Hyperbaric
Oxygen Therapy Enhances Wound Healing Processes for Diabetic Wounds
Diabetic
foot wounds are one of the major complications of diabetes and an
excellent example of the type of complicated wound which can be
treated with hyperbaric oxygen. It is well known that many diabetics
suffer circulatory disorders that create inadequate levels of oxygen
to support wound healing. Diabetic wounds present a major problem
for modern health care. The foot is the most common site of infection
in the diabetic. For diabetic patients, foot problems remain the
number one reason for hospital admission. An estimated 25% of Canadians
with diabetes develop foot problems, and one in 15 require a limb
amputation during their lifetime.
Oxygen
is one of the most versatile and powerful agents available to the
modern medical practitioner today.The therapeutic use of oxygen
under pressure is known as hyperbaric oxygen therapy (HBOT) and
has been used to assist wound healing for almost 40 years. HBOT
has several specific biological actions which can enhance wound
healing
processes:
- Oxygen
used under pressure of hyperbaric oxygen can assist wound healing.
- HBOT
is considered unnecessary simple, well-perfused wounds, but can
be used successfully in hypoxic or ischemic wounds such as diabetic
wounds, venous stasis ulcers, failing grafts and flaps, necrotising
soft tissue infections and refractory osteomyelitis.
- In
wound healing, hypoxia is an insufficient supply of oxygen which
prevents normal healing processes. HBOT provides the oxygen needed
to stimulate and support wound healing.
- HBOT
is able to combat clinical infection such as gas gangrene by acting
directly on anaerobic bacteria, enhancing leukocyte and macrophage
activity and potentiating the effects of antibiotics.
- HBOT
is a safe non-invasive, non-toxic therapy.
Hypoxia
(lack of oxygen) can be defined as an insufficient supply of oxygen
to allow the healing process to proceed at a normal rate. In a typical
wound care treatment, hyperbaric oxygen is capable of providing
tissue oxygen levels of greater than 11 times normal values. Most
chronic wounds are hypoxic and HBO provides the oxygen needed to
stimulate and support wound healing.
When
used in wound healing HBO provides a short pulse of oxygen - typically
90 minutes in a 24 hour day. HBO acts in numerous ways that affect
the wound after the treatment has stopped. There are eight principal
methods in which HBO is capable of affecting tissue:
- Pressure
effects of oxygen
- Vasoconstrictive
effects of oxygen.
- 100%
oxygen concentration effects on the diffusion gradient.
- Hyperoxygenation
of ischemic tissue.
- Down
regulation of inflammatory cytokines.
- Up-regulation
of growth factors.
- Leukocyte
effects.
- Antibacterial
effects.
Hbo
has six actions which have been used to combat clinical infection:
- Tissue
rendered hypoxic by infection is supported by oxygen.
- Neutrophils
are activated and rendered more efficient.
- Machrophage
activity is enhanced.
- Bacterial
growth is inhibited.
- The
effect of antibiotics is potentiated.
Support
of infected hypoxic tissue: Soft tissue and bone infections are
frequently accompanied by localized areas of tissue hypoxia caused
by the inflammatory processes accompanying infection and by subsequent
vascular thrombosis. As the infected tissue becomes infiltrated
with inflammatory cells the oxygen level falls. Anaerobic bacteria
are particularly susceptible to increased concentrations of oxygen.
In
properly selected patients the success rate is high and there are
few absolute contraindications. Transcutaneous oxygen levels and
doppler testing can help to predict results. HBOT in properly selected
cases, has been effective in preventing amputations, speed up healing
of chronic ulcers and fistulae, saving threatened skin flaps and
permitted surgery that would not have been possible without it.
This in turn results in improved quality of life for patients.
The
incidence of amputation in diabetics remains unacceptably high:
6 per 1,000 patients. Diabetics account for 50 - 70 percent of all
amputations performed each year. In 1986, 152,000 amputations were
done in America. Ten percent of those surgeries resulted in the
loss of a foot, 35% involved the loss of a lower leg, and 30% resulted
in the loss of the knee joint. Ipsilateral or higher amputation
occurs in 24% of cases. One complication often does unrecognized:
contralateral amputation, which occurs at a rate of 10% per year.
Diabetic
amputees also experience other difficulties. Only 50% of the patients
survive more than 3 years after the amputation (USA survey data).
Although many individuals who lose limbs traumatically can expect
to be rehabilitated to full activity, only 40 - 50% of elderly amputees
can not expect to enjoy such a successful outcome. The duration
of hospitalization for treatment of diabetic foot infections averages
22-36 days.
Amputation
offers a poor solution. Patients pay high personal costs when limbs
are lost. When an amputation occurs, patients generally remain hospitalized
for 40 days and to maximize walking ability or potential, patients
may need an additional 6-9 months of rehabilitation. Many elderly
diabetic amputees remain bound to wheelchairs for the rest of their
lives because they lack sufficient energy, balance, and strength
to walk. Their sedentary existences lead to other health problems.
Within 2 years, for example most amputees must undergo stump modification
or proximal reamputation.
Then
there are the social costs of amputation to consider. Many amputees
fail to maintain productive lives because they can no longer sustain
gainful employment. But personal costs perhaps loom the largest
in decreasing a patient's quality of life.
Three
factors predispose a diabetic to develop wound problems: neuropathy,
angiopathy and immunopathy. Neuropathies involving both peripheral
(motor and sensory fibers) and autonomic innervation are common
complications of long-standing diabetes mellitus. Such pathology
often involves a combination of these fibers. Among the most commonly
recognized neuropathies is sensory neuropathy, perhaps because of
its clear pathophysiology and the ease in evaluating the conditions.
This neuropathy contributes to the possibilities of patients becoming
infected. When patients fail to feel pain and proprioceptive sensation,
they injure themselves more easily and often fail to rapidly recognize
tissue damage and infection. Patients experiencing such problems
can also repeatedly traumatize the joints and tissue of the foot,
creating increasingly serious problems.
Motor
neuropathy causes weakness of various muscle groups, ultimately
resulting in foot deformities. Typically, weakness of the intrinsic
muscles lead to protrusion of the metatarsophalangeal joints. Such
a condition eventually causes hammer toes and pes cavus because
the weight bearing surfaces are structurally overloaded. Destruction
of callus, skin breakdown and trophic ulcerations may also develop.
Such
events open the first line of defence against infection and offer
a fertile breeding ground for invasive bacteria. Autonomic dysfunction
leads to decreased sweating. Resulting dryness may predispose the
patient to more scaling, cracking, and fissuring of the skin of
the foot. With each crack, further tissue breakdown and infection
can occur.
Angiopathy,
or the presence of peripheral vascular disease affecting the foot.
contributes to the possibility of infection. Two disease processes
may be involved, although the mechanisms are not yet clear. Microangiopathy
and chronic macroangiopathic occlusive arterial disease contribute
to vascular problems. The recent medical literature challenges the
importance of microvascular versus macrovascular changes. Now researchers
suspect microangiopathy may relate to inhibition of diapedesis of
leukocytes and exchange on immune substance through thickened capillary
basement membranes. Similarly, oxygen diffusion through thick membranes
is reduced. Prospective controlled studies have substantiated the
thickening of capillary basement membranes, a microvascular change
clinicians had postulated.
But
perhaps more importantly, diabetics experience the effects of macroscopic
obstructive arterial disease. Such disease can lead to diminished
flow through major arterial systems. The development of collateral
circulation may maintain an adequate blood supply at ambient
temperatures.
Vascular reserve is often diminished, however. One prospective study
identified vascular impairment as one of three factors significantly
more common in diabetics with foot lesions. Doppler studies were
used to assess the impairment.
Another
important pathophysiologic factor involves changes in the immune
system of the diabetic patient, when hyperglycemia occurs. Migration
of polymorphonuclear leukocytes, phagocytosis and cell-mediated
immune response are all impaired in the poorly-controlled diabetic.
Once
an infection occurs, most tight glucose control is lost. Data analyzed
in two recent reviews suggest that patients with diabetes mellitus
are predisposed to more frequent and severe infections. They are
also less capable of fighting those infections.
HBOT
offers physiological benefits for such patients. They include: improved
oxygenation of threatened margins of wounds, generation of granulation
tissue, enhanced phagocytosis and killing of select organisms. Still
other benefits are enhanced penetration of some organisms by antibiotics
whose transmembrane transport is oxygen dependent, and improved
wound healing with an increased rate of fibroblast collagen production
to support capillary angiogenesis. HBOT offers beneficial direct
bacteriostatic effect on anaerobic micro-organisms.
HBOT
is an adjunctive therapy, which in combination with other disciplines
involving treatment, will provide a powerful tool for the treating
physician.
Diabetes
Wound Care Submission to the Federal Government
Submitted by Dr. Paul Harch, President of the IHMA, to the Center
for>Medicare and Medicaid Services, November 2, 2001
ARGUMENT
FOR MEDICARE/MEDICAID COVERAGE OF HYPERBARIC OXYGEN THERAPY
TREATMENT
OF DIABETIC FOOT WOUNDS
Hyperbaric
oxygen therapy (HBOT) was first defined as a drug in 1977 by Gottlieb
(1). Unfortunately, this critical definition has been long forgotten
and substitute definitions have mis-characterized HBOT as a therapy
for "certain recalcitrant, expensive, or otherwise hopeless
medical problems."(2) This mischaracterization has resulted
in a confusing collection of different lists e.g., CMS, UHMS Accepted
Indications, and international lists(3), of seemingly unrelated
reimbursable diagnoses (chronic refractory osteomyelitis, air embolism,
cyanide poisoning, compromised flaps and grafts, carbon monoxide
poisoning, acute stroke, etc) supported by widely varying amounts
of basic science and clinical evidence. In 1999, the drug definition
of HBOT was refined and restated as the use of greater than atmospheric
pressure oxygen as a drug to treat basic pathophysiologic processes
and their diseases (4). With that definition the above lists could
now be understood as cohesive sets of diagnoses connected by HBOT
effects on the acute and/or chronic underlying pathophysiology common
to the diseases. Furthermore, the definition suggested and argued
for the application of HBOT to additional diseases that shared this
pathophysiology. The 1999 drug definition of HBOT will be used in
this paper to argue for HBOT effectiveness in the treatment of infected
diabetic foot wounds, and hence, CMS reimbursement for the same.
The argument will be constructed by identifying the underlying pathophysiology
in diabetic foot wounds, presenting the evidence for the beneficial
effects of HBOT on this pathophysiology, demonstrating a similar
benefit in patients with diabetic foot wounds, and then showing
the risk/benefit and cost/effectiveness evidence for HBOT in diabetic
foot wounds. This argument will lead to the conclusion that CMS
coverage of HBOT should be extended to diabetic foot wounds.
Diabetic
foot wounds are complex microcosms of multiple pathophysiologic
processes. The wounds are predominantly characterized by polymicrobial
infection (5,6,7,8), peripheral neuropathy (9,10,11,12), structuraldeformity
(10,13,14,15), altered immune function or increased susceptibility
to infection (16,17,18), decreased wound nitric oxide (NO) production
(19,20,21), and often hypoxia/ischemia (22,23,24,25). Decreased
NO production, infection, and hypoxia are the most important for
inhibition of wound healing. Decreased NO production is responsible
for impaired cutaneous vasodilation, decreased neurogenic vascular
response, diabetic neuropathy, and endothelial cell dysfunction
that inhibit the processes necessary for granulation tissue formation
(26). Hypoxia, on the other hand, is both necessary for and inhibitory
of wound healing (27). Hypoxia is responsible for initiating wound
healing through regulation of macrophage angiogenesis factor (28),
but impairs the cellular repair processes, which are oxygen dependent
(29). These repair processes are: leukocyte bacterial killing of
aerobes and anaerobes (30), white blood cell proteolysis of necrotic
tissue (31), thrombolysis of wound and periwound capillary microthrombi
(32), fibroblast proliferation (33), collagen synthesis(34,35,36,37,38,39,40,41),
granulation tissue formation (33,40), angiogenesis (42) , osteoclastic
and osteoblastic bone repair (43), and epithelialization (44). In
addition, hypoxia alters the rate at which wounds heal (34,35,36,37,39,40,41).
When hypoxia is combined with infection wound healing is maximally
decreased and results in the main cause of amputation in diabetic
foot wounds (24,45,46,47).
Hypoxia
and infection are also very closely related; hypoxia impairs leukocyte
bacterial killing (48,30), lowers tissue resistance to infection
(36,38,49,50,51,52,53), alters the local response to infection (38,39,51,54,55,56,57,58,59),
and facilitates growth of anaerobic and microaerophilic organisms
that further compromise the wound (60,61). Bacterial growth also
competes with normal cells for oxygen and nutrients (62) and generates
toxic byproducts. In summary, the combination of hypoxia, infection,
and decreased NO are characteristic of diabetic foot wounds and
responsible for decreased healing and increased amputation rates.
Therefore, correction of these wound factors should be the primary
goal of therapy. If these factors can be reversed improved healing
and decreased major amputations should be the result.
The
question is whether HBOT can impact these factors and lead to improved
clinical results. A review of the animal and human literature shows
that HBOT has positive drug-like effects on the pathophysiology
identified in and actual components of diabetic foot wounds. HBOT
increases tissue oxygenlevels that remain elevated for up to 4-6
hours after treatment (63,64).This correction of hypoxia directly
reverses many, if not all, of the aboveprocesses resulting from
hypoxia and initiates the wound-healing process. HBOT increases
PO2 in the region of infected tissue (65), controls infection (56),
improves leukocyte bacterial killing (51,54,56,57,58,59) has direct
toxic effects on anaerobic bacteria (66,67), suppresses exotoxin
production (68), and is synergistic with antibiotics (69,70,71,72,73,74,75).
HBOT increases fibroblast replication and collagen synthesis in
tissue (35,40) and fibroblast proliferation in fibroblasts derived
from chronic diabetic wounds (76), epithelialization (77), ischemic
tissue oxygen capacitance (64), angiogenesis (78,79,80), granulation
tissue (81), platelet derivedgrowth factor receptor mRNA (82), PDGF
receptor protein levels alone (83) or in combination with PDGF (84),
wound healing synergy with PDGF (81), vascular endothelial growth
factor in wounds (85), osteoclastic and osteoblastic activity (86,87),
and increases endothelial nitric oxide synthase (88) and NO production
(26).
NO
is important in wound repair (21,89,90) through its enhancement
of cellular immunomodulation and bacterial cytotoxicity (91), regulation
of vasodilatation (90), stimulation of cellular migration (92),
collagen deposition and cross-linking (89), inhibition of platelet
aggregation (91) and white blood cell/endothelial adhesions (93),
modulation of endothelial proliferation and apoptosis (94), and
promotion of angiogenesis (95).
In
essence, HBOT has positive effects on the great majority of the
pathological processes identified in diabetic wounds and promotes
wound repair and healing through a variety of mechanisms, many of
which are mediated by signal induction (drug-like) effects on DNA
and nitric oxide.
With
the plethora of basic science data it is no surprise that the HBOT
animal data has been validated in the human diabetic foot wound
literature. Beginning with Davis in 1987, five uncontrolled studies
have documented the success of HBOT added to a multidisciplinary
approach to treat mostly resistant non-healing diabetic foot wounds
(96,97,98,99). Limb salvage and/or healing rates were 70%, 90%,
88%, 86%, and 85%, respectively. In the 1997 Cianci study (99) the
results were shown to be durable: of 28 contacted patients of the
35 who achieved limb salvage, 27 (96%) were still healed at late
follow up. These substantial HBOT-induced limb salvage and healing
rates in uncontrolled studies have been confirmed in controlled
trials.
In
a large retrospective controlled trial Stone (100) compared diabetic
foot wound patients with low transcutaneous oxygen measurements
who received topical growth factors to similar patients who received
both growth factors and HBOT. The HBOT group had larger wounds,
more wounds/patient, and a 65% increase in the number of patients
initially recommended for amputation, yet a greater eventual limb
salvage rate, 72 vs. 53%.
In
another retrospective controlled study Oriani (101) showed a statistically
significant reduction in major amputations, 4.8% (HBOT) vs. 33%
(controls); the control group's amputation rate was nearly identical
to the amputation rate in similar patients treated five years earlier
before the use of adjunctive HBOT. These results confirmed the findings
of this same group in a prospective controlled study reported three
years earlier (102) which achieved a statistically significant improvement
in healing, 88 vs. 10%, and reduction in below knee amputation,
13 vs. 40%, in HBOT patients compared to controls.
Prospective
controlled trials have underscored the Baroni findings (102). Doctor
(103) reported a statistically significant quicker control of infection
(one of the major risk factors for amputation identified above)
and reduction in major amputation, 13% vs. 46%, in HBOT patients.
Faglia (104) duplicated the Doctor data with major amputation rates
of 9% in HBOT vs. 33% in control patients. Zamboni (105) recorded
an 80% healing rate in HBOT patients vs. 20% in controls. These
findings were recently reproduced by Abidia (106) in a randomized
prospective double-blinded study of non-healing ischemic diabetic
leg ulcers. At 12 weeks healing with complete epithelialization
was achieved in 68% of the HBOT treated ulcers vs. 29% of the control
ulcers. The median reduction in wound area was 96% in the HBOT group
and 41% in the controls (p=.043). While there was no difference
in major amputation the HBOT group reported significant improvement
in vitality (p=.01), mental health (p=.05), and general health (p=.008)
as assessed by the quality of life SF-36 Health Survey.
Lastly,
Lin (107) reported improved hemoglobin A1C, transcutaneous oxygen
measurements, and laser-Doppler perfusion scanning, all p<.01,
in the HBOT treated group of a randomized prospective controlled
trial of early diabetic foot ulcers. While the data points to improved
healing, resolution of hypoxia, and prevention of major amputations
in diabetic foot wound patients who undergo HBOT, cost-effectiveness
and risk-benefit are important considerations.
Risks
are easily addressed; HBOT is a minimal risk medical treatment where
the most common problems are middle ear and sinus barotrauma and
reversible hyperoxic myopia (108). All other risks are extremely
rare, a surprising finding given the generally complicated medical
patients treated with this modality.
Costs
have been explored by Cianci and Petrone (96), Mackey (109), and
Cianci (99) and strongly suggested to be lower with HBOT. These
costs should be even less after the 2000-2001 CMS reduction in HBOT
reimbursement. In those wounds treated with HBOT reduction in costs
would also come from avoidance of prosthesis and rehabilitation
charges [estimated to be $40-50,000-(108)], stump revision, and
reamputation. Ipsilateral, often higher, amputation occurs in 22%
of cases and after five years 50% will have undergone a bilateral
amputation (110,111).
Amputation
causes mortality and expensive morbidity, 4% and 14%, respectively,
in one study (112). Considering the durability of HBOT-induced healing,
up to 55 months (99), savings would result from prevention of stump
revisions and reamputation (102,112) and their associated morbidity
and mortality costs.
Indirect
cost savings are also important. Since only 40-50% of elderly amputees
alive after four years will have been successfully rehabilitated
(110,111) amputation often commits the patient to a wheelchair life.
This is accompanied by multiple problems, including depression and
loss of self-esteem, which are difficult to quantify. Costs "resulting
from loSss of function, life, and the skills contributed by these
patients to society are generally neglected" and "may
well be as high as 50% of the total costs of the disease."
(114). Beyond costs diabetic foot ulcers have a marked effect on
quality of life. In the Abidia study (115) above HBOT resulted in
improved quality of life measures and a reduction of depression.
The impact of such improvements are difficult to measure, but likely
are significant and contribute to the reduction in indirect costs
associated with diabetic foot ulcers and amputation. The weight
of the above data has now prompted recommendation of HBOT in diabetic
foot wounds by various groups.
In
1999, the Blue Cross/Blue Shield Tech Assessment Report for Kaiser
Permanente (116) supported HBOT for adequately perfused wounds of
the lower extremity in combination with standard wound care. These
wounds included diabetic foot wounds. Similarly, the Australian
Hyperbaric Oxygen Therapy April 2000 Draft Final Assessment Report
(117) found evidence of HBOT effectiveness in diabetic wounds and
that it could be cost-effective if rehabilitation costs are included.
Given other considerations "HBOT might have a cost effectiveness
ratio of many times those calculated above." Clinical Evidence
5 of the British Medical Journal Publishing Group came to the conclusion
that "two small RCTs suggest that systemic hyperbaric oxygen
reduces the risk of foot amputation in people with severe infected
foot ulcers."(118)
In
addition, the American Diabetes Association's 1999 Consensus Development
Conference on Diabetic Foot Wound Care recommends HBOT to treat
"severe and limb or life threatening wounds that have not responded
to other treatments, particularly if ischemia that cannot be corrected
by vascular procedures is present (119)." Lastly, and most
importantly, a recent Rapid Response Report (126) by the Evidence-based
Practice Center of the New England Medical Center endorsed HBOT
in the treatment of diabetic foot wounds. This report was funded
by a grant from the Agency for Healthcare Research and Quality (AHRQ)
to review the literature on CMS HBOT indications. They summarized
all of the recent TEC assessments, e.g. Blue Cross/Blue Shield,
Australian MSAC, etc., and HBOT literature and found that the scientific
evidence supported the use of HBOT in the treatment of diabetic
foot wounds.
The
implications of their findings cannot be overemphasized; the findings
are consistent with, and powerfully recapitulate, all of the above
evidence and arguments for HBOT in diabetic foot wounds. Because
of the above noted morbidity, mortality, direct and indirect costs
of diabetic foot wounds and amputations studies have recommended
multiple strategies to reduce lower extremity amputations (45,62,122,123,124).
The
Department of Health and Human Services' Healthy People 2000 reporttargeted
a 40% reduction in amputations in 1991 (124). This goal has not
been achieved (114). Since 50-70% of amputations in the United States
are in diabetic patients (99) any strategy that could reduce amputations
in diabetics, especially major amputations, could have a dramatic
impact on health and costs. That therapy is HBOT.
As
argued above HBOT treats the underlying pathophysiology of diabetic
foot wounds, effectively treats diabetic foot wounds in uncontrolled
and controlled clinical trials, reduces costs, improves health and
outcomes, prevents major amputations, and satisfies the directives
and goals of the Department of Health and Human Services of the
United States Government. Its use is increasingly endorsed by institutions,
including insurance companies, governments, and scientific groups
and thus has come in concert with the past thirty years' practice
habits and knowledge of hyperbaric physicians.
Interestingly,
the major source of "inappropriate use" of HBOT noted
in the OIG's October 2000 Report on Hyperbaric Oxygen Therapy was
in the physician miscoding of diabetic foot wounds as other covered
diagnoses "to align treatment practices with their own medical
judgements (3)." Both treatment practices and medical judgement
are supported by the overwhelming data presented in this report.
In
short, HBOT saves limbs and possibly lives in patients with diabetic
foot wounds. It appears that it is time to recognize this body of
data, reduce healthcare costs, and improve health and outcomes by
endorsing HBOT in the treatment of diabetic foot wounds. This can
be achieved by extending CMS coverage to this diagnosis.
Thank
you.
Paul
G. Harch, M.D. President
International Hyperbaric Medical Association
Clinical Assistant Professor and Director Hyperbaric Medicine Fellowship
Department of Medicine
Section of Emergency and Hyperbaric Medicine
Louisiana State University School of Medicine, New Orleans, Louisiana
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