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The International Journal of Lower Extremity

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2003 2: 40International Journal of Lower Extremity WoundsV S Chauhan, M Adil Rasheed, S S Pandley and V K Shukla

A Therapeutic Dilemma−−Nonhealing Wounds  

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10.1177/1534734603254690 ARTICLELOWER EXTREMITY WOUNDS 0(0); 2003CHAUHAN ET ALLOWER EXTREMITY WOUNDS 0(0); 2003NONHEALING WOUNDS

Nonhealing Wounds—A 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 di-lemma. In India, chronic wounds are caused by factors otherthan impaired circulation and diabetes, which account formost of this clinical problem in Western societies. A study of 2topical agents, placental extract and phenytoin powder, ispresented in this paper. One hundred fifty patients were ran-domly assigned to these treatments or to saline dressings(control). It was observed that patients receiving active topi-cal treatments responded better than those in the controlgroup. The importance of this finding should be viewed with

the perspective that these topical treatments are inexpensiveand easily available in India. The study also piloted measure-ments of angiogenic responses in 1 group, and the findingsencourage further exploration with the technique and topicalagent.

Key words: chronic wounds, topical therapy, randomizedstudy, angiogenesis

Chronic wounds are a drain on health care re-sources. Such wounds challenge health care pro-

viders to define and create more effective interventionstrategies. Clinically, wounds are categorized as acuteor chronic dependent on their time courses of healingand tendencies to relapse. In practice, the duration ofhealing is very variable; hence, the distinction betweenan acute and a chronic wound is arbitrary, dependenton variables including the site and the cause of thewound and the age and physical condition of the pa-tient.1 Most chronic wounds are associated with well-defined clinical entities, particularly diabetes mellitus,pressure necrosis, and venous hypertension. In India,leprotic ulcers are the most common cause ofnonhealing wounds.2

Cutaneous tissue repair is a complex, dynamic pro-cess involving 3 main overlapping phases:

• The inflammatory phase begins within 6 hours of in-jury.3 The disruption of blood vessels leads to clot for-mation and the phagocytosis of microorganisms by thereleased neutrophils, macrophages, and enzymes.

• The proliferative phase consists of the formation ofgranulation tissue consisting of a dense population ofmacrophages and fibroblasts embedded in a loose ma-trix of collagen, fibronectin, and hyaluronic acid. Theproliferation, migration, and differentiation ofkeratinocytes take place to restore surface integrity.Neovascularization or angiogenesis in a wound occursconcomitantly with fibroplasia.

• The matrix formation and remodeling phase consists ofthe accumulation of large fibrous bundles of type I col-lagen that produce the residual scar while impartingtensile strength to connective tissues.

COMMON TYPES OF NONHEALING WOUNDS

Pressure Ulcers

Hospitalized patients who are at risk for developingpressure ulcers constitute 14% to 20% of hospital casesat any one time.4 There is 4-fold increased morbidityand mortality among ill elderly patients. Increasedpressure over the bony prominences leads to compro-mised blood supply and lymphatic drainage, and thisin turn leads to tissue ischemia, which causes damageto underlying muscle and subcutaneous tissue.

When spontaneous healing is not apparent even af-ter the relief of pressure, surgical intervention becomesnecessary. Complications of pressure ulcers include in-fection, dehydration, anemia, and electrolyteimbalance.

40 LOWER EXTREMITY WOUNDS 2(1);2003 pp. 40–45

Correspondence should be sent to: Professor VK Shukla, MB BS,M.Ch(Wales), Department of General Surgery, Institute of Medical Sci-ences, Banaras Hindu University, Varanasi - 221 005, India; e-mail:vkshuklabhu@satyam.net.in.

DOI: 10.1177/1534734603254690© 2003 Sage Publications

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Diabetes Mellitus

Chronic foot ulcers are the leading cause of amputa-tion among diabetic patients.5 The risk for lower ex-tremity amputation is 15 times higher among diabeticscompared to nondiabetics. Although the fundamentalpathophysiological factors leading to ulcer formationremain ill understood, the triad of neuropathy,ischemia, and infection is considered the most impor-tant in the development of ulcers.

Below the knee, the blood vessels commonly in-volved in diabetic angiopathy are the posterior and an-terior tibial vessels, the peroneal vessels, and the smallvessels in the foot. There are multiple risk factors in-volved in the development of diabetic peripheral vas-cular disease, of which smoking, hyperglycemia, hy-percholesterolemia, and hypertension are the mostimportant.

At the Indian National Institute of Diabetics inMumbai, > 10% of all admissions for diabetes are pri-marily for foot management; at least 70% require surgi-cal intervention, and of these, at least 40% are toe orlimb amputations.6

Venous Ulcers

Chronic venous insufficiency (CVI) is often re-stricted to the end clinical stage of the syndrome of ve-nous hypertension, limb swelling, pigmentation,induration, and ulceration. Venous ulceration repre-sents the end stage of the disease process and only asmall proportion of the disease spectrum. Fibrin cuffsaround capillaries were proposed as a cause of local ox-ygen and nutrient deprivation, thereby leading to ul-ceration.7,8 This hypothesis has largely been discred-ited because fibrin deposition occurs in manyulcerated and nonulcerated tissues. It has also beensuggested that susceptibility to ulceration in CVI maybe due to release of humoral and toxic substances fromwhite blood cells trapped in subcutaneous capillariesbecause of increased venous back pressure.9

Leprotic Ulcers

Plantar ulceration is a common complication of aninsensate foot among patients with leprosy. The sitesaffected are areas of the sole that come under pressurewhile walking. Excessive walking, often on bare feet,causes injury to the tissues, which are unable to offerfeedback on account of being insensate. The injury pro-duces inflammation, which accentuates the damage,resulting in an open wound.10 Open wounds are fre-quently infected with pathogenic organisms; the infec-

tion extends into the muscles and bones, causingchronic osteomyelitis and the disintegration of the foot.

The mainstay of treatment is the topical applicationof agents and surgical debridement. There are a numberof agents available for topical use, but their costs arevaried and there are few controlled data on theirefficacy.

The aim of this study was to compare the effects of 2different topical treatments with a control. The subsid-iary aims of the study were to derive information aboutthe clinical profiles of nonhealing wounds in the healthdistrict we served and to examine the effects of chemi-cal peeling on wounds with hyperkeratotic edges. Theagents chosen for treatment were placental extract andphenytoin powder, as described in the succeedingsection.

Placental Extract

The aqueous extract of a human placenta containsvarious enzymes such as alkaline and acid phos-phatase, glutamic acid, and oxaloacetic acid; nucleo-tides such as RNA, DNA, and adenosine triphosphate;vitamins such as B10, B2, B6, pantothenic acid, biotin,para-aminobenzoic acid, folic acid, B12, choline, andinositol; amino acids such as alanine, tryptophan,valine, leucine, lysine, phenylalanine, cholesterol,fatty acids, and steroids; and trace elements. Thesecomponents exert multiple biological activities, in-cluding immunomodulatory and anti-inflammatoryactivities. They are also reported to have growth factor–like activity,11 pigmenting activity,12 and keratinocyteproliferating activity.13

Phenytoin Powder

Phenytoin (diphenylhydantoin) has been in use forsome time now and has been reported to promotewound healing. Oral phenytoin reduced the formationof blisters among patients with recessive dystrophicepidermolysis bullosa.14 There was a reported decreasein wound exudates and bacterial contamination amongpatients treated with topical phenytoin powder. It ischeap and readily available in India.

Chemical Peeling

As part of the subsidiary aims of this study, chemicalpeeling was selected to debride wound edges.Chemoexfoliation, or chemical peeling, is the applica-tion of 1 or more chemical agents to the skin to causecontrolled chemical burns, resulting in the destructionof a portion of the epidermis and or dermis through dry

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desquamation or moist maceration followed by its ex-foliation and the subsequent resurfacing of the epider-mis along with the remodeling of collagen and elasticfibers and the deposition of glycosaminoglycans dur-ing the repair process in the dermis. Numerous agentshave been used over the years. However,trichloroacetic acid (TCA), phenol, and salicylic acidare chemicals in use today.

MATERIALS AND METHODS

Study Design and Setting

A randomized controlled study was carried out atthe University Hospital, Banaras Hindu University,Varanasi, India. One hundred fifty patients withchronic, nonhealing wounds attending the WoundClinic from May 2000 to November 2001 were consecu-tively recruited to the study. Detailed histories weretaken and recorded in folders. Thorough clinical exam-inations were done, with special stress on the nervousand cardiovascular systems of patients with leprosyand diabetes mellitus. Local examination of woundswas carried out, and characteristics of wounds, includ-ing their size, discharge, floors, base edges, margins,and draining nodes were recorded.

Patients were randomly assigned to 3 groups. Group1 (n = 50) received topical Placentrex (Albert David Ltd,Kolkata, India) daily, group 2 (n = 50) receivedphenytoin 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 andchemotherapy as required. Patients were followed upat weekly intervals. Wound areas were measured at allvisits, and other findings were also recorded. Patientswere included in the study for a maximum period of 6months.

As part of the subsidiary aims of this study, tissuesamples were collected for histopathology and furtherstudies from a subset of patients in group 1who weretreated with placental extract to ascertain itsangiogenic effects (n = 9). In wound edges withhyperkeratotic margins that were in need ofdebridement, chemical peeling was carried out. Six-millimeter punch biopsies were done under local anes-thesia and sent for histopathological studies, includingangiogenesis. Microscopic angiogenesis was calcu-lated using a previously described method, the Micro-scopic Angiogenesis Grading System (MAGS).15 MAGSwas done by M. Kumar.

MAGS was based on 3 parameters of endothelial re-generation: vasoproliferation (KnN), endothelial cell

hyperplasia (KcE), and endothelial cytology (KxX). Anumerical grade was given to each of these variablesand an overall index (range, 0–100) of endothelial re-generation was calculated:

MAGS = KnN + KcE + KxX.

Swabs were taken for culture and sensitivity andsent for microbiological examination. Hematologicalprofiles and radiological examinations of involvedparts were also done on all patients.

Statistical Analysis

All observations were tabulated and interpreted interms of percentage, mean, median, and standard devi-ation. To test the significance of associations and differ-ences of the mean, Student t tests, chi-square tests, andvariance ratio tests (F) were applied.

RESULTS

Wound Epidemiology

Epidemiological profiles of the patients revealedthat the maximum number of patients were in the fifthdecades of their lives and above. The age range wasfrom 4 to 78 years, with a mean age of 43.20 ± 15.56years. Of the patients, 81.55% were male.

Wound duration varied from 6 weeks to 20 years, themean duration being 1.63 ± 3.22 years. Approximately33% of the patients had wounds of < 3 months’duration.

In the present study, 61 patients (59.22%) hadleprotic ulcers. Venous ulcers and diabetic ulcers werethe next most common presentations. The study indi-cated that leprosy was the most common primary etio-logical problem leading to nonhealing ulcers in thisarea of India, which is consistent with a previous obser-vation by our group.2 In the former study, leprosy wasalso the main cause of leg wounds, accounting for 40%of cases, with diabetes mellitus being the next mostcommon cause in 23% of all patients. The repeated ob-servations from this Center contrast with those ofKnighton et al,16 who documented that cutaneous,nonhealing wounds were most frequently caused bydiabetes (58%), trauma (16%), decubitius ulcers(14%), venous stasis ulcers (6%), and arterial insuffi-ciency (6%). Thus, chronic lower extremity woundshave different causations in Western societies as op-posed to India.

The most common site of the presentation of non-healing wounds in this study was the foot (74.76%).

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Plantar aspects accounted for > 64.08% of wounds, theplantar surface, the pad of the great toe, the heel, andthe head of the first metatarsal area being the predomi-nant sites. This could be explained by the fact that thesepatients had sensory loss over their feet, and these areaswere exposed to excess mechanical stress. Birke et al17

found the first metatarsal head to be the most commonsite of ulceration in their series of patients with plantarulcers due to leprosy and diabetes.

Healing Rates

The calculated surface wounds are presented in Ta-ble 1. Also presented are 50% reductions in wound ar-eas in the study population (Table 2). Healing was as-sessed by calculating the time taken to achieve a 50%reduction in wound surface area. This is presented inTable 2.

These results demonstrate that patients in groups 1and 2 responded favorably to the assigned treatments,compared to those in group 3 (the control group).

MAGS measurements on the subset of patients fromgroup 1 are discussed in the succeeding section.

DISCUSSION

The main aim of this study was to examine the ef-fects of placental extract and phenytoin powder onchronic, cutaneous wounds of different etiologies. Theother purpose of the study was to identify the epidemi-ology of chronic, cutaneous wounds in the health dis-trict in which we serve. We also had subsidiary aims tostudy the effects of chemical peeling, an alternative to

surgical debridement, and the angiogenic effects of pla-cental extract on wounds.

To examine the effects of the topical treatmentsused, area reductions at 2 weekly intervals were com-pared against control values. The z statistics from thesecomparisons are presented in Table 3. Favorable re-sponses were obtained in both groups that received ac-tive treatment. Placental extracts, known to containgrowth factors and anti-inflammatory agents,11 werehelpful in healing chronic wounds in this study. Astudy on the healing of full-thickness punch wounds 8mm in diameter in rat models showed that with thetopical application of placental extract, complete heal-ing occurred in an average of 12.15 days, compared to16.66 days among an untreated group.11 No adverse ef-fects were reported in this study. It would appear thatthis treatment is beneficial in clinical and experimentalanimal models.

Patients in this study also benefited from topicaltreatment with phenytoin powder: > 50% healing at 8weeks was observed in 48% of patients. There were noside effects in this group either. Lodha et al18 reportedthat phenytoin reduced edema and inflammation andaccelerated the growth of healthy tissue among patientswith large abscesses.

Bansal and Mukul19 compared the role of phenytoinin the treatment of chronic trophic ulcers in leprosy.Over a 4-week period, the mean percentage of woundvolume reduction measured was greater among thephenytoin group (72.1% ± 19.9%) compared to con-trols (55.5% ± 21.6%). Muthu Kumar Swamy et al20 re-

LOWER EXTREMITY WOUNDS 2(1); 2003 43

NONHEALING WOUNDS

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

Group Before Treatment After Treatment Values

Group 1 15.25 (SD = 19.8) 3.6 (SD = 7.28) t = 1.57, P < .001Group 2 15.20 (SD = 15.2) 4.80 (SD = 7.5) t = 1.71, P < .01Group 3 11.33 (SD = 23.45) 7.6 (SD = 17.75) t = 0.71, P > 0.5

Table 2. 50% Healing of Wounds:Three Groups at Various Time Intervals

50% Healing Group 1 Group 2 Group 3of Wounds (%) (%) (%)

At 2 wk 10.00 6.06 3.33At 4 wk 40.00 39.39 3.33At 6 wk 52.50 45.45 20.00At 8 wk 67.50 48.48 23.33

Table 3. Significance Comparison (z value) of AreaChanges in the Groups in the Study

Compared to the Control Group (group 3)

Group 1 vs Group 1 vs Group 2 vsPeriod Group 2 Group 3 Group 3

At 2 wk 0.61 1.07 0.51At 4 wk 0.05 3.54*** 3.44***At 6 wk 0.60 2.76** 2.14*At 8 wk 1.64 3.66*** 2.07*

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

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ported the use of topical phenytoin in diabetic foot ul-cers among 50 patients compared to controls. Bothgroups improved, though the wounds treated with top-ical phenytoin healed more rapidly, the mean time tocomplete healing being 21 and 45 days for the treat-ment and control groups, respectively. These reportsare consistent with the observations in this report usingtopical phenytoin.

Other Aims

This study showed that leprosy is the most commoncause of chronic wounds in this health district servedby the authors, followed by diabetes mellitus. This mayhave implications for health care planning, because theincidence of diabetes is increasing in India, as it isworldwide. The faster healing obtained in this studyshould encourage the use of simple topical treatmentsthat are inexpensive and available locally.

In the subset of patients from group 1 (n = 9) who re-ceived topical Placentrex, there was an increase inmean angiogenic scores with treatment. A comparisonof the means showed the increase to be statistically sig-nificant (P < .01). Details are presented in Table 4.

Twenty cases of nonhealing wounds had hyper-keratotic edges. In 10 of these 20 cases, TCA or carbolicacid was applied on the edges at weekly intervals, withimmense benefits showing the advantage of this meth-odology over surgical debridement. Another advantagein favor of chemical peeling is that no formal training isneeded, compared to the skills essential to conduct

sharp surgical debridement. This observation is inter-esting and needs to be developed in future studies.

This study suggests the potential of placental extractand phenytoin powder in the management ofnonhealing wounds. Future studies should followwounds through to closure in order to gain a fuller un-derstanding of the potential of these topical therapies.It is suggested that the perceived benefits of topical pla-cental extracts may be due to multiple effects onangiogenesis, collagen synthesis, and epithelial cellproliferation. It is noteworthy that patients with ve-nous ulcers did not receive compression bandaging,because it is not available in India. Another observationis that malignant changes in trophic wounds are rare inIndia.

REFERENCES

1. Kirsner RS, Eaglstein WH. The wound healing process. DermatolClin 1993;11(4);629-40.2. Saraf SK, Shukla VK, Kaur P, Pandey SS. A clinico-epidemiolog-

ical profile of non-healing wounds in an Indian hospital. J WoundCare 2000;9(5):247-50.3. Nwomeh BC, Yager DR, Cohen IK. Physiology of the chronic

wound. Clin Plast Surg 1998;25(3):341-56.4. Allman RM, Laprade CA, Noel LB, et al. Pressure sores among

hospitalized patients. Ann Intern Med 1986;105(3):337-42.5. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb

amputation: basis for prevention. Diabetes Care 1990;13(5):513-54.6. Satne SR. Managing the diabetic foot in developing countries. Int

Diabetes Fed Bull 1993;38:16-8.7. Burnand KG, Whimster I, Naidoo A, Browse NL. Pericapillary fi-

brin in the ulcer-bearing skin of the lower limb: the cause oflipodermatosclerosis and venous ulceration. Br Med J 1982;285:1071-2.8. Browse NL, Burnand KG. The cause of venous ulceration. Lancet

1982;2:243-5.9. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes

of venous ulceration: a new hypothesis. Br Med J 1988;296:1726-7.10. Coleman WC, Brand PW, Birke JA. The total contact cast: a ther-apy for plantar ulceration on insensitive feet. J Am Podiatry Assoc1984;74(11):548-52.11. Mukherjee B. Pharmacological and biochemical screening ofPlacentrex. Department of Pharmacology, University College of Med-icine, Calcutta University, WB. Quarterly Project Report–January toMarch 1997.12. Pal P, Roy R, Dalth PK, Dutta AK, Biswas B, Bhadra R. Hydroalcolosi human placental extract: skin pigmenting activity and grosschemical composition. Int J Dermatol 1995;34(1):61-6.13. O’Keefe EJ, Payne RE Jr, Russel N. Keratinocyte growth-promot-ing activity from human placenta. J Cell Physiol 1985;124:439-45.14. Valle KJ, Bauer EA. Enhanced biosynthesis of human skin colla-genase in fibroblast cultures from recessive dystrophicepidermolysis bullosa. J Clin Invest 1980;66(2):176-87.15. Brem S, Cotran R, Folkman J. Tumor angiogenesis: a quantitativemethod for histologic grading. J Natl Cancer Inst 1972;48(2):347-56.16. Knighton DR, Ciresi KF, Fiegel VD, et al. Classification and treat-ment of chronic non-healing wounds. Successful treatment withautologous platelet-derived wound healing factors (PWDHF). AnnSurg 1986;204:322-30.

44 LOWER EXTREMITY WOUNDS 2(1); 2003

CHAUHAN ET AL

Table 4. Histopathology Findings Relating toAngiogenesis Before Treatment Commenced and 2

Weeks Hence

Serial MAGS Score MAGS ScoreNumber Before Treatment After Treatment

1 53 532 18 343 33 494 39 575 44 496 65 737 31 468 41 339 51 65

Mean MAGSscore 41.66 ± 13.88 51.00 ± 13.06

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

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17. Birke J, Novick A, Patout C, Coleman W. Healing rates of plantarulcers in leprosy and diabetes. Lepr Rev 1992;63:335-74.18. Lodha SC, Lohiya ML, Vyas MCR, Sudha B, Goyal RR, Harsh MK.Role of phenytoin in healing of large abscess cavities. Br J Surg1991;78:105-8.

19. Bansal NK, Mukul. Comparison of topical phenytoin with nor-mal saline in the treatment of chronic trophic ulcers in leprosy. Int JDermatol 1993;32(3):210-3.20. Muthu Kumar Swamy MG, Sivakumar G, Manoharan G. Topicalphenytoin in diabetic ulcers. Diabetic Care 1991;14(10):909-11.

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