An Analysis of the Effectiveness of Skin Grafting to Treat Chronic Venous Leg Ulcers

The pathology of chronic venous leg ulcers (CVLUs) often presents itself and greatly influences the everyday life of the patient. Nearly 150,000 Lithuanian patients suffer from chronic venous insufficiency of the legs—almost 30,000 of which are attributed to venous leg ulcers.¹ The literature states that the frequency of CVLU varies from 0.18% to 1.9% of the entire population.^2–4 It should be noted that the frequency of CVLU depends on the age of the patient. In the group of patients who are older than 65 years, CVLU appear in 36 people of 100,000 and accounts for 3.6% of the population.^2–4 In almost 80% of all leg ulcer cases, the origination of ulcers is due to chronic venous insufficiency.
In Western countries leg ulceration increases among elderly people because of risk factors, such as smoking, obesity, and increases in diabetes.⁵ The gender of a patient is also significant. According to various studies, the proportion of men and women with leg ulceration fluctuates from 1:1.5 to 1:3.^6–8 These studies all note that the most common cause of CVLU is insufficient venous blood circulation. In this case, a CVLU opens due to the increased leg vein pressure. The main reason for that is the insufficiency of surface and deep veins and perforating vein valves. These veins and their valves must function well and are necessary so that blood can be pumped back to the heart during contraction of calf muscles (muscle pump). Valve leakage emerges as a result of post-thrombosis syndrome or it may be as congenital disease of valves or veins.
The primary clinical symptoms of chronic venous insufficiency of the legs are:
• edema
• lipodermatosclerosis
• hyperpigmentation
• hyperkeratosis
• atrophie blanche^.9,10
According to International Wounds Treatment Committee data from 2001, the cost for treatment of trophic ulcers is the highest among all surgical treatments for wounds. Therefore, it is often discussed which treatment is most effective, costs less, and heals chronic leg ulcers the fastest. Two possible treatment methods are conservative and surgical—there are many ways to perform them. The treatment of the disease that caused the ulcer and the local treatment of the ulcer must be noted. However, it is often impossible to eliminate the cause of disease with conservative or surgical treatment, especially when the vein deficiency and leg ulcers have existed for a long time, or if the patient was operated on only after the ulcer had epithelized. Conservative CVLU treatment may be concentrated solely on the treatment of an ulcer (bandaging with various bandages), on the etiologic factor (compressive therapy, medicaments, and exercises) or both.
The full epithelization of an ulcer may take several months or even years. Sometimes an ulcer does not fully heal for several years with conservative treatment.
In most countries ulcers are treated by partial-thickness skin autografting (ADP).^11,12
This study was undertaken to assess the effectiveness of skin autografting at 6 months post treatment. The tasks of the study were to 1) evaluate risk factors of ulcer origination on patients with large chronic venous leg ulcers; 2) identify the difference of epithelization speed between large chronic venous ulcers with conservative treatment versus skin autografting; 3) evaluate the cosmetic results of large CVLUs after skin autografting and conservative treatment.

Materials and Methods

The clinical study began January 2001 and ended June 2005. The study evaluated the effectiveness of various methods for healing large chronic venous leg ulcers (CVLUs). A prospective analysis of the disease course and treatment results after 6 months for 2 groups of patients was performed. Group S consisted of patients that were treated with surgical skin autografting. Group C consisted of patients treated only by conservative means. The patients were treated during from 2001–2005 at the Department of Plastic Surgery and Burns, Kaunas Medicine University Hospital and at the Clinic of Skin and Venereal Diseases (CSVD) of Kaunas Medicine University Hospital (KMUH). The aims of the analysis were to evaluate the influence on the speed of epithelization (healing) on ulcers treated either by surgical skin autografting or conservative treatment. The speed of epithelization, measured by the decrement in ulcer area within a 6-month period, was analyzed. The independent ethics commission of KMU approved the study. The questionnaire data, which were designed specifically for the study, the medical histories of patients with venous ulcers that had been open for more than 6 months and the area of which was greater than 50 cm² were studied. One hundred thirty four patients were studied. Sixty patients had leg ulcers of nonvenous origin, 3 patients refused to participate in the study, and 71 patients who had a CVLU (40 patients of group S and 31 of group C) returned for additional analysis.
Patients were randomly assigned to either group S (surgical treatment) or to group C (conservative treatment). A nurse, who at the time worked with the investigator, pulled out 1 of 2 cards that had either a “+” (surgery) or “-” (conservative treatment). The following was performed on each patient during his or her initial visit:
1. The patient was introduced to the study and to the method of treatment (conservative or surgery) that was selected by random draw
2. The microflora of the ulcer was identified (a sample was taken from the fundus of the ulcer)
3. The symptoms of inflammation were evaluated (secretion, swelling, febrile, blush, pain)
4. The vitals of the unharmed and ulcered calves were measured (above the popliteus, above the thickest part of a calf (about 10 cm below popliteus, and above tarsus)
5. The area of the ulcer was measured (in cm²)
6. A photo of the ulcer was taken
7. Patients completed questionnaires by which the authors evaluated the morphological peculiarities and patient history data of large CVLUs.
Patients in group S were operated on only when the ulcer had no necrotic areas and there were no symptoms of infection, when the general state of patient’s health was good, and when any concomitant diseases had been compensated. Skin transplantation was performed by autografting the punctured skin (0.2 mm–0.3 mm thick) on the renewed fundus of an ulcer (or ulcers). If on the day of discharge the remaining area of an ulcer was from 5 cm² to 15 cm² where epithelization had not occurred it was considered that a part of the transplant did not naturalize. If the area was larger than 15 cm² it was considered that the whole transplant did not naturalize.
The patients in group C, excluding those who visited the outpatient department of KMUH, were ordered to the Clinic of Skin and Venereal Diseases (CSVD) outpatient department of KMUH and were hospitalized there and treated with hydrocolloid bandages, in accordance with the standard protocol, and compression therapy. On the day of discharge, the epithelization of group c ulcers was evaluated in the same manner as group S.
A biopsy was taken for each patient prior to the operation to identify any malignancies because the results of the biopsy could influence the treatment method.
Both patient groups were asked to visit the outpatient department of KMUH after 6 months in order to evaluate the speed of epithelization.
Statistical analysis. The data was processed with Statistica version 5 for Windows. The absolute numbers (n) of data, their percentage (%), and the average values of measured rates with standard fault are indicated in the current study.
Student’s t-test was used to compare statistical averages of 2 groups of measured rates, and for a small number of patients (N < 30), the U criteria of Mann-Whitney was applied. Paired t-test criteria and Wilcoxon’s criteria were used to compare the averages of multiple ranges. Monofactorial dispersive analysis was used to compare the averages of both groups. The level of significance was (P = 0.05). Chi-squared criteria were applied to check the hypothesis of concatenation of categorized features. For a small number of cases, the precise criteria of Fisher were applied.

Results

In the Department of Plastic Surgery and Burns of the Clinic of Surgery of KMUH, the Clinic of Skin and Venereal Diseases, and in the Consultative Clinic of KMUH, 153 patients with large leg ulcers (> 50 cm²) that did not to heal (> 6 months) were treated and analyzed from January 2001 to June 2005 (Table 1). After assessing each patient’s history for diseases and other clinical states, measuring the ulcer area, evaluating arterial blood pressure by Doppler, performing Duplex ultrasound analysis, and taking biopsy of the ulcer bottom, large CVLUs were diagnosed in 60.8% of patients. Seventy-one patients returned for examination after 6 months and on average 40 of these patients had been treated by surgery and 31 had received conservative treatment. The average age of patients involved in the study was 65.9 ± 11.1 years. The patients had ulcers for approximately 109 months (Figure 1).
Risk factor analysis. Within the 6-month study period, 71 patients participated. The KMUH physicians ascertained CVLU risk factors that may induce leg ulceration. The analysis of these factors is shown in Table 2.
According to the literature, old age and patient gender are statistically significant in regard to the origination of CVLUs^1,2,7–12; therefore, the authors chose to analyze these risk factors. The majority of patients were hospitalized 1 to 20 times (M = 2). The localization of ulcers was as follows: in the left calf (20), right calf (36), and both calves (15). Fifty percent of the patients lived in cities and 50% in villages.
Factors analyzed before hospitalization. The average age of patients with a large CVLU on whom surgery was performed was 69 ± 10.3 years. They had ulcers for 116.9 months (on average 6 to 360 months). The size of ulcers fluctuated from 50 cm² to 800 cm² (m = 236.8 cm²). The average age of patients who were treated conservatively was 61.8 ± 11 years. They had open ulcers for 98.4 months (on average 6 to 390 months). The size of ulcers ranged from 50 cm² to 690 cm² (m = 182.3 cm²).
Group S consisted of 16 men and 24 women. Group C consisted of 15 men and 16 women. Five patients in group S stated that their ulcers were healing while the other 35 said that their ulcers were not healing but were expanding, weeping, and were more painful. At the beginning of the study, only 1 patient’s ulcers in group C were healing while the other 30 patients stated that their ulcers were not healing.
Analyzation of microflora from both groups did not successfully grow pathogens in samples taken from 35 ulcers (Table 3).
It was also discovered that there was a significant difference between the real reason for leg ulceration and that imagined by a patient. At the beginning of the study, the majority of patients in both groups either did not know the cause of their leg ulceration or they thought that the reason was not venous in origin.
Analysis of surgically-treated patients. Group S patients spent 1.87 days on average (from 0 to 15) in the hospital before the surgery was performed (Figure 2).
While evaluating blood indications singularized leucocytes (as one of the indications of the inflammation) were found. The amount of leucocytes did not exceed the top limit of the norm and on an average it was 7.91 x 10⁹, although pathogenic microorganisms often contaminated the bottom of an ulcer and the disease lasted for a long period of time (m = 107.6 months).
In order to rule out other blood diseases and diabetes, the amount of thrombocytes in the blood and glycemia were measured. The average amount of thrombocytes in the blood was 315.27 x 10¹² and glycemia (5.57 mmol/L).
Two patients were diagnosed with squamous cell carcinoma after fundus biopsies were taken and pathological/histological analysis was performed. Those patients were eliminated from the study and were treated according to the recommendations of the consulting physicians (oncologist, dermatologist, and plastic surgeon). Other pathological/histological data showed that the analyzed material in all cases had been described as lesions typical to chronic inflammation. Vasculitis was not diagnosed in any cases after pathological/histological analysis.
Analysis of autodermotransplant naturalization. Twenty-seven (67.5%) ulcers in group S patients epithelized completely, (ie, a partial-thickness skin graft that completely naturalized), and part of the transplant did not naturalize in 13 (32.5%) patients. There were no cases of complete transplant rejection or maturation of the plasticized skin.
Group S patients spent 3 to 20 days in the hospital (average 10.7 days). Overall, these patients spent 18.7 days in the hospital.
Analysis of patients treated conservatively. On 2 occasions an examiner evaluated the results of hospital analysis and treatment, first as patients were hospitalized at KMUH DSVD, and second on the 10th day (the patients of group C spent 10 days in the hospital) when patients were discharged from the hospital.
Blood evaluation separated out the amount of leucocytes as one of the indications of inflammation. The amount of leucocytes did not exceed the top limit of normal values. Tissue biopsy of the ulcer fundus was taken from the area of local ischemia and found that the skin tissue of all patients of group C had changes typical of chronic inflammation.
The epithelized areas of group C ulcers were analyzed in the same manner as group S ulcers. There were no cases of complete skin epithelization after 10 days of treatment. Within the 10-day period, the skin purged and the symptoms of inflammation were reduced; however, ulcer area remained the same or increased (5 cm²–10 cm²) because hydrocolloid bandages had been used and caused all dead tissue to be removed. Patients who were treated conservatively spent 10 to 16 days in the hospital (average 10.3 days).
Comparative analysis of conservative versus surgical treatment. Patients from both groups were seen again after 6 months and re-administered the questionnaire. The skin had completely epithelized in 27 cases (67.5%) and did not epithelize in 13 cases (32.5%). The average area of ulcers was 16 cm² (6 cm² to 52 cm²). Compared to initial ulcer area (m = 279 cm²), the area seen at 6 months post-treatment was rather small and did not influence patient quality of life or influenced it insignificantly (Figure 3).
None of the ulcers in group C patients healed completely (100%). Ulcer size increased in 17 patients and decreased in 14 patients. The average area of ulcers was 171.12 cm² (8 cm² to 720 cm²). The decrease in the average area was insignificant (P > 0.5) compared to the previous area (m = 182.29 cm²; Figure 4).
Analysis of microflora was performed in cases where ulcers were incompletely healed. The contamination of ulcers did not change much in either group during the 6-month period. The most common pathogens found were S aureus and P aeruginosa. The distribution of microorganisms in the microbiological samples is shown in Table 4.
Despite the fact that compressive therapy was applied in both groups, the calves of the majority of patients did not become thinner and a statistically significant regression of edema was not found during the repeated study (after 6 months). Assessing the change in average size of the largest and smallest calve girth, it was found that after approximately 6 months, the largest calf girth of patients in group S decreased by 2 cm, while in group C by 0.5 cm. Calf girth in 4 patients in group C increased. However, these changes were not statistically reliable
(P > 0.05).
Comparative analysis of data between group S and group C. To evaluate the effectiveness of skin autografting surgery while treating a large CVLU, the differences in data for both groups obtained approximately 6 months post-treatment was evaluated.
At the beginning of the study, both groups were homogeneous because factors, such as the period of illness, the place of residence (a city or a village), gender, and blood analysis was insignificantly different between groups (P > 0.05; Table 5).
The majority of patients of both S and C groups (~ 80%) did not know the cause of their leg ulceration. Despite the fact that the studied patients had seen other physicians before the study, the cause of leg ulceration was established by the surgeon for the first time.
While assessing personal expenses of patients, it was found that statistically significantly expenses increased in the C group, despite the fact that income of patients remained the same and did not exceed 145 Euro on average (Table 6).

Discussion

Skin autografting is a method of treatment that decreases the area of chronic venous leg ulcers (CVLU) or heals them completely, thus improving a patient’s quality of life. Skin autografting should be the primary treatment in cases of CVLUs because the area of the CVLU decreases faster (or heals completely), and it improves quality of life for the patient.
Like the data of various sources of literature shows, it was discovered during the study that the majority of patients are of elderly age.^1–3,6 The population is getting older in Western countries; therefore, the frequency of leg ulceration is also increasing.⁵
Although there were more patients older than 65 years in the group of patients who were operated on, the results were better in this group. Therefore, the age of the patient did not have any significant influence on the treatment outcome.
The study was comprised of 32 men and 39 women (1:1.2). The majority of investigators claim that the rate of men and women with open ulcers fluctuates from 1:1.⁵ to 1:3.^6–8 The fact that women with open ulcers dominated the results of the present study is apparent, but the small sample is the most likely cause for such a small difference in open ulcers between genders.
The only statistically significant factor for having an open CVLU was the age of the patient (> 60 years). Since the study consisted of patients whose ulcers had been open for a long time (m = 109 months), risk factors, such as ulcers opening due to telangiectasia, varicose of veins, edema, or changes of skin were not analyzed.^5,9,13–15 The authors believe that the majority of patients would not remember or could not remember precisely when the ulcer opened.
The price of all means of bandaging needed for the treatment, the total period of nursing, medicaments, and other means necessary for the treatment of skin complications, travels to a physician, lost work time, additional care and time, should be included in the total price of ulcer treatment. According to the study data, the patients of group S spent on average 10.7 days at the hospital and spent from 0 to 15 days until the operation. Part of the time spent in the hospital was for ulcer preparation prior to the operation: removal of the residual necrotic mass, decrease of inflammation of surrounding tissues, elimination of microorganism contamination, and the stimulation granular tissue growth. The patients of group C on average spent 10.3 days at the hospital. Thus, group S patients spent more time at the hospital, (they had undergone operative procedure), therefore, the patients of S group spent more money for the treatment at the hospital. However, after the treatment at the hospital, the ulcers of group S patients epithelized completely in 67.5% cases, ie, the remaining area of an ulcer was < 5 cm² or the ulcer was completely closed. There were no cases where the remaining area of an ulcer was larger than 15 cm² in group S. However, in group C none of the ulcers healed completely or the area became even larger when the necrotic mass was cleaned. Larger ulcers (up to 600 cm²) needed to be covered with hydrocolloid bandages on the patients of group C. Twelve of these patients were seen in the ambulatory center or the primary healthcare center to have their ulcers bandaged. Other patients were provided with nursing care in their homes. Therefore, within the period of 6 months the total expenses for the treatment of ulcers both at hospital and in ambulatory care were higher for the patients in group C. The sum of these expenses was not counted and may be a part of a successive study.
According to the data of the literature used, the treatment of venous ulcers by autografting an autotransplant of partial-thickness skin is successful in up to 90% of cases, but the risk of skin recrudescence is about 50%.^11,12 According to the data of other researchers, 48% of venous leg ulcers heal within 6 months if treated with the mentioned method and 67% heal within a year.¹⁶ During that same study, only ulcers with an average area of 13.5 cm² had been analyzed.^16,17 The ulcer area of patients in the present study was large (m = 279 cm²). There were no cases of complete rejection of a transplant and a part of transplant did not naturalize for 32.5% of S group patients. After approximately 6 months, ulcers naturalized completely in 67.5% of repeatedly examined patients from group S. At that time, the average area of ulcers was about 16 cm². These ulcers had less influence or did not influence the patients’ quality of life.
Although good results with skin autografting for treating CVLUs have been shown, the literature indicates that this method should be applied only if conservative treatment or etiopathogenetic surgical treatment are not successful, because autografts, like surgery, have complication risks.^18,19 During the present study, ulcers were open for approximately for 109 months and had been treated previously with various treatment methods. Therefore, patients were only operated on in cases where other methods of treatment had not been successful.
The following microorganisms are most commonly found in CVLUs: S aureus (up to 88%), Enterococcus (up to 74%), Pseudomonas (up to 60%), and Enterobacteriaceae (up to 40%). Streptococcus and skin microflora were the most frequently grown microorganisms in the ulcers.^20,21 In all analyzed cases there were no symptoms of inflammation of the ulcers or of surrounding tissues. In such cases, antibiotic therapy is not recommended.^20,21 The present study revealed that the most common causes of ulcers were S aureus and P aeruginosa. A blood analysis was performed at the beginning of the study; however, it did not show that the mentioned microorganisms, infection of surrounding tissues, or exhaustion of an organism caused the ulcers. The amount of leucocytes and erythrocytes corresponded to the norm (approximately WBC = 7.75–7.91 x 10⁹; RBC = 4.10–4.29 x 10¹²). Prophylaxis with antibiotics was not given to patients who were operated on because of these pathogens. Penicillin was injected only once during the surgery to prevent patients from purulent complications caused by streptococcus.
According to other research, transplanted skin has an antimicrobial impact.^19,22,23 The positive changes of skin, hypoderma, muscles, tendons, periosteum, and bones were noticed after ADP.^19,22,23 There were no cases of skin purulence after the transplantation of skin on the renewed fundus of an ulcer. It could be explained by antimicrobial characteristics of the skin graft or by prophylaxis with penicillin that was injected during the skin fundus renewal surgery.
As the tissue crust of the fundus is cleaned by a dermatome, microorganisms are removed as well. If some microorganisms remain there, this amount is too little to cause purulent complications; therefore, an organism is able to fight against microorganisms on its own.
The literature describes cases when ulcers are complicated with sepsis or necrotizing fasciitis because they were treated improperly. This disease is dangerous to a patient’s life.^18,19,24 Ulcers in group C that did not heal completely after 6 months and all ulcers in group S were analyzed. Noticeable changes in microorganisms, most frequently S aureus and P aeruginosa, were found. Based on this, it could be said that antibiotic therapy to exterminate these pathogens is not advisable, unless clear symptoms of inflammation or infection are seen, because in group S there were no cases of purulence of ulcers 6 months after a surgery, and the same was true for group C—there were no cases of purulent complications that would evolve the soft tissues around the ulcer during the observation period.
Deep CVLUs were recrudesce in 10%–16% of cases if compressive therapy is applied properly and in 97%–100% of cases if it is not applied.²² Compressive stockings are the most effective and economically sound method for treatment of ulcers and prophylaxis of recrudescence. Moreover, it is possible to achieve very good results by bandaging ulcers with elastic bandages, but improper compressive therapy produces even worse results than no therapy at all.^25,26 Based on the experience of other researchers,^25,26 a tremendous amount of time was dedicated to ascertain the importance of compressive therapy to treat ulcers and to determine ways to prevent repeated opening of CVLUs. All patients from group C and S were encouraged to wear compressive stockings (35–40 mmHg) in the morning as soon as he/she awoke and to remove the stockings before going to bed at night.
Although the patients were taking medications to improve microcirculation, venous flow, and lymph drainage, the authors believe that the compressive therapy is responsible for the 6-month period where there were no cases of new ulcers opening in the group of operated patients. The authors (and others²⁶) believe that pentoxifylline provides a more positive influence on the epithelization of ulcers than placebo. They also do not recommend a plump refusal to this medicament.²⁶ The literature also provides broad studies about the positive influence of phlebotropic medicaments on the speed of ulcer epithelization and indicates their positive influence; therefore, in the authors’ opinion, this medicament should not be derogated.^27–30

Conclusion

According to the data from all factors that were analyzed, age is the only influence on the origination of large CVLU (P < 0.05). Large chronic venous ulcers (> 50 cm²) were closed within 2–3 weeks and remained closed 6 months following skin autografting compared to a conservatively treated population in which none of the wounds were closed at 6 months, although there was a reduction in wound size in 50% of the patients.