Does the Pattern of Venous Insufficiency Influence Healing of Venous Leg Ulcers after Skin Transplantation?

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1 Eur J Vasc Endovasc Surg 25, 562±567 (2003) doi: /ejvs , available online at on Does the Pattern of Venous Insufficiency Influence Healing of Venous Leg Ulcers after Skin Transplantation? M. L. Kjaer 1, B. Jorgensen 1, T. Karlsmark 1, P. Holstein 1, L. Simonsen 2 and F. Gottrup 1 1 Copenhagen Wound Healing Center and 2 Department of Clinical Physiology, Copenhagen University Hospital, Bispebjerg, Denmark Aims: this study aimed to investigate the influence of venous insufficiency on results in venous leg ulcers treated with ulcer excision, meshed split-skin transplantation and correction of superficial venous insufficiency in the wound area. Design: retrospective cohort study. Setting: Copenhagen Wound Healing Center. Methods: in 113 patients with venous leg ulceration, examined preoperatively with colour Duplex scanning (CDS), prognostic factors of healing and recurrence within 1 year were analysed using logistic regression. Results: cumulative 1-year healing rate was 65% (73 patients) and 13 (12%) had recurrence of ulceration 1 year postoperatively. Initial ulcer size (OR: 0.97(95% CI: 0.96±0.99)), minor local superficial venous surgery (OR: 2.38 (95% CI: 1.04±5.46)), sufficient popliteal vein (2.97 (1.05±8.42)) and non-compliance with compression therapy (OR: 0.27 (95% CI: 0.11±0.71)) influenced the prognosis of healing positively. No statistically significant differences in healing and recurrence between patients with isolated superficial and mixed superficial/deep venous insufficiency was found. Conclusion: non-healing venous leg ulcers can be treated with ulcer excision, meshed split-skin transplantation and correction of superficial venous insufficiency in the wound area with beneficial results irrespective of underlying pattern of venous insufficiency as determined by CDS. Key Words: Venous leg ulcer; Colour duplex scanning; Meshed split-skin transplantation; Ulcer excision; Prognostic factor; Superficial venous surgery; Diabetes mellitus. Introduction Chronic leg ulceration has been estimated to affect 0.19% of the population 445 years old, with an annual incidence of 3.5 per 1000 people. 1 Venous insufficiency is present in 70% 2 of the patients, affecting predominately female and older patients. 3±6 At present ulcer duration as well as initial ulcer size are acknowledged prognostic factors of healing. 7±9 It has been documented that correcting the superficial insufficiency leads to healing of the ulcer. 10±14 Deep venous insufficiency have been shown to be a negative prognostic factor of healing and time to heal. 15±18 Moreover it is associated with higher recurrence rates. 19,20 These findings have led to the recommendations that patients with active ulceration and mixed superficial and deep venous insufficiency should be treated conservatively with compression therapy and that corrective superficial venous surgery should be Please address all correspondence to: M. L. Kjaer, Copenhagen Wound Healing Center, Bispebjerg Hospital, Bispebjerg Bakke 23, DK-2400 Copenhagen NV. performed only in patients with isolated superficial venous insufficiency. 21 This treatment strategy, however, does not address the problem of non-healing ulcers. In spite of adequate conservative and surgical treatment as recommended many ulcers fail to heal. Such patients suffer long-term morbidity and pose considerably strain on health care resources. 22,23 Ulcer excision and skin-transplantation with or without correction of superficial venous insufficiency has been described as a successful way of obtaining healing. 24±27 The influence of the pattern of venous insufficiency on ulcer healing regarding the efficacy of this treatment modality has, however, not been investigated previously. This was the aim of the present study. Materials and Methods A consecutive series of venous leg ulcer patients treated surgically between November 1996 to June 2001 from the Copenhagen Wound Healing Center 28 was retrospectively analysed. 1078±5884/03/ $35.00/0 # 2003 Elsevier Science Ltd. All rights reserved.

2 Skin-transplantation in Leg Ulcers 563 Diagnostic procedure The inclusion criteria were a leg ulcer and venous insufficiency confirmed by Color Duplex scanning (CDS). CDS was performed with 5 and 7.5 MHz linear-array transducers (Sonoline Elegra ultrasound system, Siemens Medical Systems Issaqua, WA, U.S.A.). The patients were examined in 25 antitrendelenburg position. The examination included the greater saphenous, lesser saphenous, common femoral, superficial femoral, popliteal, gastrocnemius, mid-thigh, and calf perforating veins. Reflux was defined as more than 0.8 s of retrograde flow. 29 Patients with significant arterial insufficiency, i.e., an ankle arm pressure index below 0.8 or a toe pressure below 60 mmhg, using the strain-gauge technique (Medimatic, Copenhagen, Denmark), were excluded. material and repeatedly during the treatment course. Haemolytic streptococci were always treated with penicillin 1 million units intra-venously three times daily. Otherwise antibiotics were given only in case of invasive infection. After 2 days of restricted ambulation in a wheel chair with elevation of the leg the wound was inspected with respect to ``graft take'' and clinical appearance. Unrestricted walking was allowed on the fifth postoperative day. The patients were discharged on the 10th postoperative day after inspection of the donorsite. All patients were treated with compression bandage and after healing with grade 2 compression knee-stockings. The routine program implied follow-up for at least 1 year. Patients failing to enter the routine follow-up program were contacted by telephone for the outcome information. Treatment All patients had been unsuccessfully treated elsewhere, surgically and/or conservatively, before reference to the Copenhagen Wound Healing Center. Indication for surgery was conservative treatment including compression bandage for 3 months without progress in healing. The patients were admitted 2 days prior to surgery for wound bed preparation and oedema control. The wound bed and the lipodermatosclerotic skin surrounding the ulcer were excised to a distance of approximately 2 cm from the edge of the wound. This strategy led to seemingly healthy, bleeding tissue, resulting often in exposed fascia. Only in case of subcutaneous calcifications the excision might be more extensive. Then split-skin graft, taken with a Zimmer dermatome from the anterior part of the contralateral leg was meshed as required. The graft was dressed with Carbovax gauze containing nitrofuranzone, vaseline gauze (Jelonet), rubber sponge and a compressing bandage. The donor site was dressed with 2 layers vazeline gauze (Jelonet). Insufficient local superficial veins and perforators in the wound area marked with ink according to CDS were resected. Because of the risk of infection saphenofemoral or popliteal resections and stripping was not performed and prophylactic peroperative single shot antibiotics (1 g Cephuroxim and 160±240 mg gentamycin) were administered. The procedure was performed under general or spinal anaesthesia. Heparin was given subcutaneously from the day before operation and until the patient was allowed to walk. The excised tissue was examined by pathologists for malignancy and other specific aetiology. Routine bacteriological tests were made on the excised wound bed Factors evaluated The following factors were analysed: Initial ulcer size (measured by length and breadth), ulcer duration, Diabetes mellitus, previous deep venous thrombosis, previous venous surgery, superficial insufficiency (greater and lesser saphenous vein insufficiency, perforator insufficiency and insufficiency due to communicating veins), deep venous insufficiency (popliteal and other deep vein insufficiency), additional perforator surgery, additional minor local venous superficial surgery. Compliance to the postoperative compression therapy was evaluated at each visit in the outpatient clinic by presence of oedema and quality of the bandage. If oedema caused by insufficient compression was present the patient was characterised as non-compliant. Healing (defined as complete epithelialization) within 1 year, recurrence (any leg ulcer appearances after healing) within 1 year, the time to heal and the time to recurrence for each patient was recorded. Patients admitted for additional split-skin transplantation before completion of 12 months follow-up were considered not healed. Patients operated bilaterally were entered only once, determined by the first ulcer arisen, and patients requiring retransplantion were included only once as well. Statistics The logistic regression analysis provides an estimate of the magnitude of an association. It is displayed in the form of odds ratio (OR). The OR describes the probability of achieving a specific outcome when a

3 564 M. L. Kjaer et al. specific prognostic factor is present, the larger positive value the stronger positive association and vice versa. In the multivariate model the associations are tested taking the influences of other associations into account. To assess the magnitude of the effect of the chosen prognostic factors a two-stage univariate followed by multivariate) logistic regression was performed. Healing within 1 year was used as the dependent variable. The multivariate model included factors considered to be clinically and statistically important factors p in the univariate model). The linearity of the relationship between continuous variables and outcome was assessed using quadratic terms. Test for interaction and goodness of fit ensured the appropriateness of the multivariate model. Healing and recurrence differences in subgroups were evaluated using the Chi squared test. A p-value of 0.05 was considered statistical significant. The statistical analysis was conducted using SPSS for Windows version 8.0. Table 1. Clinical characteristics of the patients. n %) n healed %) n ˆ 73 n recurrence %) n ˆ 13 Gender female) 63 56) 43 68) 8 62) Previous major surgery 23 20) 15 65) 4 32) to the legs Previous ulcer 96 86) 60 63) 9 69) Previous skintransplantation 34 30) 20 59) 5 39) Previous DVT 40 37) 24 60) 5 39) Previous vein surgery 52 46) 33 63) 7 54) Diabetes mellitus 8 7) 3 4) 0 Fully mobile 75 69) 50 67) 9 69) Retired 70 62) 45 63) 7 54) Age Mean sd) years ) ) ) ABI Mean sd) ) ) ) Toe pressure Mean sd) mmhg ) ) ) Initial ulcer size Mean sd)cm ) ) ) Ulcer duration Mean sd) months ) ) ) Results In all 113 patients with venous leg ulceration entered the study constituting 23% 113/501) of the patients referred to the Copenhagen Wound Healing Center for venous leg ulceration in the study period. Fortyfive of the patients were operated bilaterally and 17 patients were retransplanted within 1 year of operation. Follow-up was complete for all patients although outcome information was obtained by telephone interview for 21 patients. Demographic information is displayed in Table 1. The healing and recurrence results are displayed in Table 2. Seventy-three patients 65%) healed within 1 year postoperatively. Of these patients 13 had recurrence of ulceration 1 year after operation. Five patients had experienced minor relapse but were healed again 1 year postoperatively. Thus 53% of the patients were healed 1 year after surgery. Twenty-three patients 20%) had isolated superficial venous insufficiency, the majority having both greater and lesser saphenous vein insufficiency. Ninety 80%) patients had mixed superficial and deep venous insufficiency and 75 66%) had popliteal vein insufficiency involvement. Accumulated healing and recurrence rates in relation to time are displayed in Figure 1. The figure shows that 66% of the patients, which heal within 12 months, heal within 3 months of surgery and 75% of the patients, experiencing recurrence of ulceration within 12 months, do so within 6 months of operation. Table 2. Healing and recurrence results displayed by insufficiency type, surgical and follow-up characteristics. n %) n healed %) n ˆ 73 n recurrence %) n ˆ 13 Insufficiency type Isolated superficial 23 20) 15 65) 1 7) insufficiency Mixed superficial/deep insufficiency 90 80) 58 64) 12 21) Insufficiency of individual veins irrespective of others) Short Saphenous vein 69 61) 42 61) 9 21) Long Saphenous vein 90 80) 58 64) 12 21) Perforator vein 82 73) 50 61) 9 18) Communicator vein 10 9) 6 60) 1 16) Popliteal vein 75 66) 45 60) 9 20) Surgical performance Perforator surgery 69 61) 45 65) 4 9) Minor local venous resection 61 54) 47 77) 6 13) Follow-up complications Infection in follow-up period 7 6) 5 71) 1 20) Poor Compression compliance 33 29) 13 39) 3 23) % of patients Months Heal ed Recurred Fig. 1. Twelve months cummulative healing/recurrence rates of the 113 patients measured from time of operation. All patients were followed-up for at least 1 year postoperatively.

4 Skin-transplantation in Leg Ulcers 565 Table 3. Logistic regression for all patients of considered influential factors of healing and recurrence. Results are presented as odds ratios (OR) with confidence intervals of 95% (CI). Healing OR univariate (95% CI) p Healing OR multivariate (95% CI) p Risk factors Diabetes mellitus 0.16 (0.04±0.65) (0.17±4.73) 0.92 Previous DVT 0.73 (0.32±1.65) (0.25±1.43) 0.25 Previous vein surgery 1.15 (0.53±2.51) (0.46±2.35) 0.98 Initial ulcer size (categorised 0.99 (0.991±0.993) (0.96±0.99) 0.02 with increments of 5 cm 2 ) Ulcer duration (categorised 0.99 (0.98±1.01) (0.98±1.04) 0.40 with increments of 6 months) Perforator surgery 1.07 (0.48±2.35) (0.52±3.75) 0.48 Minor local superficial vein surgery 3.35 (1.49±7.52) (1.04±5.46) 0.04 Compression non-compliance 0.22 (0.09±0.51) (0.11±0.71) 0.01 Insufficiency Superficial insufficiency 0.57 (0.10±3-25) (0.22±8.45) 0.73 Deep insufficiency 1.42 (0.56±3.62) (0.44±5.31) 0.49 No Popliteal insufficiency 2.35 (0.91±6.01) (1.05±8.42) 0.04 Healing multivariate model: Duration, duration squared, ulcer size, ulcer size squared, binary DM, and minor local vein resection. No statistically significant healing difference between patients with isolated superficial insufficiency and patients with mixed superficial and deep venous insufficiency was identified (65% (15/23) vs 64% (58/92) (Table 2). Healing rates in individual vein subgroups (irrespective of insufficiency of other veins) were about the same. An observed recurrence difference of 7% (1/15) for patients with isolated superficial venous insufficiency versus 21% (12/58) for patients with mixed superficial/deep venous insufficiency was statistical insignificant. The univariate analysis (Table 3) showed that Diabetes mellitus, initial ulcer size, minor local venous surgery and compression non-compliance was statistically significantly associated with healing. For instance when adding minor local superficial venous surgery to the treatment the ulcers were 2.38 (95% CI: 1.49±7.52) times more likely to heal. In the multivariate regression analysis the correlation between insufficiency in the popliteal vein and decreased healing became apparent. Patients without popliteal vein insufficiency were 2.97 (95% CI: 1.05± 8.42) times more likely to heal than patients with popliteal vein insufficiency. The association of diabetes mellitus and healing, however, could not be confirmed in the multivariate model. In order to investigate, whether the observed beneficial effect of local superficial venous surgery exclusively was due to a positive effect in the subgroup of patients with isolated superficial insufficiency, the regression analysis was also performed after exclusion of this group. The result of this analysis confirmed the beneficial effect of local superficial venous surgery for patients with mixed superficial and deep venous insufficiency (OR 7.03 (95% CI: 2.69±18.35) p ). OR for insufficiency in the popliteal vein was 0.22 (95% CI: 0.03± 1.31, p ˆ 0.09), but in this subgroup a level of statistical significance was not reached. Discussion The present series is different from most other studies in that the patients are older and the ulcers of longer duration. The patients had long histories of unsuccessful treatment and showed no tendency towards healing despite optimal compression therapy. Also the proportion of patients with mixed superficial and deep venous insufficiency was higher than in most similar studies. Taking these factors into account the healing and recurrence rates are comparable to previous studies. Studies of skin transplantation report 3 months healing rates as diverse as 100, and 26% 31 and 6 months recurrence rates of 40%, 25 although the type of venous insufficiency was unknown and the ulcers were smaller or of shorter duration. In a randomised trial 24 investigating perforator surgery and skin transplantation a 12-month healing rate of 40% was described for patients with deep venous and perforator insufficiency. Bello et al. 32 reported a 12 months healing rate of 74% in a series of 122 limbs with isolated superficial venous insufficiency subjected to superficial venous surgery, although the healing rate was only 60% for patients with ulcers 410 cm 2. Also, recurrence rates of 28±95%

5 566 M. L. Kjaer et al. for patients with deep venous insufficiency have been described. 15,19 The main result of this study is that the outcome of ulcer excision and split skin transplantation was satisfactory with healing in more than half of the cases, irrespective of the underlying pattern of venous insufficiency, initial ulcer size and ulcer duration. The study, moreover, shows that venous correction adjacent to the ulcer improved healing results. Brittenden et al. 16 showed that insufficiency in the popliteal vein was associated with decreased healing rates. The present study also identifies popliteal vein insufficiency as a negative prognostic factor of healing. When the analysis was performed including only the patients suffering from mixed venous insufficiency, popliteal vein insufficiency was again associated with decreased healing rates, but not to a level of statistical significance. This can possibly be attributed low sample-size. Apart from these findings the pattern of venous insufficiency did not influence the outcome. Studies of venous leg ulcer patients treated conservatively 7,8,17,33 have also failed to identify conclusively the pattern of venous insufficiency as prognostic factors of healing and recurrence. Ulcer duration and initial ulcer size are well documented prognostic factors in healing. 7±9 Healing was, however, not influenced by ulcer duration in the present study. A possible explanation is that the ulcer tissue material, which is probably not favourable for healing, was removed by the surgical excision. The size of the initial ulcer influenced statistically significantly the healing rate (p ) but the OR of 0.97 (95% CI: 0.96±0.99) is without clinical significance. Our study confirms 34,35 that compliance with compression treatment is correlated to outcome, but as this indicator is susceptible to bias one should interpret the results with caution. This result, however, stresses the importance of efficient compression therapy and underscores the need for an objective tool of measuring the efficiency of compression treatment in research as well as in daily clinical practice. An additional important issue is the durability of the ulcer healing. In this study there was no statistically significant difference in the recurrence rate between patients with isolated superficial and mixed venous insufficiency. This result might be due to a type II statistical error. Better results might perhaps be achieved, if a more extensive superficial venous surgical strategy, including sapheno-popliteal and sapehno-femoral junction surgery, was applied. Due to the increased risk of infection the present department, however, do not perform extensive superficial venous surgery and split-skin transplantation simultaneously. Instead we have adopted a strategy of secondary venous correction after healing of the skin transplant. However, only few of the patients accepted secondary venous surgical correction and none of the included patients were operated in the study period. CDS is useful in mapping the venous system as guidance for corrective vein surgery. It is, however, less useful in determining the healing prognosis as documented in a number of papers as well as in the present report. Physiologic quantification of venous function might perhaps be more valuable. Phlebography and ambulatory venous pressure measurements are not suitable for repeated measurements in screening and follow-up and the validity of plethysmografical testing has been questioned. 36,37 Improving the CDS with quantification of the reflux 38±43 have not yet been widely adopted, but the discriminative capacities are promising. In conclusion ulcer excision, meshed split-skin transplantation and surgical correction of local superficial venous insufficiency is an option in the treatment of non-healing venous leg ulcers. 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