The International Journal of Lower Extremity

Wounds
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Nonhealing Wounds−−A 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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is presented in this paper. 40–45 Downloaded from ijl. placental extract and phenytoin powder. Key words: chronic wounds. Institute of Medical Sciences. 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. which causes damage to underlying muscle and subcutaneous tissue.ARTICLE 10. It was observed that patients receiving active topical treatments responded better than those in the control group. In India. India Chronic wounds of the lower extremity are a therapeutic dilemma. DOI: 10.2003 pp.1177/1534734603254690 © 2003 Sage Publications 40 the perspective that these topical treatments are inexpensive and easily available in India. which account for most of this clinical problem in Western societies. pressure necrosis.1 Most chronic wounds are associated with welldefined clinical entities. fibronectin. India. migration. hence. LOWER EXTREMITY WOUNDS 2(1). In practice. and differentiation of keratinocytes take place to restore surface integrity.Ch(Wales). MD. MS. When spontaneous healing is not apparent even after the relief of pressure.net.3 The disruption of blood vessels leads to clot formation and the phagocytosis of microorganisms by the released neutrophils. and VK Shukla. the distinction between an acute and a chronic wound is arbitrary. and this in turn leads to tissue ischemia. Banaras Hindu University. Department of Dermatology and Venereology. The study also piloted measurements of angiogenic responses in 1 group. One hundred fifty patients were randomly assigned to these treatments or to saline dressings (control). topical therapy. Department of General Surgery. randomized study. dehydration. and the findings encourage further exploration with the technique and topical agent. MCh(Wales) Department of General Surgery. 2003 Nonhealing Wounds—A Therapeutic Dilemma VS Chauhan. e-mail: vkshuklabhu@satyam. SS Pandley. MBBS. The importance of this finding should be viewed with C hronic wounds are a drain on health care resources.in.1177/1534734603254690 CHAUHAN LOWER NONHEALING EXTREMITY ET AL WOUNDS WOUNDS 0(0). M Adil Rasheed. dynamic process involving 3 main overlapping phases: • The inflammatory phase begins within 6 hours of injury.4 There is 4-fold increased morbidity and mortality among ill elderly patients. chronic wounds are caused by factors other than impaired circulation and diabetes.com at Airlangga University on April 30. Varanasi . 2012 . macrophages. Increased pressure over the bony prominences leads to compromised blood supply and lymphatic drainage. • 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. The proliferation. particularly diabetes mellitus. Such wounds challenge health care providers to define and create more effective intervention strategies. MD. Complications of pressure ulcers include infection. leprotic ulcers are the most common cause of nonhealing wounds. dependent on variables including the site and the cause of the wound and the age and physical condition of the patient.221 005. Correspondence should be sent to: Professor VK Shukla. 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. Clinically. Institute of Medical Sciences. A study of 2 topical agents. In India.sagepub. and hyaluronic acid.2 Cutaneous tissue repair is a complex. Varanasi. M. Banaras Hindu University. the duration of healing is very variable. and electrolyte imbalance. wounds are categorized as acute or chronic dependent on their time courses of healing and tendencies to relapse. surgical intervention becomes necessary. anemia. MB BS. Neovascularization or angiogenesis in a wound occurs concomitantly with fibroplasia. and enzymes. and venous hypertension.

9 Leprotic Ulcers Plantar ulceration is a common complication of an insensate foot among patients with leprosy. the blood vessels commonly involved in diabetic angiopathy are the posterior and anterior tibial vessels. choline. the peroneal vessels. resulting in the destruction of a portion of the epidermis and or dermis through dry LOWER EXTREMITY WOUNDS 2(1). and the small vessels in the foot. the infec- tion extends into the muscles and bones. They are also reported to have growth factor– like activity. and of these. is the application of 1 or more chemical agents to the skin to cause controlled chemical burns. vitamins such as B10. It is cheap and readily available in India. valine. chemical peeling was selected to debride wound edges. Chemoexfoliation. causing chronic osteomyelitis and the disintegration of the foot. resulting in an open wound. lysine.8 This hypothesis has largely been discredited because fibrin deposition occurs in many ulcerated and nonulcerated tissues. and infection is considered the most important in the development of ulcers. Below the knee. The injury produces inflammation. fatty acids. Placental Extract The aqueous extract of a human placenta contains various enzymes such as alkaline and acid phosphatase. B6. and oxaloacetic acid. or chemical peeling. at least 70% require surgical intervention. and trace elements. At the Indian National Institute of Diabetics in Mumbai.7. amino acids such as alanine.com at Airlangga University on April 30. 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.13 Phenytoin Powder Phenytoin (diphenylhydantoin) has been in use for some time now and has been reported to promote wound healing. leucine. hypercholesterolemia. folic acid. Although the fundamental pathophysiological factors leading to ulcer formation remain ill understood. para-aminobenzoic acid. DNA. Oral phenytoin reduced the formation of blisters among patients with recessive dystrophic epidermolysis bullosa. These components exert multiple biological activities. Fibrin cuffs around capillaries were proposed as a cause of local oxygen and nutrient deprivation. cholesterol. the triad of neuropathy. Excessive walking. 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. glutamic acid. and ulceration. B12. which accentuates the damage. induration.12 and keratinocyte proliferating activity.14 There was a reported decrease in wound exudates and bacterial contamination among patients treated with topical phenytoin powder. as described in the succeeding section. 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. and steroids.NONHEALING WOUNDS Diabetes Mellitus Chronic foot ulcers are the leading cause of amputation among diabetic patients.10 Open wounds are frequently infected with pathogenic organisms. and inositol. which are unable to offer feedback on account of being insensate. biotin. B2. including immunomodulatory and anti-inflammatory activities.11 pigmenting activity. The mainstay of treatment is the topical application of agents and surgical debridement. tryptophan. The sites affected are areas of the sole that come under pressure while walking. 2012 41 . > 10% of all admissions for diabetes are primarily for foot management. thereby leading to ulceration. pantothenic acid. ischemia. limb swelling.sagepub. often on bare feet. and adenosine triphosphate. nucleotides such as RNA.6 Venous Ulcers Chronic venous insufficiency (CVI) is often restricted to the end clinical stage of the syndrome of venous hypertension. The agents chosen for treatment were placental extract and phenytoin powder. and hypertension are the most important.5 The risk for lower extremity amputation is 15 times higher among diabetics compared to nondiabetics. Venous ulceration represents the end stage of the disease process and only a small proportion of the disease spectrum. of which smoking. pigmentation. Chemical Peeling As part of the subsidiary aims of this study. 2003 Downloaded from ijl. at least 40% are toe or limb amputations. There are multiple risk factors involved in the development of diabetic peripheral vascular disease. phenylalanine. causes injury to the tissues. hyperglycemia.

Patients were followed up at weekly intervals. India. The age range was from 4 to 78 years. chemical peeling was carried out.76%). and arterial insufficiency (6%). median. Microscopic angiogenesis was calculated using a previously described method.15 MAGS was done by M. trichloroacetic acid (TCA). accounting for 40% of cases. base edges. Venous ulcers and diabetic ulcers were the next most common presentations. with a mean age of 43. endothelial cell 42 hyperplasia (KcE). and standard deviation. Patients were randomly assigned to 3 groups.55% were male. One hundred fifty patients with chronic. and draining nodes were recorded. trauma (16%). Varanasi.2 In the former study. In wound edges with hyperkeratotic margins that were in need of debridement. 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. and endothelial cytology (KxX). Of the patients. 0–100) of endothelial regeneration was calculated: All observations were tabulated and interpreted in terms of percentage. MAGS was based on 3 parameters of endothelial regeneration: vasoproliferation (KnN). and other findings were also recorded. Wound areas were measured at all visits. As part of the subsidiary aims of this study.56 years. Thus. 2012 . nonhealing wounds attending the Wound Clinic from May 2000 to November 2001 were consecutively recruited to the study. discharge. Swabs were taken for culture and sensitivity and sent for microbiological examination.sagepub. 100 mg) locally. Patients were also given systemic antibiotics and chemotherapy as required. with diabetes mellitus being the next most common cause in 23% of all patients. Kolkata. 2003 Downloaded from ijl. To test the significance of associations and differences of the mean. In the present study. LOWER EXTREMITY WOUNDS 2(1). Local examination of wounds was carried out.63 ± 3. India) daily. chi-square tests. Numerous agents have been used over the years. India. chronic lower extremity wounds have different causations in Western societies as opposed to India. The repeated observations from this Center contrast with those of Knighton et al. n = 50) was treated with normal saline applied topically. A numerical grade was given to each of these variables and an overall index (range. mean. including angiogenesis. 61 patients (59. leprosy was also the main cause of leg wounds. Student t tests. The study indicated that leprosy was the most common primary etiological problem leading to nonhealing ulcers in this area of India. Thorough clinical examinations were done. the Microscopic Angiogenesis Grading System (MAGS). Group 1 (n = 50) received topical Placentrex (Albert David Ltd. Detailed histories were taken and recorded in folders.22%) had leprotic ulcers. Parke Davis. floors.16 who documented that cutaneous.com at Airlangga University on April 30. venous stasis ulcers (6%). 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). The most common site of the presentation of nonhealing wounds in this study was the foot (74. Statistical Analysis A randomized controlled study was carried out at the University Hospital. and salicylic acid are chemicals in use today.20 ± 15. including their size.22 years. Patients were included in the study for a maximum period of 6 months. decubitius ulcers (14%).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. Approximately 33% of the patients had wounds of < 3 months’ duration. 81. with special stress on the nervous and cardiovascular systems of patients with leprosy and diabetes mellitus. Wound duration varied from 6 weeks to 20 years. However. and characteristics of wounds. and group 3 (the control group. Hematological profiles and radiological examinations of involved parts were also done on all patients. Banaras Hindu University. margins. nonhealing wounds were most frequently caused by diabetes (58%). Kumar. group 2 (n = 50) received phenytoin powder (Dilantin capsule. which is consistent with a previous observation by our group. Sixmillimeter punch biopsies were done under local anesthesia and sent for histopathological studies. the mean duration being 1. phenol. MATERIALS AND METHODS Study Design and Setting MAGS = KnN + KcE + KxX. and variance ratio tests (F) were applied.

Over a 4-week period. 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. We also had subsidiary aims to study the effects of chemical peeling. P < .07* *P < .6%).com at Airlangga University on April 30.66*** Group 2 vs Group 3 0.75) Table 2. an alternative to t = 1.44*** 2.25 (SD = 19. area reductions at 2 weekly intervals were compared against control values.33 Plantar aspects accounted for > 64. Healing was assessed by calculating the time taken to achieve a 50% reduction in wound surface area.61 0.45 48.6 (SD = 7.71.5% ± 21. These results demonstrate that patients in groups 1 and 2 responded favorably to the assigned treatments.33 20.5) 7. Placental extracts. 2012 43 .20 (SD = 15.05 0. P > 0. To examine the effects of the topical treatments used. and these areas were exposed to excess mechanical stress.NONHEALING WOUNDS Table 1.71. Also presented are 50% reductions in wound areas in the study population (Table 2).50 67.50 Group 2 (%) Group 3 (%) 6. There were no side effects in this group either.00 40.14* 2. 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. Favorable responses were obtained in both groups that received active treatment.08% of wounds.001. MAGS measurements on the subset of patients from group 1 are discussed in the succeeding section.00 52.80 (SD = 7.06 39.54*** 2.15 days. Healing Rates The calculated surface wounds are presented in Table 1.5 Table 3.64 Group 1 vs Group 3 1. known to contain growth factors and anti-inflammatory agents.00 23. and the head of the first metatarsal area being the predominant sites. The z statistics from these comparisons are presented in Table 3.001 t = 1. This could be explained by the fact that these patients had sensory loss over their feet.51 3. complete healing occurred in an average of 12.33 3. P < . 2003 Downloaded from ijl.28) 4. Lodha et al18 reported that phenytoin reduced edema and inflammation and accelerated the growth of healthy tissue among patients with large abscesses. the pad of the great toe. Muthu Kumar Swamy et al20 re- LOWER EXTREMITY WOUNDS 2(1). and the angiogenic effects of placental extract on wounds.1% ± 19.01.76** 3. the mean percentage of wound volume reduction measured was greater among the phenytoin group (72.05.2) 11. compared to 16.48 Values 3. DISCUSSION The main aim of this study was to examine the effects of placental extract and phenytoin powder on chronic.9%) compared to controls (55.01 t = 0.6 (SD = 17.33 (SD = 23.57. **P < .11 No adverse effects were reported in this study. It would appear that this treatment is beneficial in clinical and experimental animal models. 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 0.66 days among an untreated group.39 45. This is presented in Table 2. compared to those in group 3 (the control group). Bansal and Mukul19 compared the role of phenytoin in the treatment of chronic trophic ulcers in leprosy. Patients in this study also benefited from topical treatment with phenytoin powder: > 50% healing at 8 weeks was observed in 48% of patients. the heel.45) 3.sagepub. 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 (%) 10.11 were helpful in healing chronic wounds in this study.07 3. Mean Surface Area (cm2) With Standard Deviations for All Treatment Groups Group Before Treatment Group 1 Group 2 Group 3 After Treatment 15. ***P < . cutaneous wounds in the health district in which we serve. surgical debridement. cutaneous wounds of different etiologies. The other purpose of the study was to identify the epidemiology of chronic.60 1. the plantar surface.8) 15.

Browse NL.105(3):337-42.124:439-45. J Cell Physiol 1985. Pressure sores among hospitalized patients. Quarterly Project Report–January to March 1997. Whimster I. J Wound Care 2000.CHAUHAN ET AL Table 4. The total contact cast: a therapy for plantar ulceration on insensitive feet. Payne RE Jr. followed by diabetes mellitus. Br Med J 1982. REFERENCES 1. with immense benefits showing the advantage of this methodology over surgical debridement. Details are presented in Table 4. Brand PW. Ciresi KF. collagen synthesis. A clinico-epidemiological profile of non-healing wounds in an Indian hospital. WB. Ann Intern Med 1986.285: 1071-2. Pharmacological and biochemical screening of Placentrex. 4. Ann Surg 1986. Dermatol Clin 1993.204:322-30. respectively. Physiology of the chronic wound. Saraf SK. This observation is interesting and needs to be developed in future studies. the mean time to complete healing being 21 and 45 days for the treatment and control groups. though the wounds treated with topical phenytoin healed more rapidly.9(5):247-50. P = .13(5):513-54. because it is not available in India. Calcutta University.2:243-5. as it is worldwide. 12. Pecoraro RE. Int Diabetes Fed Bull 1993. Valle KJ. O’Keefe EJ. In the subset of patients from group 1 (n = 9) who received topical Placentrex.66(2):176-87. Nwomeh BC. Noel LB. Successful treatment with autologous platelet-derived wound healing factors (PWDHF).11(4). Birke JA. Laprade CA. Bauer EA. Classification and treatment of chronic non-healing wounds. Thomas P. Pal P. 3. Dalth PK. Naidoo A. Lancet 1982. 10. 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. Other Aims This study showed that leprosy is the most common cause of chronic wounds in this health district served by the authors. J Am Podiatry Assoc 1984.48(2):347-56. 2. Fiegel VD. because the incidence of diabetes is increasing in India.88 MAGS Score After Treatment 53 34 49 57 49 73 46 33 65 51. Hydroal colosi human placental extract: skin pigmenting activity and gross chemical composition. Russel N. 9. LOWER EXTREMITY WOUNDS 2(1). Roy R. Pandey SS. Cohen IK. Burnand KG. Bhadra R. TCA or carbolic acid was applied on the edges at weekly intervals. In 10 of these 20 cases. Br Med J 1988.25(3):341-56.com at Airlangga University on April 30. there was an increase in mean angiogenic scores with treatment. Both groups improved. Mukherjee B. The cause of venous ulceration. 6. A comparison of the means showed the increase to be statistically significant (P < .74(11):548-52. Tumor angiogenesis: a quantitative method for histologic grading.296:1726-7. 15. 2003 Downloaded from ijl.38:16-8.34(1):61-6. Dutta AK. Burgess EM. These reports are consistent with the observations in this report using topical phenytoin. University College of Medicine.06 MAGS = Microscopic Angiogenesis Grading System. J Clin Invest 1980. J Natl Cancer Inst 1972. 8. Dormandy JA. 7. Department of Pharmacology. It is noteworthy that patients with venous ulcers did not receive compression bandaging. Shukla VK.01.01). 14. Satne SR. et al. Diabetes Care 1990. Clin Plast Surg 1998. 2012 . Coleridge Smith PD. Managing the diabetic foot in developing countries. Another advantage in favor of chemical peeling is that no formal training is needed. The faster healing obtained in this study should encourage the use of simple topical treatments that are inexpensive and available locally. Scurr JH. ported the use of topical phenytoin in diabetic foot ulcers among 50 patients compared to controls. t = 3. 13. Cotran R. Yager DR. Pathways to diabetic limb amputation: basis for prevention. Biswas B. Future studies should follow wounds through to closure in order to gain a fuller understanding of the potential of these topical therapies. Eaglstein WH. Kaur P. Brem S. This may have implications for health care planning. Keratinocyte growth-promoting activity from human placenta. Int J Dermatol 1995. The wound healing process. et al. Coleman WC. compared to the skills essential to conduct 44 sharp surgical debridement. This study suggests the potential of placental extract and phenytoin powder in the management of nonhealing wounds. Pericapillary fibrin in the ulcer-bearing skin of the lower limb: the cause of lipodermatosclerosis and venous ulceration. Another observation is that malignant changes in trophic wounds are rare in India. 11. Knighton DR.66 ± 13. Kirsner RS.00 ± 13.23. Enhanced biosynthesis of human skin collagenase in fibroblast cultures from recessive dystrophic epidermolysis bullosa. 16. Allman RM. It is suggested that the perceived benefits of topical placental extracts may be due to multiple effects on angiogenesis. 5. and epithelial cell proliferation. Reiber GE. Twenty cases of nonhealing wounds had hyperkeratotic edges. Folkman J. Causes of venous ulceration: a new hypothesis. Browse NL.sagepub.629-40. Burnand KG.

19. Bansal NK. Muthu Kumar Swamy MG. Comparison of topical phenytoin with normal saline in the treatment of chronic trophic ulcers in leprosy. Lepr Rev 1992. Vyas MCR. Br J Surg 1991. Lodha SC.sagepub. Goyal RR. Harsh MK. Mukul. Patout C.78:105-8.63:335-74. Novick A.com at Airlangga University on April 30. Topical phenytoin in diabetic ulcers.NONHEALING WOUNDS 17. LOWER EXTREMITY WOUNDS 2(1).32(3):210-3. 18. Birke J. Diabetic Care 1991. Sivakumar G. Manoharan G. Role of phenytoin in healing of large abscess cavities. 2003 Downloaded from ijl. 20. Healing rates of plantar ulcers in leprosy and diabetes. Sudha B. 2012 45 .14(10):909-11. Lohiya ML. Coleman W. Int J Dermatol 1993.