The International Journal of Lower Extremity

Wounds
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Nonhealing WoundsA Therapeutic Dilemma

V S Chauhan, M Adil Rasheed, S S Pandley and V K Shukla

International Journal of Lower Extremity Wounds 2003 2: 40
DOI: 10.1177/1534734603002001007
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ARTICLE

10.1177/1534734603254690
CHAUHAN
LOWER
NONHEALING
EXTREMITY
ET AL
WOUNDS
WOUNDS 0(0); 2003

Nonhealing WoundsA Therapeutic Dilemma

VS Chauhan, MBBS, M Adil Rasheed, MD, SS Pandley, MD,
and VK Shukla, MS, MCh(Wales)
Department of General Surgery, Department of Dermatology and Venereology,
Institute of Medical Sciences, Banaras Hindu University, Varanasi, India

Chronic wounds of the lower extremity are a therapeutic dilemma. In India, chronic wounds are caused by factors other
than impaired circulation and diabetes, which account for
most of this clinical problem in Western societies. A study of 2
topical agents, placental extract and phenytoin powder, is
presented in this paper. One hundred fifty patients were randomly assigned to these treatments or to saline dressings
(control). It was observed that patients receiving active topical treatments responded better than those in the control
group. The importance of this finding should be viewed with

hronic wounds are a drain on health care resources. Such wounds challenge health care providers to define and create more effective intervention
strategies. Clinically, wounds are categorized as acute
or chronic dependent on their time courses of healing
and tendencies to relapse. In practice, the duration of
healing is very variable; hence, the distinction between
an acute and a chronic wound is arbitrary, dependent
on variables including the site and the cause of the
wound and the age and physical condition of the patient.1 Most chronic wounds are associated with welldefined clinical entities, particularly diabetes mellitus,
pressure necrosis, and venous hypertension. In India,
leprotic ulcers are the most common cause of
nonhealing wounds.2
Cutaneous tissue repair is a complex, dynamic process involving 3 main overlapping phases:
The inflammatory phase begins within 6 hours of injury.3 The disruption of blood vessels leads to clot formation and the phagocytosis of microorganisms by the
released neutrophils, macrophages, and enzymes.

Correspondence should be sent to: Professor VK Shukla, MB BS,

M.Ch(Wales), Department of General Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, India; e-mail:
vkshuklabhu@satyam.net.in.
DOI: 10.1177/1534734603254690
2003 Sage Publications

40

the perspective that these topical treatments are inexpensive

and easily available in India. The study also piloted measurements of angiogenic responses in 1 group, and the findings
encourage further exploration with the technique and topical
agent.

Key words: chronic wounds, topical therapy, randomized

study, angiogenesis

The proliferative phase consists of the formation of

granulation tissue consisting of a dense population of
macrophages and fibroblasts embedded in a loose matrix of collagen, fibronectin, and hyaluronic acid. The
proliferation, migration, and differentiation of
keratinocytes take place to restore surface integrity.
Neovascularization or angiogenesis in a wound occurs
concomitantly with fibroplasia.
The matrix formation and remodeling phase consists of
the accumulation of large fibrous bundles of type I collagen that produce the residual scar while imparting
tensile strength to connective tissues.

COMMON TYPES OF NONHEALING WOUNDS

Pressure Ulcers
Hospitalized patients who are at risk for developing
pressure ulcers constitute 14% to 20% of hospital cases
at any one time.4 There is 4-fold increased morbidity
and mortality among ill elderly patients. Increased
pressure over the bony prominences leads to compromised blood supply and lymphatic drainage, and this
in turn leads to tissue ischemia, which causes damage
to underlying muscle and subcutaneous tissue.
When spontaneous healing is not apparent even after the relief of pressure, surgical intervention becomes
necessary. Complications of pressure ulcers include infection, dehydration, anemia, and electrolyte
imbalance.

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NONHEALING WOUNDS

Diabetes Mellitus
Chronic foot ulcers are the leading cause of amputation among diabetic patients.5 The risk for lower extremity amputation is 15 times higher among diabetics
compared to nondiabetics. Although the fundamental
pathophysiological factors leading to ulcer formation
remain ill understood, the triad of neuropathy,
ischemia, and infection is considered the most important in the development of ulcers.
Below the knee, the blood vessels commonly involved in diabetic angiopathy are the posterior and anterior tibial vessels, the peroneal vessels, and the small
vessels in the foot. There are multiple risk factors involved in the development of diabetic peripheral vascular disease, of which smoking, hyperglycemia, hypercholesterolemia, and hypertension are the most
important.
At the Indian National Institute of Diabetics in
Mumbai, > 10% of all admissions for diabetes are primarily for foot management; at least 70% require surgical intervention, and of these, at least 40% are toe or
limb amputations.6
Venous Ulcers
Chronic venous insufficiency (CVI) is often restricted to the end clinical stage of the syndrome of venous hypertension, limb swelling, pigmentation,
induration, and ulceration. Venous ulceration represents the end stage of the disease process and only a
small proportion of the disease spectrum. Fibrin cuffs
around capillaries were proposed as a cause of local oxygen and nutrient deprivation, thereby leading to ulceration.7,8 This hypothesis has largely been discredited because fibrin deposition occurs in many
ulcerated and nonulcerated tissues. It has also been
suggested that susceptibility to ulceration in CVI may
be due to release of humoral and toxic substances from
white blood cells trapped in subcutaneous capillaries
because of increased venous back pressure.9
Leprotic Ulcers
Plantar ulceration is a common complication of an
insensate foot among patients with leprosy. The sites
affected are areas of the sole that come under pressure
while walking. Excessive walking, often on bare feet,
causes injury to the tissues, which are unable to offer
feedback on account of being insensate. The injury produces inflammation, which accentuates the damage,
resulting in an open wound.10 Open wounds are frequently infected with pathogenic organisms; the infec-

tion extends into the muscles and bones, causing

chronic osteomyelitis and the disintegration of the foot.
The mainstay of treatment is the topical application
of agents and surgical debridement. There are a number
of agents available for topical use, but their costs are
varied and there are few controlled data on their
efficacy.
The aim of this study was to compare the effects of 2
different topical treatments with a control. The subsidiary aims of the study were to derive information about
the clinical profiles of nonhealing wounds in the health
district we served and to examine the effects of chemical peeling on wounds with hyperkeratotic edges. The
agents chosen for treatment were placental extract and
phenytoin powder, as described in the succeeding
section.
Placental Extract
The aqueous extract of a human placenta contains
various enzymes such as alkaline and acid phosphatase, glutamic acid, and oxaloacetic acid; nucleotides such as RNA, DNA, and adenosine triphosphate;
vitamins such as B10, B2, B6, pantothenic acid, biotin,
para-aminobenzoic acid, folic acid, B12, choline, and
inositol; amino acids such as alanine, tryptophan,
valine, leucine, lysine, phenylalanine, cholesterol,
fatty acids, and steroids; and trace elements. These
components exert multiple biological activities, including immunomodulatory and anti-inflammatory
activities. They are also reported to have growth factor
like activity,11 pigmenting activity,12 and keratinocyte
proliferating activity.13
Phenytoin Powder
Phenytoin (diphenylhydantoin) has been in use for
some time now and has been reported to promote
wound healing. Oral phenytoin reduced the formation
of blisters among patients with recessive dystrophic
epidermolysis bullosa.14 There was a reported decrease
in wound exudates and bacterial contamination among
patients treated with topical phenytoin powder. It is
cheap and readily available in India.
Chemical Peeling
As part of the subsidiary aims of this study, chemical
peeling was selected to debride wound edges.
Chemoexfoliation, or chemical peeling, is the application of 1 or more chemical agents to the skin to cause
controlled chemical burns, resulting in the destruction
of a portion of the epidermis and or dermis through dry

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CHAUHAN ET AL

desquamation or moist maceration followed by its exfoliation and the subsequent resurfacing of the epidermis along with the remodeling of collagen and elastic
fibers and the deposition of glycosaminoglycans during the repair process in the dermis. Numerous agents
have been used over the years. However,
trichloroacetic acid (TCA), phenol, and salicylic acid
are chemicals in use today.
MATERIALS AND METHODS
Study Design and Setting

MAGS = KnN + KcE + KxX.

Swabs were taken for culture and sensitivity and

sent for microbiological examination. Hematological
profiles and radiological examinations of involved
parts were also done on all patients.
Statistical Analysis

A randomized controlled study was carried out at

the University Hospital, Banaras Hindu University,
Varanasi, India. One hundred fifty patients with
chronic, nonhealing wounds attending the Wound
Clinic from May 2000 to November 2001 were consecutively recruited to the study. Detailed histories were
taken and recorded in folders. Thorough clinical examinations were done, with special stress on the nervous
and cardiovascular systems of patients with leprosy
and diabetes mellitus. Local examination of wounds
was carried out, and characteristics of wounds, including their size, discharge, floors, base edges, margins,
and draining nodes were recorded.
Patients were randomly assigned to 3 groups. Group
1 (n = 50) received topical Placentrex (Albert David Ltd,
Kolkata, India) daily, group 2 (n = 50) received
phenytoin powder (Dilantin capsule; Parke Davis,
India; 100 mg) locally, and group 3 (the control group; n
= 50) was treated with normal saline applied topically.
Patients were also given systemic antibiotics and
chemotherapy as required. Patients were followed up
at weekly intervals. Wound areas were measured at all
visits, and other findings were also recorded. Patients
were included in the study for a maximum period of 6
months.
As part of the subsidiary aims of this study, tissue
samples were collected for histopathology and further
studies from a subset of patients in group 1who were
treated with placental extract to ascertain its
angiogenic effects (n = 9). In wound edges with
hyperkeratotic margins that were in need of
debridement, chemical peeling was carried out. Sixmillimeter punch biopsies were done under local anesthesia and sent for histopathological studies, including
angiogenesis. Microscopic angiogenesis was calculated using a previously described method, the Microscopic Angiogenesis Grading System (MAGS).15 MAGS
was done by M. Kumar.
MAGS was based on 3 parameters of endothelial regeneration: vasoproliferation (KnN), endothelial cell
42

hyperplasia (KcE), and endothelial cytology (KxX). A

numerical grade was given to each of these variables
and an overall index (range, 0100) of endothelial regeneration was calculated:

All observations were tabulated and interpreted in

terms of percentage, mean, median, and standard deviation. To test the significance of associations and differences of the mean, Student t tests, chi-square tests, and
variance ratio tests (F) were applied.
RESULTS
Wound Epidemiology
Epidemiological profiles of the patients revealed
that the maximum number of patients were in the fifth
decades of their lives and above. The age range was
from 4 to 78 years, with a mean age of 43.20 15.56
years. Of the patients, 81.55% were male.
Wound duration varied from 6 weeks to 20 years, the
mean duration being 1.63 3.22 years. Approximately
33% of the patients had wounds of < 3 months
duration.
In the present study, 61 patients (59.22%) had
leprotic ulcers. Venous ulcers and diabetic ulcers were
the next most common presentations. The study indicated that leprosy was the most common primary etiological problem leading to nonhealing ulcers in this
area of India, which is consistent with a previous observation by our group.2 In the former study, leprosy was
also the main cause of leg wounds, accounting for 40%
of cases, with diabetes mellitus being the next most
common cause in 23% of all patients. The repeated observations from this Center contrast with those of
Knighton et al,16 who documented that cutaneous,
nonhealing wounds were most frequently caused by
diabetes (58%), trauma (16%), decubitius ulcers
(14%), venous stasis ulcers (6%), and arterial insufficiency (6%). Thus, chronic lower extremity wounds
have different causations in Western societies as opposed to India.
The most common site of the presentation of nonhealing wounds in this study was the foot (74.76%).

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NONHEALING WOUNDS

Table 1. Mean Surface Area (cm2) With Standard Deviations for All Treatment Groups
Group

Before Treatment

Group 1
Group 2
Group 3

After Treatment

15.25 (SD = 19.8)

15.20 (SD = 15.2)
11.33 (SD = 23.45)

3.6 (SD = 7.28)

4.80 (SD = 7.5)
7.6 (SD = 17.75)

Table 2. 50% Healing of Wounds:

Three Groups at Various Time Intervals
50% Healing
of Wounds

At 2 wk
At 4 wk
At 6 wk
At 8 wk

Group 1
(%)

10.00
40.00
52.50
67.50

Group 2
(%)

Group 3
(%)

6.06
39.39
45.45
48.48

Values

3.33
3.33
20.00
23.33

Plantar aspects accounted for > 64.08% of wounds, the

plantar surface, the pad of the great toe, the heel, and
the head of the first metatarsal area being the predominant sites. This could be explained by the fact that these
patients had sensory loss over their feet, and these areas
were exposed to excess mechanical stress. Birke et al17
found the first metatarsal head to be the most common
site of ulceration in their series of patients with plantar
ulcers due to leprosy and diabetes.
Healing Rates
The calculated surface wounds are presented in Table 1. Also presented are 50% reductions in wound areas in the study population (Table 2). Healing was assessed by calculating the time taken to achieve a 50%
reduction in wound surface area. This is presented in
Table 2.
These results demonstrate that patients in groups 1
and 2 responded favorably to the assigned treatments,
compared to those in group 3 (the control group).
MAGS measurements on the subset of patients from
group 1 are discussed in the succeeding section.
DISCUSSION
The main aim of this study was to examine the effects of placental extract and phenytoin powder on
chronic, cutaneous wounds of different etiologies. The
other purpose of the study was to identify the epidemiology of chronic, cutaneous wounds in the health district in which we serve. We also had subsidiary aims to
study the effects of chemical peeling, an alternative to

t = 1.57, P < .001

t = 1.71, P < .01
t = 0.71, P > 0.5

Table 3. Significance Comparison (z value) of Area

Changes in the Groups in the Study
Compared to the Control Group (group 3)
Period

Group 1 vs
Group 2

At 2 wk
At 4 wk
At 6 wk
At 8 wk

0.61
0.05
0.60
1.64

Group 1 vs
Group 3

1.07
3.54***
2.76**
3.66***

Group 2 vs
Group 3

0.51
3.44***
2.14*
2.07*

*P < .05. **P < .01. ***P < .001.

surgical debridement, and the angiogenic effects of placental extract on wounds.

To examine the effects of the topical treatments
used, area reductions at 2 weekly intervals were compared against control values. The z statistics from these
comparisons are presented in Table 3. Favorable responses were obtained in both groups that received active treatment. Placental extracts, known to contain
growth factors and anti-inflammatory agents,11 were
helpful in healing chronic wounds in this study. A
study on the healing of full-thickness punch wounds 8
mm in diameter in rat models showed that with the
topical application of placental extract, complete healing occurred in an average of 12.15 days, compared to
16.66 days among an untreated group.11 No adverse effects were reported in this study. It would appear that
this treatment is beneficial in clinical and experimental
animal models.
Patients in this study also benefited from topical
treatment with phenytoin powder: > 50% healing at 8
weeks was observed in 48% of patients. There were no
side effects in this group either. Lodha et al18 reported
that phenytoin reduced edema and inflammation and
accelerated the growth of healthy tissue among patients
with large abscesses.
Bansal and Mukul19 compared the role of phenytoin
in the treatment of chronic trophic ulcers in leprosy.
Over a 4-week period, the mean percentage of wound
volume reduction measured was greater among the
phenytoin group (72.1% 19.9%) compared to controls (55.5% 21.6%). Muthu Kumar Swamy et al20 re-

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CHAUHAN ET AL

Table 4. Histopathology Findings Relating to

Angiogenesis Before Treatment Commenced and 2
Weeks Hence
Serial
Number

1
2
3
4
5
6
7
8
9

MAGS Score
Before Treatment

53
18
33
39
44
65
31
41
51

Mean MAGS
score

41.66 13.88

MAGS Score
After Treatment

53
34
49
57
49
73
46
33
65

51.00 13.06

MAGS = Microscopic Angiogenesis Grading System; t = 3.23, P = .01.

ported the use of topical phenytoin in diabetic foot ulcers among 50 patients compared to controls. Both
groups improved, though the wounds treated with topical phenytoin healed more rapidly, the mean time to
complete healing being 21 and 45 days for the treatment and control groups, respectively. These reports
are consistent with the observations in this report using
topical phenytoin.
Other Aims
This study showed that leprosy is the most common
cause of chronic wounds in this health district served
by the authors, followed by diabetes mellitus. This may
have implications for health care planning, because the
incidence of diabetes is increasing in India, as it is
worldwide. The faster healing obtained in this study
should encourage the use of simple topical treatments
that are inexpensive and available locally.
In the subset of patients from group 1 (n = 9) who received topical Placentrex, there was an increase in
mean angiogenic scores with treatment. A comparison
of the means showed the increase to be statistically significant (P < .01). Details are presented in Table 4.
Twenty cases of nonhealing wounds had hyperkeratotic edges. In 10 of these 20 cases, TCA or carbolic
acid was applied on the edges at weekly intervals, with
immense benefits showing the advantage of this methodology over surgical debridement. Another advantage
in favor of chemical peeling is that no formal training is
needed, compared to the skills essential to conduct
44

sharp surgical debridement. This observation is interesting and needs to be developed in future studies.
This study suggests the potential of placental extract
and phenytoin powder in the management of
nonhealing wounds. Future studies should follow
wounds through to closure in order to gain a fuller understanding of the potential of these topical therapies.
It is suggested that the perceived benefits of topical placental extracts may be due to multiple effects on
angiogenesis, collagen synthesis, and epithelial cell
proliferation. It is noteworthy that patients with venous ulcers did not receive compression bandaging,
because it is not available in India. Another observation
is that malignant changes in trophic wounds are rare in
India.
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