C l ini c a l and labo r a t o r y st u dy Prediction in leg ulcer healing K E Y WORD S clinical test, out-come, predictive value, quality assurance, leg ulcer Prediction of healiTZg in patients with venous leg ulcers G. B. E. Jemec, T. Karlsmark, T. Brink-Kjrer and H. C. Wulf ----------------- ------~ ABSTR AC T Background. The treatment of venous leg ulcers is often prolonged. This is perceived as unsatisfactory by patients who desire more precise information about the prognosis. There is a need for predictive information about the most likely expected outcome of treatment. This information may not only aid the counseling of patients but also the allocation of resources. A predictive score system based on clinical aspects of leg ulcers has been suggested, but not independently tested. Methods. This study was conducted as a prospective study of patients referred to a hospital to assess the pred ictive value and accuracy of a previously proposed predictive test (scores O - 1 O). A score of 5 or less in the proposed predictive index was associated with complete or partial healing (P= 0.04). Results. No significant correlation was found between any of the general biochemical factors at first presentation and ultimate wound healing. lnitial wound size correlated significantly with final wound size and rate of healing. The study confirmed that ulcer area and duration as well as patients age can be combined in a predictive score tor the rate of wound healing. The variation of outcomes tora given score was, however, widely suggesting that the proposed test might be of a rather limited use as a guide to the prognosis of individual patients. Routine examination of general biochemical factors in patients with venous leg ulcers does not appear to have a significant predictive value with regard to the outcome of ulcer t reatment. Introduction Biophysical and clin ica l investigations in to the pathogenesis of leg ulcers give va luable predictive information and make a clinically useful classification possible (1, 2, 3, 4, 5) . A number of new treatments have become available but conservative therapy most often remains a lengthy process. Patients frequently wish to have an info rmation about the prognosis . Such information is rarely published and may vary greatly be tw een institutio ns , making historlcai o r bib lio - graphical references less useful in the actual counseling of the patient. There is therefore a practical need for methods, which can give this information. In addition to accuracy, it is important that a pre- dictive test functions in a routine clinical setting, i.e . acta dermatovenerologica A.P.A. Vol 8, 99, No 1 19 Prediction in leg ulcer healing Clinical and laboratory study Table l. The results of routine biochemical testing in patients with venous leg ulcers. Hemoglobin (mmol/1) White Blood celi count (*109/1) Sodium (mol/1) Potassium (mmol/1) Creatinine (mmol/1) Glucose (mmol/1) Albumin (mmol/1) ASAT (U/1) Alkaline phosphatase (U/1) while subject to the unpredictable variations in therapy and to various external factors such as e.g. infection. A predictive test has limited value if it only works in a strictly controlled environment - it must be rugged to be of any use. A prognostic index to predict tirne of healing has been suggested based on ulcer area, ulcer duration, patient's age and possible deep vein involvement as measured by photoplethysmography (6). The test has, however, not been independently validated. It was therefore decided to study the predictive value of this test to a group of patients undergoing routine treat- ment. o 3-9 3 (10) 136 - 146 o 3.5 - 5.0 o 0.040 - 0.110 10 (0.183) 4.0 - 8.4 2 (17.3) 600 - 830 o (257) 1 O - 14 15 (37) 80 - 275 6 (400) In contrast to physical measurements of e.g. blood pressure, the significance of biochemical investigation was not similarly investigated ancl therefore remains unclear at present. Anecdotal reports ancl clinical impression suggest those biochemical investigations of e.g. albumen or hemoglobin may, occasionally, be useful in practical management of patients with leg ulcers. We have therefore assessed the usefulness of the proposecl prognostic inclex in routine treatment ancl undertaken a simple evaluation of the predictive value of general biochemical factors in the routine mana- gement of venous leg ulcers. Table II. The outcome of routine treatment of venous leg ulcers compared with pre-treatment assessment according to Skene et al. 6• Lower scores are re/ated to a better average rate of healing (P= 0.04). Ulcers in the high score group increased at an average rate of 2 cm2 per month. 20 4 (26) 4 (26) 24 (-10 - 58) -2 (-16 - 12) acta dermatovenero/ogica A.P.A. Vol 8, 99, No 1 ! Clinical and laboratory study Materials and methods This study was conducted as a part of the quality assurance project at the department of dermatology of a tertiary referral center. A total of 79 consecutive new patients referred to the Department of dermatology at Rigshospitalet 1992-95 for the treatment of leg ulcers were studied. All patients had their ankle/brachial blood pressure ratio or the distal blood pressure (toe) measured. Blood samples were drawn for routine analysis of the factors listed in Table I, and the outline of the ulcers was traced for calculation of wound area. Ulcers were classified according to the following definitions (7, 8): Venous ulcer: Arm/ankle index > 0.8 or toe blood pressure > 60 mm Hg. In cases where patients objected to measurement of distal blood pressure or where the ulcers prevented measuring, the following clinical definition was used: Warm, clinically well-perfused feet were taken to indicate a predominantly venous cause of leg ulcers if the patient was not diabetic and did not suffer from connective tissue diseases. The following patients were excluded: 7 with arteriosclerotic ulcers, 4 with diabetic ulcers , 2 with unclassifiable ulcers, 7 due to skin grafting and 8 were !ost during follow-up. Only patients fulfilling the above mentioned criteria for venous ulceration were studied. All patients were treated according to the routine regimen used in the Department, consisting of a short- stretch double-layer compression bandage (Com- prilan®, Beiersdorf, Germany) applied daily, and ointment dressings (changed on alternate days) or hydrocolloid dressings changed as appropriate. Treatment was however not standardized and variations therefore occurred dependent on various factors , e.g. infection, or minor differences in the approach by different physicians. It was expected that a clinically usefol test would be accurate even under these conditions. After a period (mean: 18 months; 95% confidence interval 14- 21 months) oftreatmentthewound area was measured, and the rate of healing in cm2 per month calculated. The following correlations were studied: The ability of biochemical factors to explain wound size or wound dura ti on, and the predictive value of biochemical testing for assessment of wound size 18 months later. Three patients had concomitant diseases (1 blind patient, 2 patient with rheumatoid arthritis). Patients' ability to walk at the tirne of the first examination varied from normal (21 patients), to partial (necessitating support or cane, 11 patients) to wheel chair bound (7 patients), while no specific information on mobility was available for the remaining 11 patients Six patients were !ost to follow-up, leaving a subgroup of 45 patients available for the study of the previously proposed prognostic index. The index was calculated for each ulcer at the start of the investigation, and these scores acta dermatovenerologica A.P.A. Vol 8, 99, No 1 Prediction in leg ulcer healing were compared with actual outcome 18 months later. The original index was calculated by adding scores for ulcer size, ulcer duration, patient's age and deep vein involvement as measured by photoplethysmography. The scores ranged O - 5 for area, O - 2 for ulcer duration, O - 3 for patient's age and O - O.S for deep vein involvement, giving a total range ofO to 10.5 in steps of0.5 points. We modified the score and performed the calculation without the photoplethysmography, which is not available in our department. Because of photoplethysmography 's contribution to the overall index is ve1y low, its omission was not considered to impair the resull~. The modified score bas a range of O - 10 in steps of 1 point. The inclex scores were grouped into two categories: < 6 based on the data suggested by Skene et al., ancl the rate of healing compared. The numbers of patienl~ showing complete healing, partial healing and no healing or actual worse- ning were also compared. Non-parametric statistics (Mann Whitney and Krus- kall-Wallis test), Chi-square tests as well as nrnltiple linear regression analysis were used. Results The 51 patients had a mean age ± standard deviation of74.1 ± 13.8 years and a sex ratio of 1 : 1.8 (18 men/32 women). The mean size ± standard deviation of the ulcers was 25.9 ± 62,9 cm 2, and the mean ulcer duration ± standard deviation was 55.8 ± 116.2 months. No significant correlation was found between the baseline biochemical studies and wound area or wound duration at the first consultation. A number of biochemical abnor- malities were found, see Table I, but none correlated with wound healing or ultimate wound size. The proposecl predictive test showed significantly more patients with a score of <5 had complete healing of their ulcers (P = 0.04) as can be seen from Table II. General physical parameters showed a significant correlation with the outcome of treatment. Multiple linear regression analysis showed that patients' age, ulcer duration and wound size are significantly correlatecl to both fina! wound size (P < 0.001) and rate ofhealing (P = 0.002). Initial wouncl size was, however, the one physical component, which was most signi- ficant, and correlated to both fina! wound size and rate of healing (P < 0.001). Discussion Conservative leg ulcer therapy is usually a long process and patients' expectation to know the prognosis is justified. Benchmarking, i.e. comparison with other centers is clifficult, as the outcome of routine treatment is rarely reported. This may be of lesser importance as the experience can vary considerably both between and within different institutions. Prognosis should therefore 21 Clinical and labora t ory study ideally be established for individual patients by the use of appropriate testing. Multiple linear regression analysis confirmed that patient's age, ulcer duration and ulcer size are significantly correlated to both fina! wound size and rate of healing. The predictive ability of the index was compared with the outcome of treatment. Three groups were identified: patients with completely healed ulcers, patients with partially healed ulcers, and patients with unchanged or increasing ulcer area. Statistically signi- ficant differences were seen, suggesting that the test was able to predict the outcome of treatment in patients. A score of 5 or less was found to be predictive of a better average rate of healing but not of a higher likelihood of complete healing, as can be seen from Table II. The number of patients was insufficient for further stratification of scores, and the variation of outcomes for a given score was large (wide conficlence intervals of the mean healing rate). The proposed test may therefore only be of limited use as a guide to the prognosis of incliviclual patients. Biochemical factors, which could hypothetically either promote or slow clown the healing of ulcers were studied as possible predictive parameters. No correlation to . wound size or ulcer cluration was seen, and the predictive value of the chosen biochemical investiga- tions was not significant. Few biochemical abnormalities were seen, ancl the majority of these were thought to be clinically insignificant, see Table I. Two cases of hyperglycemia were found by the screening. No other new diseases were discovered by routine testing, but Prediction in leg ulcer healing this may be clue to the setting in a tertia1y referral center where patients have usually been seen by severa! phy- sicians prior to referral. Potentially initiating and poten- tially predisposing factors were studied. Hypothetical initiators of healing, such as e.g. hemoglobin did not show any correlation to the rate of wound healing, nor did potential inhibitors, such as sodium, potassium or albumen which could predispose to ulceration by increasing e.g. edema. Abnormal tests clid not have a discernible negative influence on the wouncl healing. In contrast to the information obtained by biophysical investigation of the vessels, general biochemical investi- gation cloes therefore not appear to have any significant value for the description or prospective assessment of treatment outcome ofvenous leg ulcers (9). The results suggest that in good accordance with clinical experience, the ulcer size at the initial evaluation may be the most important prognostic factor. The results do not support the inclusion of specific tests to the standard biochemical investigations except for gluco- suria in patients with venous leg ulcers in a tertiary referral center. If general biochemical parameters have any influence on the treatment outcome of venous leg ulcers, it is speculatecl that this occurs only in conjunc- tion witl1 other and clinically relevant factors. More accurate information about the prognosis of individual patients is an important aspect of quality assurance in dermatology (10). This study suggests that even in areas where the outcome is clearly defined (healing of ulcers) tl1e current metl1oclology be stili not sufficiently developed. l. Baker SR, Stacey MC, Jopp-McKay AG, Hoskin SE, Thompson PJ. Epidemiology of chronic venous ulcers. Br J Surg 1991; 78: 864 - 7. AUTHORS' ADDRESSES 2. Cornwall JV, Lewis JD. Leg ulcers revisited. Br J Surg 1983; 70: 681. 3. Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med] 1985; 290: 1855 - 6. 4. Callam MJ, Harper DR, Dale JJ, Ruckley CV. Arterial disease in chronic leg ulceration: an underestimated hazard? Lothian and Forth Valley leg ulcer study. Br MedJ 1987; 294: 929 - 31. 5. Ruckley CV, DaleJJ, Callam MJ, Harper DR. Causes of chronic leg ulcer. Lancet 1982; 2: 615 - 16. 6. SkeneAl, SmithJM, Dore CJ, CharlettA, Lewis]D. Venous legulcers: a prognosticindex to predici tirne to healing. Br MedJ 1992; 305: 1119- 21. 7. Impasato AM, Kirn GE, Davidson T, et al. Intermittent claudicatio: its natura! course. Surgeiy 1975; 119: 75 -8. 8. Lowe G. Drugs in cerebral and peripheral arterial disease. Br Med J 1990; 300: 524 - 8. 9. The Alexander House Group. Census paper on venous leg ulcers. Phlebology 1992; 7: 48 - 58. 1 O. Jemec GBE, Wulf HC. Quality assurance in dermatology- development of a framework. Int J Dermatol 1997; 36: 721 - 6. Gregor B.E. Jemec, MD, consultant dermatologist, Department of Dermatology, D92, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark. Tony Karlsmark, MD, consultant dermatologist, same address Tove Brink-Kjaer, RN, research nurse, same address Hans Christian Wulf, MD, PhD, professor, same address acta dermatovenerologica A.P.A. Vol 8, 99, No 1 -------------------------------- 23