative incidence of foot ulcer of 5.8%, and determined that, for
the 2 years following diagnosis, the attributable cost for a 40-to-60-year-old male
with a new foot ulcer was $27,9876 The Undersea and Hyperbaric Medical
Society's 1999 Committee Report states the cost of treating non-healing lower
extremity diabetic ulcers totals more than $200 million annually. Gordois et al.7
determined that in 2001 the mean annual cost of treating an uninfected diabetic
foot ulcer was $9,306, whereas that of treating an infected foot ulcer was
$24,582, and that of a foot ulcer with osteomyelitis was $45,579. In the United
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States, the average hospitalization cost: $31,264; average amputation cost:
$40,000; estimated Total (excluding rehabilitation and related medical and
surgical disability care): $71,264; with an average of $30,000 for rehabilitation,
the total cost is: $ 101,264.
In a study of anatomic, pathophysiologic, and environmental factors contributing
to the development of incident diabetic foot ulcers, Reiber et al.8 determined that
the most common components of a patient’s causal pathway to foot ulcers were
neuropathy (78%), minor traumatic event (77%), and foot deformity (63%),
followed by edema (37%), ischemia (35%), and callus formation (30%).
Foot ulcers may become chronic, non-healing wounds. Often painful, they
always require vigilant attention to prevent infection. Because foot and leg ulcers
precede amputations in a majority of instances, the importance of promoting
wound healing cannot be overstated, and the need for therapeutically effective
and cost-effective measures for the prevention and treatment of diabetic foot
ulcers is self-evident.
Oxygen has long been recognized as having an important role in wound healing,
and much research in recent years has been aimed at elucidating this role at the
cellular and molecular levels.9
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The recent development of a self-contained miniature device (EpiFLO®) that
delivers transdermal oxygen therapy directly to the wound bed has made it
possible for some patients to remain ambulatory while receiving oxygen therapy
at the site of the ulcer (in contrast to the confinement and intermittent exposure
associated with the use of a hyperbaric oxygen chamber or being attached to an
oxygen tank to get topical oxygen therapy).
The following are six case reports of chronic lower limb wounds in patients with
diabetes who were treated with transdermal sustained oxygen therapy (TSOT) to
promote wound healing.
Methods
Oxygen was delivered to the wound via a small, self-contained device (EpiFLOSD,
Ogenix Corporation, Cleveland, Ohio) that produces 100% O2 at 3 mL/h
continuously by means of a battery-driven electrochemical reaction. A sterile
cannula leading from the device to the wound site which is covered by an
occlusive dressing provides direct delivery of oxygen to the wound at ambient
humidity 24 hours a day. The device is a single-patient, single-use, 7-day or 15day disposable apparatus.
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Case Reports
Case 1
A 77-year-old white male with diabetes presented with a 5-month-old neuropathic
foot ulcer (2.5 cm long x 2.5 cm wide x 1 cm deep) with osteomyelitis. The
patient had a prior history of two toe amputations because of wounds. Belowthe-knee amputation was planned because previous therapies, including
revascularization of area had failed. Fifteen weeks after the initiation of TSOT
(EpiFLOSD ), the osteomyelitis was resolved and the wound had closed
completely.10
Case 2
A 74-year-old male with insulin-dependent diabetes with a history of renal failure
was undergoing dialysis at the time of presentation. In addition to severe leg
edema, he had a 48-week-old open weeping ulcer (72 x 80 x 2 mm) on the left
lower extremity (Figure 2A). The ulcer had progressed and enlarged during the
previous 12 months despite multimodal treatment (silver nitrate, topical and
systemic antibiotics, and Ace wrap). Treatment with TSOT (EpiFLOSD ) was
initiated and continued until the wound closed. One week after initiation of TSOT
treatment, excellent granulation tissue and early re-epithelialization were
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observed and the patient reported less pain. At Week 2, re-epithelialization
tissue had improved significantly and the wound dimensions had decreased.
The wound was covered with DuoDERM® (ConvaTec). At Week 3 the wound
had almost closed (wound dimensions had decreased from 60 x 100 x 1 mm at
Week 1 to 15 x 10 x 1 mm at Week 3) (Figure 2B). Twice during Week 3 the
EpiFLOSD canula was temporarily dislodged, but this did not negatively influence
the overall healing. After 4 weeks of treatment, the wound had completely
closed.
Case 3
A 68-year-old female with a 15-year history of diabetes had a fairly painful ulcer
on the dorsum of the foot that remained open with no evidence of healing despite
multimodal treatments. The lesion was nonpurulent, had no odor, and had been
stable for 12 years, measuring 60 x 60 x 3 mm (Figure 3A). One week after the
initiation of TSOT (EpiFLOSD ) treatment, a large amount of exudate was noted,
as was increased bleeding on debridement, but there was no change in the size
of the lesion.
During weeks 2-8, persistent drainage and a foul-smelling
discharge were noted, but the wound never became infected. The lesion was
healing slowly and steadily, measuring 40 x 40 x 2 mm at Week 8. At Week 9,
the lesion was fully granulated, drainage was minimal, and the depth of the
wound decreased to 0.5 mm. The pain had completely resolved during this
period. Extensive re-epithelialization was observed at Week 10 and the lesion
was reduced to 10 x 15 x 0.0 mm (Figure 3B). Our data extend through only
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Hirsh et al., Page 9
Week 10 because the patient suddenly expired before the wound completely
healed.
Case 4
A 32-year-old male with diabetes had an ulcer (4 x 4 x 2 mm) with 100% red
granulation tissue and macerated edges on the plantar aspect of the left great
toe (Figure 4A). The wound had been open for 6 months. Prior treatment
included wet to dry therapy with iodine gel to control infection and absorb the
wound exudate. One week after EpiFLOSD treatment, the wound was reduced to
pinpoint size (1 x 1 x 0 mm), and after two weeks, the ulcer was completely
closed and healed (Figure 4B).
Case 5
A 50-year-old female with diabetes mellitus had two neuropathic ulcers that had
not healed for 24 months, one 3.5 cm x 1.8 cm x 1.5 cm on the right plantar foot
and the other 3.8 cm x 1.2 cm x 0.8 cm on the right medial foot (Fig 5A). Prior to
presenting at the wound care clinic, the patient had been hospitalized, received
antibiotic therapy and debridement. The patient was treated with TSOT only for
the wound on the right medial foot ;for the next eight weeks, dressings being
changed QOD as necessary depending on drainage and then weekly until
healed. The TSOT treated wound healed in 8 weeks (Fig 5B). The wound on
the right plantar foot did not receive TSOT, but received regular dressing
changes. This wound healed in two weeks. It appears the TSOT treatment on
the right medial foot wound had beneficial spill-over effects on the wound on the
right plantar foot.
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Case 6
A 54-year-old male with diabetes and a deformed Charcot foot had a 4-month-old
foot ulcer (8.0 cm x 6.0 cm x 0.8 cm on presentation) on the left plantar aspect of
the heel area of the left foot (Fig 6A) as well as another wound on the lateral
distal aspect of the left foot in an area where toes had been amputated. The
treatment history of the left plantar wound consisted of wet to dry dressings for
several months prior to TSOT (EpiFLOSD).. A scheduled amputation was
anticipated, but delayed for a trial of TSOT. The oxygen therapy closed the
chronic ulcer in 20 weeks (Fig 6B) and amputation was cancelled..
Results
A summary of the six case reports is presented in Table 1. Despite the chronic
nature of the wounds (aged 4 months to more than 15 years) and their nonresponsiveness to previous treatments, all wounds in this case series treated
with TSOT responded within 2 to 20 weeks, within which time 5 of the 6 wounds
had healed completely. In two cases scheduled amputations were cancelled. In
all cases, an occlusive form of dressing was applied to enhance the oxygen
therapy and the treatment was well-tolerated and without complications. Due to
the nature of this therapy, none of the patients were restricted in any fashion.
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Discussion
The results presented in each of the six case reports above demonstrate the
efficacy and safety of EpiFLOSD, a transdermal sustained oxygen delivery
system, in promoting wound healing in instances of recalcitrant wounds despite
prior multimodal efforts to help them heal.
In a study by Oyibo et al.,11 the area of a foot ulcer at presentation was correlated
with healing time and also predicted healing of the ulcer in diabetic patients with
new foot ulcers. These investigators showed also that the presence of ischemia
was a predictor of nonhealing, and, as would be expected, neuroischemic ulcers
and infected ulcers took longer to heal than those without these confounding
factors. Age, sex, type of diabetes, duration of diabetes at presentation, and site
of foot ulcer did not influence the outcome of diabetic foot ulcers.
In their study of the outcomes of diabetic foot ulcers after 6 to 12 months in 194
patients who presented with new foot ulcers, Oyibo et al. found that the median
(interquartile range; IQR) ulcer area in patients whose ulcers healed was 1.1
(0.5-2.6) cm2 whereas the median (IQR) ulcer area in patients whose ulcers did
not heal was 1.4 (0.7-3.5) cm2. Median (IQR) ulcer areas of 3.9 (1.4-5.4) cm2
were associated with amputation.11
If ulcer area according to Oyibo et al.11 had been used as a predictor of healing in
our cases, only one of the six would have been predicted to heal, and the other
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five would have been predicted to have led to amputation. However, our cases
demonstrate that sustained transdermal oxygen therapy promoted healing even
in ulcers refractory to various previous therapies and with areas as large as 58
cm2, and that the healing occurred within.2 to 20 weeks. In fact, amputations
had been scheduled for two of the cases but were cancelled because of the
healing. Treating physicians noted that within approximately 1 to 2 weeks of
initiation of the use of EpiFLOSD, the wounds produced an exudate, and this was
followed by the process of epithelialization.
A recent animal study demonstrated improved epithelial healing in a rabbit ear
wound model using the same transdermal sustained oxygen delivery device. 9
The results of the animal study as well as the observations noted in the current
case reports suggest that transdermal sustained oxygen delivery promotes
epithelial wound healing in cases of leg and foot ulcers in patients with diabetes.
If further research with transdermal sustained oxygen therapy in diabetic and
other chronic—and possibly also acute—wounds yields similar results, it is likely
that the physical and economic burdens of at least some of the complications of
diabetes will be mitigated.
It is reasonable to assume from the results presented here that the costs of
treatment of diabetic leg ulcers in this case series were decreased with the use of
EpiFLOSD compared to the probable costs of continued treatment of recalcitrant
wounds or to the costs of amputation and follow-up care. EpiFLOSD can be up to
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Hirsh et al., Page 13
50% less costly than other advanced wound care therapies when comparing the
device cost to that of other devices and treatments. Randomized controlled trials
currently under way will capture health econometric data—including other costs
such as nursing time, dressings and other components—and further the cost
benefit analysis over the entire episode.
Conclusion
The results of the six cases reported here provide strong support for the use of
transdermal sustained oxygen therapy in promoting the healing of diabetic foot
and leg ulcers that were refractory to other prior treatments. Large wound areas
(up to 58 cm2) that would have been predicted not to heal and amputation may
have been necessary were healed within 20 weeks of initiation of transdermal
sustained oxygen therapy, and in two cases, scheduled amputations was
cancelled. The healing ability of a continuous oxygen therapy device
(EpiFLOSD) has shown to reduce the amputation potential in healing chronic
wounds and has also shown that the continuous flow of oxygen has also
eliminated pain associated with such wounds. It is reasonable to assume that
Transdermal Sustained Oxygen Therapy can reduce the financial burden of
chronic diabetic ulcers.
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Acknowledgments
We thank Alan Hirsh, M.D., Alex Hirsh, M.D., Scott Hirsh, D.P.M., Philibert Fluck,
PT, and David Skrobot, D.P.M. for providing the data and photographs from their
cases and for their assistance in reviewing the manuscript.
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References
1.
Harris MI. Chapter 1: Summary. In: Diabetes in America. 2nd ed: National
Diabetes Data Group, National Institutes of Health, National Institute of Diabetes
and Digestive and Kidney Diseases, NIH Publication No. 95–1468; 1995. p. 1-14.
2.
Palumbo PJ, Melton LJ. Peripheral vascular disease and diabetes. In:
Harris MI, Hamman RF, editors. Diabetes in America. Washington, DC: U.S.
Government Printing Office, NIH publication no. 85-1468; 1985. p. XV 1-21.
3.
Ramsey S, Newton K, Blough D, et al. Incidence, outcomes and cost of
foot ulcers in patients with diabetes. Diabetes Care 1999;22:382-387.
4.
Reiber GE, Boyko EJ, Smith DG. Chapter 18. Lower extremity foot ulcers
and amputations in diabetes. In: Diabetes in America. 2nd ed: National Diabetes
Data Group, National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases. NIH Publication No. 95-1468; 1995. p. 409-428.
5.
National Institute of Diabetes and Digestive and Kidney Diseases.
National Diabetes Statistics Fact Sheet: general information and national
estimates on diabetes in the United States, 2003. Bethesda, MD: U.S.
Department of Health and Human Services, National Institute of Health, 2003.
Rev. ed. Bethesda, MD: U.S. Department of Health and Human Services,
National Institute of Health, 2007. NIH Publication No. 08-3892; 2008 June.
6.
Mackey WC, McCullough JL, Conlon TP, et al. The costs of surgery for
limb-threatening ischemia. Surgery 1986;99(1):26-35.
7.
Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The Health
Care Costs of Diabetic Peripheral Neuropathy in the U.S. Diabetes Care
2003;26(6):1790-1795.
8.
Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident
lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care
1999;22(1):157-62.
9.
Said HK, Hijjawi J, Roy N, Mogford J, Mustoe T. Transdermal sustaineddelivery oxygen improves epithelial healing in a rabbit ear wound model. Arch
Surg 2005;140(10):998-1004.
10.
Wilson C, Hirsh S, Hirsh A, Burk M. Transdermal, Sustained Oxygen
Therapy Promotes Healing of a Diabetic Foot Ulcer in a Patient with
Osteomyelitis – A Case Report. Wound Healing Society Annual Meeting.
Chicago; 2005 (Poster presentation).
11.
Oyibo SO, Jude EB, Tarawneh I, et al. The effects of ulcer size and site,
patient's age, sex and type and duration of diabetes on the outcome of diabetic
foot ulcers. Diabetic Medicine 2001;18(2):133-138.
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Table
Table 1. Summary of Cases
Cas
e
No.
1
M/F
Patient Age
M
77
5 months
2.5 cm x 2.5 cm x 1 cm
6.25 cm2
Time to heal
with
EpiFLO(SD)
15 weeks
2
M
74
48 weeks
7.2 cm x 8.0 cm x 0.2 cm
57.6 cm2
4 weeks
Yes
3
F
68
12 years
6.0 cm x 6.0 cm x 0.3 cm
36 cm2
No
4
M
32
6 months
0.4 cm x 0.4 cm x 0.2 cm
0.2 cm2
Extensive
epithelialization
& reduction of
lesion to 10
mm x 15 mm x
0 mm at 10
weeks
2 weeks
2 weeks
(dressing
changes only;
no EpiFLO)
8 weeks
No
20 weeks
(EpiFLO
treatment from
Weeks 6 to 26)
Yes
5
6
F
M
50
54
Wound Age
Wound size
Wound area
cm2
24 months
3.5 cm x 1.8 cm x 1.5 cm on right plantar foot
6.3
24 months
3.8 cm x 1.2 cm x 0.8 cm on right medial foot
This wound was treated with EpiFLO, while the
adjoining wound above was not treated with
EpiFLO.
8.0 cm x 6.0 cm x 0.8 cm
4.6 cm2
4 months
Transdermal Oxygen to Diabetic Wounds: 6 Cases
48 cm2
Amputation
Scheduled
?
No
No
No
Hirsh et al., Page 17
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Figures
FIGURE LEGENDS
Figure 1. Case 1—Non-healing 5-month-old neuropathic foot ulcer with
osteomyelitis in 77-year-old male with diabetes at Week 0 (A); osteomyelitis
was resolved and wound was healed after 15 weeks of treatment with
EpiFLOSD (B).
Figure 2. Case 2—Non-healing unresponsive weeping ulcer at week 0 (A) on
lower right leg of 74-year-old male with insulin-dependent diabetes and renal
failure; after 4 weeks of EpiFLOSD treatment, wound was completely closed
(B).
Figure 3. Case 3—A chronic, non-healing, diabetic foot ulcer with a vascular
component that had been stable for 12 years (A) in a 68-year-old female was
significantly reduced after 10 weeks of treatment with EpiFLOSD (B).
Figure 4. Case 4—A diabetic foot ulcer that had not healed for 6 months (A)
in a 32-year-old male was completely closed after 2 weeks of treatment with
EpiFLOSD (B).
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Figure 5. Case 5—Non-healing neuropathic right medial foot ulcer (A) in 50year-old female with diabetes healed after 8 weeks of EpiFLOSD treatment (B).
Figure 6. Case 6—Four-month-old wound (A) in a 54-year-old male with
diabetes mellitus and Charcot foot healed after 26 weeks of treatment, first
with 6 weeks of wet-to-dry dressings only, followed by 20 weeks with
EpiFLOSD (B).
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Figure 1 (A)
Figure 1 (B)
Courtesy of Alan Hirsh, MD, Orange Village, OH
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Figure 2 (A)
Figure 2 (B)
Week 0
Week 4
Courtesy of Alex Hirsh, MD, Cleveland, OH
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Figure 3(A)
Figure 3 (B)
Courtesy of Alan Hirsh, MD, Orange Village, OH
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Figure 4 (A)
Figure 4 (B)
Courtesy of David Skrobot, DPM, Zanesville, OH
Transdermal Oxygen to Diabetic Wounds: 6 Cases
Hirsh et al., Page 24
Fig. 5A
Week 0
Fig. 5B
Week 8
Fig. 6A
Week 0
Fig. 6 B
Week 26
Courtesy of Philibert Fluck, PT, U.S.Virgin Islands
Transdermal Oxygen to Diabetic Wounds: 6 Cases