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Guest book
   
Guidelines for
Diagnostics and Treatment of Venous Leg Ulcers

Developed by the Guideline Subcommittee of the
European Dermatology Forum
 
 
Subcommittee Members:
 
Prof. Dr. H.A.M. Neumann, Rotterdam (The Netherlands)
Prof. Dr. A. Cornu-Thénard, Paris (France)
Prof. Dr. M. Jünger, Greifswald (Germany)
Prof. Dr. K. Munte, Rotterdam (The Netherlands)
Prof. Dr. H. Partsch, Vienna (Austria)
Prof. Dr. A. A. Ramelet, Lausanne (Switzerland)
Prof. Dr. M. Streit, Aarau (Switzerland)
Prof. Dr. V. Wienert, Aachen (Germany)
 
 
Members of EDF Guideline Committee
 
Prof. Dr. Werner Aberer, Graz (Austria)
Prof. Dr. Martine Bagot, Créteil (France)
Prof. Dr. Lasse Braathen, Bern (Switzerland)
Prof. Dr. Sergio Chimenti, Rome (Italy)
Prof. Dr. José Luis Diaz-Perez, Bilbao (Spain)
Prof. Dr. Vladimir Hegyi, Bratislava (Slovak Republic)
Prof. Dr. Lajos Kemény, Szeged (Hungary)
Prof. Dr. Hans Christian Korting, Munich (Germany)
Prof. Dr. Gillian Murphy, Dublin (Ireland)
Prof. Dr. Martino Neumann, Rotterdam (The Netherlands)
Prof. Dr. Tony Ormerod, Aberdeen (UK)
Prof. Dr. Annamari Ranki, Helsinki (Finland)
Prof. Dr. Fenella Wojnarowska, Oxford (UK)
 
Chairman of EDF Guideline Committee:
 
Prof. Dr. Wolfram Sterry, Berlin (Germany)  
Expiry date: 3/2011  
 
List of conflicts of interest:
 
No conflicts
 
 
GENERAL
The need for European guidelines in dermatology is indicated by the ongoing development in European dermatology. The EDF, the EADV and the ESDR headed by the UEMS, also officially approved by the European Community, form the structure of pan European dermatology.
The European guidelines differ substantially from individual national guidelines. The main differences are:
a. No restrictions by different national regulations.
b. No restrictions imposed by local rules on drug distribution, re-embursement facilities, etc.
The diagnosis and treatment of venous leg ulcers is an important item within all European dermatological departments. Although this is not exclusive for this particular speciality, phlebology surgeons, physicians interested in vascular medicine and general practitioners also treat patients with venous leg ulcers.
However, the most difficult cases are treated by dermatologists.
The European Dermatological Forum has therefore decided to produce a European guideline on this subject. The process went as follows1:

The process went as follows:
 
INTRODUCTION
This guideline on the management of venous leg ulcers has been prepared by the guidelines committee of the European Dermatological Forum (EDF) and based on the already existing guideline prepared by the Dutch Society for Dermatology and Venereology. It presents evidence-based guidance for treatment, identifying the strength of evidence available at the time of preparation of the guideline, and a brief overview of epidemiological aspects, diagnosis and investigation (level S3).
Aim
This guideline is a document with recommendations and management instructions supporting the daily practice whereby the optimum treatment (especially healing and prevention of recurrence) of the patient is central. The guideline is based on the results of scientific research and contiguous opinions directed at explicating good medical practice. The document is intended as a guideline for the everyday diagnostics and treatment of venous leg ulcers by dermatologists or other medical specialists.
Problem description and initial questions
Questions regarding the diagnostics, the treatment, the follow-up treatment and the organization of care of venous leg ulcers were answered for the purpose of developing the guideline.
Working group
The Commission on guidelines of the European Dermatological Federation (EDF) inaugurated the Chairman of the working group on wound healing during its annual meeting in January 2004.
This guideline is the first on wound healing and covers the subject of venous leg ulcers.
Scientific basis
The guideline is based as much as possible on proof provided in published scientific research. Relevant articles were looked for via systematic search, carried out in Medline, Cochrane and Cinahl databases from 1995 to 2006. Previously searched literature was used for literature prior to 1995. Hereby, it must be remarked that evidence-based medicine started relatively late in Phlebology. This means that much of the Anglo-Saxon literature is a repeat of the earlier efforts (at international meetings) published in French, German, Swiss, Italian or Spanish literature.
In addition to the articles found via literature search, articles were extracted from requested list of references. Articles that remained after selection by the members of the working group are cited as the basis for the various conclusions. The selected articles were subsequently assessed on the quality of the research and were graded for the strength of proof by the members of the working group. The classification that was used hereby is shown in Table I.
One may consider that European references, especially in German and French, are underestimated compared to those from North America due to the of lack of papers cited in PubMed / M/code in the field of phlebology.
The assessment of the various articles can be found in the different texts under the heading "scientific basis". The scientific proof is then briefly summarized in a conclusion. The most important literature, including the strength of proof on which this conclusion has been based, is mentioned in the conclusion. Since evidence-based medical (EBM) publications are limited - in this journal - in a field in which it is hard to recruit enough and comparable patients - no improvement in the treatment of leg ulcers may be achieved, especially with surgical techniques (think of paratibial fasciotomy, etc.). Therefore, the experience of experts is essential, and the "recommendation" is a good way to present it (Level D).
For a recommendation, besides the scientific proof, often other aspects such as patients' choices, costs, availability (in various echelons) of organizational aspects are important. These aspects are mentioned under the heading "other considerations". The recommendation is the outcome of the available proof and other considerations.
Following this procedure increases the transparency of the guideline. It offers room for an efficient discussion during the meetings of the working group and moreover increases the clarity for the user of the guideline.
 For articles concerning: intervention (prevention or therapy)
A1 Systematic reviews of at least several studies of A2-level, whereby the results of individual studies are consistent.
A2 Randomized comparative clinical study of good quality (randomized, double blind controlled trials) of adequate size and consistency.
B Randomized clinical trials of moderate quality or inadequate size or other comparative study (not randomized, comparative cohort study, patient-control-study).
C Non-comparative study.
D Opinion of experts, for example, the members of the working group.

 For articles concerning: diagnostics
A1 Study into the effects of diagnostics on clinical outcomes in a prospectively followed well-defined patient group with a previously defined policy on grounds of the to be investigated test results, or decision study into the effects of diagnostics on clinical outcomes, whereby results of study of A2-level are used as a basis, and adequate consideration has been given to mutual dependence of diagnostic tests.
A2 Study in light of a reference test, whereby criteria have been defined beforehand for the investigation test and for a reference test, with a good description of the test and the studied clinical population; it must concern an adequately large series of consecutive patients and must make use of pre-defined cut-off values, and the results of the test and the 'golden standard' must have been assessed independently. In situations in which multiple, diagnostic tests play a role, in principle, a mutual dependence and the analysis should be adjusted to this, e.g. with logical regression.
B Comparison with a reference test, description of the investigated test and population, but excluding the characteristics that are mentioned further in A.
C Non-comparative study.
D Opinion of experts, for example, members of the working group.

 Level of the conclusions
1 One systematic review (A1) of at least 2 independently conducted studies of level A1 or A2.
2 At least 2 independently conducted studies of level B.
3 One study of level A2 or B or a study of level C.
4 Opinion of experts, for example, the members of the working group.
Legal significance of guidelines
Guidelines are not legal regulations, but "evidence-based" insights and recommendations, which should be satisfied by the care providers in order to provide good quality care. Considering that these recommendations are mainly based on the "average patient", the care providers may, if required, deviate from the recommendations on the basis of their professional autonomy. Deviation from the guidelines is necessary if the situation of the patient requires it. Any deviation from the guideline should be based on arguments and should be documented.
Revision
The client / responsible authority will determine at the latest in 2010 whether this guideline is still valid. If required, a new working group is inaugurated for the purpose of revising the guideline. The guideline will become invalid if new developments make revisions necessary.
 
CHAPTER 1. Epidemiology, Etiology and Symptomatology
1.1 Epidemiology
A venous leg ulcer is a defect in pathologically altered tissue on the lower leg on the basis of chronic venous insufficiency (CVI). CVI is a symptoms complex based on an inadequate venous return, which leads to a decompensation of the venous and microcirculatory function. Chronic venous ulceration is the severest manifestation of this disorder1. A venous ulcer with no tendency to heal within 6 weeks to 3 months or that has not healed within a year after optimum phlebological therapy is designated as therapy resistant2. About three-quarters of all leg ulcers are generally considered to be mainly of venous origin20.

Epidemiological data is more difficult to interpret than expected at first sight because of methodological differences. It makes a big difference whether a whole population, a particular group of individuals in a certain region or a patient population is investigated. The manner of registration also influences the outcome. Even filled-out polls, polls filled out by an investigator, special questionnaires on the presence of ulcers and whether or not a physical examination was conducted all have a considerable influence on the results3.

In German studies, the prevalence of venous ulcers was reported in 1% in the population, and in 4-5% of those individuals older than 80 years2. This was in keeping with the findings that 1-2% of the adult population either has or had a venous ulcer4,5. In the western countries, a prevalence of active venous ulcers in the general population older than 18 years was reliably estimated to be at 0.3%5,6. An ulcer is encountered 2 to 3 times as often in women of all age groups7. There is a clear increase with age. Chronic ulcers below the age of 60 years are unusual1. The prevalence among the elderly may be quite high (12.6% of leg ulcers (C5-C6) in a Swedish rural population older than 70 years17. However, up to 50% of leg ulcers are caused by superficial venous insufficiency18,19.

The prevalence of active and healed ulcers together is about 1%1. The prognosis is not very good. About 50% of the treated ulcers had healed within 4 months1, about 20% had still not healed after 2 years and about 8% had not healed after 5 years5,6. The annual recurrence was 6-15%6. The total risk of recurrence was about 3-15%1 and the risk of recurrence within the first year was 30-57%2. The majority of the ulcers recurred at least once1. Carpentier et al reported no significant difference between the prevalence of varicose veins in different areas in France14, but noted a consistent difference between sexes; 50.5% of those affected were women and 30.1% were men. No data was available on leg ulcers.
1.2 Etiology
Venous insufficiency was noted to be the most important cause in a large number of venous ulcers. Moreover, arterial insufficiency, diabetes mellitus, vasculitis, malignancy, infections and other less frequent causes for ulceration may accompany venous disease.
In a large number of cases, long-term complications of deep venous thrombosis, the so-called post-thrombotic syndrome, causes CVI. Estimates vary (as do the used definitions), but on average, 1 in 3 patients who suffer from a deep venous thrombosis develops post-thrombotic complications in the subsequent 5 years. The chance of developing CVI after a thrombotic leg is lower when medical elastic compression hosiery (MECH) is worn8,9.
There are different mechanisms for pumping the blood effectively against the pull of gravity. The cooperation between the venous valves and the calf muscle pump is the most important factor. The blood is pumped towards the heart while walking, whereas the valves prevent backflow. As a consequence, the venous pressure drops when the person is walking. A reflux of the blood occurs when this mechanism fails (in upright position) and an increased pressure develops in the veins of the lower legs (increased ambulatory venous pressure or venous hypertension).
First of all, varices will develop because of the increased venous pressure. The venous pressure will also increase in the venules and in the capillaries upon further decompensation. As a result of this increased intra-capillary pressure, the capillary filtration fraction will increase and edema will develop because of the leakage of fluid. Besides the leakage of fluid, there is also a leakage of high molecular weight substances such as fibrin. This can be demonstrated as a "cuff" around the capillaries. Initially, the thought was that these fibrin cuffs formed a barrier for the diffusion of oxygen resulting in local anoxia and ulceration10. However, this theory was refuted by the fact that fibrin cuffs around capillaries have been demonstrated in other skin diseases without any disturbance in the transcutaneous oxygen tension. The trapping of leukocytes in the capillaries and the release of free radicals have also been proposed as a possible explanation11. Furthermore, the transmission of high venous pressures to the dermal microcirculation results in the stimulation of an inflammatory process in which cytokine and growth factor release leads to leukocyte migration into the interstitium and the triggering of further inflammatory events. This process is associated with the intense dermal fibrosis and tissue remodeling seen in chronic venous insufficiency22.
In capillary microscopy, thrombus formation in the capillaries of the skin was not only observed in white atrophy lesions but also in other cutaneous manifestations of CVI. This was also proposed as an explanation for the ulceration. Finally, it was demonstrated that the fibrin cuffs around the venous leg ulcer do not capture oxygen, but probably growth factors, so that these are less active in the wound.
In spite of all these hypotheses, the exact mechanism of the skin abnormality and ulceration still remains obscure.
1.3 Symptomatology
The venous leg ulcer arises either "spontaneously" or often after a minor trauma. The complaints of the patient as a result of the ulcer may vary from less pronounced to very pronounced. Venous leg ulcers can be painful. The complaints of pain may be prominent in the ulcerative phase of white atrophy or if accompanied by other factors such as an infection.
Clinically, venous leg ulcer is a part of CVI. Patients with CVI develop various skin abnormalities over a period of time. The percentage of patients who develop symptoms remains unknown because it has never been properly mapped.
The venous ulcer is generally located on the medial or lateral side of the ankle4. A particular form is the ulceration in acroangiodermatitis2 of the forefoot. If the ulcer is located on another part of the lower leg, then one must strongly suspect that causes other than venous insufficiency play a role.
The clinical characteristics of CVI are generally known. For the sake of completeness they are mentioned here once again: varicosity, edema, corona phlebectatica, hyper-pigmentation, dermato-et liposclerosis, white atrophy and the ulcer12 . Stasis dermatitis is a manifestation of CVI.
The changes in the skin in venous insufficiency are a result of changes in the macro- and microcirculation. It is unclear why in one patient an extensive dermato-et liposclerosis is formed, whereas in another patient white atrophy is prominent. Local factors possibly play a role in this. This should be investigated further.
1.4 Quality of life
Venous ulcers have a substantial impact on patients' lives and affect most issues of health-related quality of life (HRQOL) such as bodily pain, health transition, mental health, social functioning and vitality21. Treatment, and especially healing of venous ulcers, results in a significant improvement in these areas. Nonetheless, a few specific HRQOL instruments have been developed. Studies indicated that these instruments were suboptimal and that generic instruments such as the SF-36, SF-12 and EuroQoL-5D are recommended for the purpose of measuring the impact on patients' lives, for time being16.
 
Literature
1.   The Venous Forum of the Royal Society of Medicine and Societas Phlebologica Scandinavica. The management of chronic venous disorders of the leg: an evidence-based report of an international task force. Phlebology 1999; 14 Suppl 1:23-5.
2.   Korting HC, Callies R, Reusch M, Schlaeger M, Schöpf E, Sterry W. Dermatologische Qualitätssicherung. Leitlinien und Empfehlungen München 2000; 202-10.
3.   Krijnen RMA, de Boer EM, Bruynzeel DP. Epidemiology of venous disorders in the general and occupational populations. Epidemiol Rev 1997; 19:294-309.
4.   Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg; extent of the problem and provision of care. Br Med J (Clin Res Ed) 1985; 290:1855-6.
5.   Guidelines for the diagnosis and therapy for diseases of the veins and lymphatic vessels: Evidence-based report by the Italian College of Phlebology. Int. Angiology 2001; 20 Suppl 2:1-73.
6.   Nicolaides AN. Investigation of Chronic Venous Insufficiency: a consensus statement.
Circulation 2000; 102:123-63.
7.   The Alexander House Group Consensus paper on venous leg ulcers. Phlebology 1992; 7: 48-58.
8.   Brandjes DP, Buller HR, Heijboer H, Huisman MV, De Rijk M, Jagt H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:759-62.
9.   Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7.
10.   Browse NL, Burnand KG. The cause of venous ulceration. Lancet 1982;ii: 243-5.
11.   Coleridge Smith PD, Thomas P, Scurr JK Dormandy JA. Causes of venous ulceration: a new hypothesis. Br Med J 1988; 296:1726-7.
12.   Philips T, Stanton B, Provan A, Lew R. A study of the impact of leg ulcers on quality of life: financial, social and psychological implications. J Am Acad Dermatol 1994;31:49-53.
13.   Rabe E, Pannier-Fischer F, Gerlach H, Breu FX, Guggenbichler S, Zabel M. Guidelines for sclerotherapy of varicose veins. Dermatol Surg. 2004;30: 687-93.
14.   Carpentier PH, Maricq HR, Biro C, Poncot-Makinen CO, Franco A. Prevalence, risk factors, and clinical patterns of chronic venous disorders of lower limbs: a population-based study in France. J Vasc Surg. 2004; 40: 650-9.
15.   Charles H. Does leg ulcer treatment improve patients quality of life? J Wound Care 2004; 13: 209-13.
16.   Iglesias CP, Birks Y, Nelson EA, Scanlon E, Cullum NA. Quality of life of people with venous leg ulcers: a comparison of the discriminative and responsive characteristics of two generic and a disease specific instruments. Qual Life Res. 2005; 14: 1705-18.
17.   Marklund B, Sulau T, Lindholm C. Prevalence of non healed and healed chronic leg ulcers in an elderly rural population. Scand J Prim Health Care 2000; 18: 58-60.
18.   Tassiopoulis AK, Golts E, Oh DS, Labropoulos N. Current concepts in chronic venous ulceration.
Eur J Vasc Endovasc Surg. 2000 Sep;20(3):227-32.
19.   Bergan JJ, Schmid-Schonbein GW, Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic venous disease. N Engl J Med. 2006 Aug 3; 355(5): 488-98.
20.   Chaby G, Viseux V, Ramelet AA, Ganry O, Billet A, Lok C. Refractory venous leg ulcers: a study of risk factors. Dermatol Surg. 2006 Apr; 32(4): 512-9.
21.   Kahn SR, M'lan CE, Lamping DL, Kurz X, Berard A, Abenhaim LA. Relationship between clinical classification of chronic venous disease and patient-reported quality of life:
Results from an international cohort study. J Vasc Surg. 2004; 39: 823-8.
22.   Nicolaides AN.Chronic venous disease and the leukocyte-endothelium interaction: from symptoms to ulceration. Angiology. 2005 Sep-Oct;56 Suppl 1:S11-9.
 
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CHAPTER 2. DIAGNOSTICS
The differential diagnosis of the crural ulcer is large. Still, there are several diagnoses that can be said to occur the most frequently. It is essential to immediately establish a correct diagnosis as adequately as possible, considering that different diagnoses have totally different approaches and treatments. An incorrect diagnosis may have dramatic consequences for the patient in several situations1.
2.1 Anamnesis
Scientific basis
A good anamnesis is indispensable. Many patients with a crural ulcer have an extensive previous medical history and comorbidity. Good studies into the value of specific items for the anamnesis are lacking.
Conclusion
Level 4 Good studies on the value of specific items for anamnesis are not available. Nevertheless, a good anamnesis is indispensable.
Level D
Other considerations
Field experience and consensus within the various disciplines indicated that the previous medical history as well as the family anamnesis and the specific aspects of the ulcer must be dealt with extensively in the anamnesis (see Table).

Subject Anamnesis
Previous medical history Varicosity and treatment of varices
Venous thrombosis
Leg ulcer
Peripheral arterial vascular disorder (including complaints of intermittent claudication)
Diabetes mellitus
Rheumatoid arthritis
Extensive leg trauma
Medication use
Mobility and nutritional status
Family anamnesis Varicosity
Venous thrombosis
Leg ulcers
Vascular disorder
Specific aspects Duration of the ulcer
Pain
Previous treatment
Fever and other symptoms of infection
Agility of the ankle joint
Recommendation 1
The working group recommends that the previous medical history, family anamnesis and specific aspects are dealt with extensively during the anamnesis (see Table).
 
2.2 Physical examination
The international CEAP classification was designed to obtain an unequivocal description of the abnormalities in patients2. This classification was revised in 200453. The physical examination is the leading feature in this classification.

C E A P
Clinical status (clinic) Etiology Anatomy Pathophysiology
C0 no visible abnormalities Ep primary As superficial Pr reflux
C1 teleangiectasias or reticular veins Es secondary Ap perforating Po obstruction
C2 varices Ec congenital Ad deep Pr,o reflux and obstruction
C3 edema En no venous cause identified An no venous location identified Pn no venous pathophysiology identified
C4 Changes in skin and subcutaneous tissue secondary to CVD      
C5 healed ulcer      
C6 active, open ulcer      
S symptomatic, including ache, pain, tightness, skin irritation, heaviness, and muscle cramps, and other complaints attributable to venous dysfunction      
A asymptomatic      
Recommendation 2
The working group recommends the use of CEAP classification for physical examination. In addition, the size, site and characteristics of the ulcer should be recorded.
 
2.3 Supplementary investigation
2.3.1 Venous investigation

Venous Doppler

Scientific basis
Doppler sonography is a simple, practical and cheap technique for the diagnosis of venous reflux.
Comparative studies have mainly been done with descending phlebography, duplex diagnostics and venous pressure measurements. The sensitivity and the specificity of Doppler diagnostics in uncomplicated varicosis of the greater saphenous vein (GSV) and the saphenofemoral insufficiency are high (>92%). However, the sensitivity and especially the specificity are clearly lower in case of the recurrence varicosis of the GSV, or in reflux in the fossa poplitea and in venae perforantes (<70%)3-6. Besides, Doppler diagnostic strongly depends on the investigator. The value of the Doppler diagnostic is doubtful considering that in a considerable number of cases of venous leg ulcers there is an insufficiency in the deep venous system or an insufficiency in the venae perforantes.
Conclusion
Level 2 Doppler has a low sensitivity and a low specificity in the diagnostics of the deep venous system and the venae perforantes.

B   Raju 19903; McMullin 19925; Rautio 20026
Recommendation 3
The use of Doppler in the diagnostics of venous leg ulcer is not advised for routine investigation of the deep venous system and the venae perforantes.
Venous Duplex

Scientific basis
Duplex ultrasonography is a combination of B-mode echography and Doppler sonography. The technique was initially utilized for the diagnostic of deep venous thrombosis. It was Van Bemmelen who, towards the end of 1980s, demonstrated that the diagnostic of varices and venous insufficiency could be conducted reliably with duplex7. One could look at the diameter, the duration of the reflux, the presence of flow and the compressibility of the vein.
The duration of the reflux in normal proximal veins of the leg is <1 sec. and <0.5 sec. in the distal veins8. There is no clear demonstrable difference between the induction of the reflux signal (in the proximal deep veins) between the classic Valsalva maneuver and the "rapid cuff inflation"9. The former is preferred, considering its simplicity.
Similarly to Doppler, the diagnostic strongly depends on the investigator. The variation coefficient of the reflux measurements is considerable (30-45%), but the inter-observer reliability is good (kappa 0.86) if the above-mentioned cut-off points of the reflux are strictly adhered to.
Although it is difficult to correlate Duplex to another technique, comparative studies on clinical investigation, venous pressure measurements, plethysmographic techniques and descending phlebography were conducted. The best correlation was found using descending phlebography, which demonstrated a sensitivity of 79-100% in investigations into reflux in the deep system. The specificity was clearly lower (63-88%)10.
Duplex scanning for the detection of deep venous insufficiency correlated well with descending phlebography. The sensitivity (79-100%) was good, but the specificity (63-94%) was somewhat lower11. CEAP classification can be established only if Duplex has been performed.
Conclusion
Level 2 It has been demonstrated that duplex diagnostic has high sensitivity and specificity in the diagnostics of the superficial and deep venous system of the legs.

A2 Baker 199310
B Masuda 199211
C Magnusson 19954
Other considerations
A disadvantage of the duplex diagnostics is that there are patients on whom the technique may be laborious to carry out because of mobility problems. However, the investigation is less burdensome for the patient, relatively cheap and may be repeated easily. Furthermore, duplex diagnostic is the standard venous investigation, which allows further classification of chronic venous insufficiency and classification-related treatment.
Recommendation 4
Duplex investigation is the preferred technique for patients with a venous leg ulcer.
Scientific basis
Phlebography is a radiological technique in which contrast fluid is injected into the venous vascular system. A distinction between ascending phlebography and descending phlebography is made. In the ascending phlebography, contrast fluid is injected into a vein in the back of the foot, whereas in the descending phlebography, the contrast fluid is injected into the femoral vein, after which a Valsalva maneuver is performed. Descending phlebography has been compared with deep venous pressure measurements. The sensitivity was good (70-100%), but the specificity was relatively low (40-75%)3.
Duplex diagnostic has largely replaced phlebography. However, phlebography may still be valuable in distinguishing between primary and secondary varices, in identifying the level of obstruction in the femoral and the iliac veins, in detecting incompetence of the gastrocnemius veins and in determining the level of reflux in the deep venous system as well as the status of the valves.
Conclusion
Level 2 Descending phlebography has a high sensitivity but a low specificity for specifying venous incompetence.

B Raju 19903
Other considerations
The investigation is burdensome for the patient and is expensive.
Recommendation 5
Descending phlebography is not the diagnostic of (first) choice for a leg ulcer. The technique should be used only on indication. The sensitivity is then high.
Direct venous pressure measurement

Scientific basis
An increased ambulatory venous pressure causes venous pathology. There is a clear correlation between this pressure and the extent of pathology12. This pressure can be invasively measured directly by means of a cannula in a superficial foot vein. There is a good correlation between this pressure in a foot vein and the pressure in the deep veins at the ankle height13. Superficial venous insufficiency can be distinguished from deep venous insufficiency by occluding the superficial system by means of a tourniquet14. The direct venous pressure measurement is seldom used because of its invasive character and the fact that the procedure is complicated.
Indirect venous pressure measurement

Scientific basis
Strain gauge plethysmography was already described by Whitney in 1953 and was developed further into a method for measuring venous pressure indirectly by Brakkee and Vendrik in the 1960s15,16. This method was developed further for the purpose of measuring the venous pressure indirectly in the 1990s, by Van Gerwen - whereby the complete measurement was carried out while the patient was lying down17. The method was validated by Janssen, who demonstrated a good correlation with directly measured venous pressure18.
In this so-called "lying position" pump function test, volume changes in the legs were measured using a mercury strain gauge.
An increase in venous pressure such as that in the upright position is simulated with the help of a pressure cuff on the upper legs. This increase in pressure is accompanied by an increase in the venous volume. When the maximum increase has been reached, standardized calf muscle exercises are performed whereby the calf muscle pump pushes the blood through the cuff towards the heart. The mercury strain gauge again registers the decrease in the volume as a result of the calf muscle pump.
The decrease in volume is accompanied by a decrease in pressure. The measured decrease in volume can be calculated into a decrease in pressure by determining a pressure-volume relationship.
The decrease in pressure is a good measure of the function of the calf muscle pump of the deep veins.
This method is not used much because a good commercial version is not yet available. Moreover, the investigation is time-consuming and can only be carried out in a mobile and cooperative patient.
Photoplethysmography

Scientific basis
The principle of the photoplethysmography, whereby the transmission of light through the skin is measured as a measure of the change in blood volume in the skin, was already described in 1937 by Herzman19. This technique was initially used for arterial investigation, but was modified for venous investigation by Abramowitz in 197920. The technique was further developed into a standardized digital version by Wienert and Blazek in the 1980s21,22.
The measurement is generally done in the sitting position with a measuring probe fixed to the medial side of the lower leg above the ankle, whereby standardized calf muscle exercises are performed. The volume of blood in the skin under the probe is measured.
The most important parameter of the photoplethysmography is the venous refill time. There is a good correlation between the refill time measured with direct venous pressure measurement and with photoplethysmography19,23.
However, the relationship between the refill time and the level of venous insufficiency is not good24,25.
The influence of the superficial venous system on the refill time may be eliminated using small pressure cuffs when the refill time is short. A clear increase in the refill time after occlusion of the superficial varices indicated a good deep venous function. Unfortunately, the measurements did not lend themselves well for interpretation26.
Other plethysmographic methods for venous investigation

Scientific basis

Volume changes may also be measured with air plethysmography and foot volumetry, whereby the refill time also acts as the most important parameter27,28. These are not discussed further here because they are not used routinely.
Conclusion
Level 3 Plethysmographic investigation can provide information on deep venous insufficiency and on the function of the calf muscle pump.
A good, reliable, simple plethysmographic test with which the function of the calf muscle pump can be registered as a number is not widely available.
An increase in the venous refill time measured after occlusion of the superficial system may indicate a negative influence of the superficial varicosis on the ambulatory venous pressure.

Ref C
Van Gerwen 199217; Janssen 199618; Hertsmann 193719; Abramowitz 197920;
Wienert 198221; Blazek 198922; Nickolaides 198723; van Bemmelen 199224;
Bays 199425; Rutgers 199326
Recommendation 6
Photoplethysmography is not advised for routine investigation because of its low sensitivity and specificity. The remaining plethysmographic methods are not widespread enough at the moment to enable a recommendation.
2.3.2 Other investigation

Systolic ankle pressure index

Scientific basis
It was demonstrated in a number of studies that up to 30% of the total number of patients with a leg ulcer suffer from peripheral arterial vascular disorder. The ulcers hereby may be the result of this peripheral arterial vascular disorder alone or in combination with venous insufficiency. Location of the ulcer may be an indication for peripheral arterial vascular disorder. Therefore, the chances of this occurring in combination with ulceration of the foot are considerably higher than when ulceration is around the ankle29.
A supplementary investigation of vascular function is required for a correct estimation of the presence and the seriousness of this peripheral arterial vascular disorder as the anamnesis and the physical examination are not enough. The palpation of the ankle/artery at the back of the foot appeared to be insensitive, even carried out by experienced hands, and does not exclude arterial disorder30-32. Measuring the systolic ankle pressure in comparison with the systolic arm pressure and calculating the systolic ankle pressure index using a Doppler instrument provides a reliable indicator for the presence of an arterial obstructions. A prerequisite for a valid assessment is that the measurements should be performed in a standardized manner33. An arterial abnormality in an arteriogram is largely excluded (chance >95%) if the systolic ankle pressure index is > 0.8. Measuring the systolic ankle pressure index is not always reliable in the case of patients with diabetes mellitus because compression of the arteries may not be possible (medial sclerosis).
Conclusion
Level 3 An estimated 25% of the patients with a leg ulcer has arterial insufficiency54. The palpation of the ankle/artery at the back of the foot is an unreliable test. A systolic ankle pressure index does provide a reliable indication.

C Stoffers 199633
Recommendation 7
It is recommended that patients with a leg ulcer should be subjected to an additional investigation by measuring systolic ankle pressure index. Further arterial investigation can be undertaken on indication.
Microbial cultures and antibiotics

Scientific basis
Most of the leg ulcers are either contaminated or colonized by bacteria or yeast over a period of time. In larger studies, positive results of cultures were reported in all ulcers35. There is a clear relationship between the size of the ulcer, the duration of the ulcer and the age of the patient34. Staphylococcus aureus, Streptococci (not group A beta hemolytic) and Pseudomonas aeruginosa were observed in most cultures. The presence of anaerobic bacteria was reported in up to 30% of the cases in one study36. Finally, Candida albicans and other fungi were also encountered in 15 to 30% of the ulcers55.
It was reported in a number of studies that there was no relationship between a positive bacterial culture result and slow wound healing37-40. Various authors then also concluded that there was no reason for routine cultures in a venous leg ulcer. A sample for culture is obtained if there are signs of cellulitis or erysipelas, increased pain, an increase in the size of the ulcer, erythema around the wound and a purulent exudate. There is one randomized study in which the effect of antibiotics in the treatment of clinically uninfected ulcers was investigated41. However, there was no statistically significant difference between the patients who were treated with antibiotics and those who were not.
Conclusion
Level 3 It is meaningless to routinely obtain a sample from a venous leg ulcer for culture. Culturing and eventual prescription of antibiotics is only indicated if there are signs of an infection of the wound.

B Alinovi 198641
Recommendation 8
A swab from a venous leg ulcer for culture is warranted only if there are signs of an infection or before surgery on leg ulcers. Oral or intravenous treatment with antibiotics should then also be considered.
Biopsy

Scientific basis
If an ulcer has an atypical appearance or responds inadequately to the therapy, then the possibility of another diagnosis such as a malignancy or a malignant degeneration should be considered and a skin biopsy should be obtained42.
Conclusion
Level 3 A biopsy from the edge of the wound may rule out the possibility of a malignancy or a malignant degeneration if the venous leg ulcer responds inadequately to therapy or has an atypical appearance.

C Yang 199642
Recommendation 9
Taking multiple biopsies should be considered if an ulcer does not respond or responds inadequately to therapy and has an atypical appearance.
Contact allergological investigation

Scientific basis
Eczema cruris in CVI occurs frequently and is often unjustly diagnosed as cellulitis or erysipelas.
A possible contact allergy must always be considered in the case of patients with a long previous history of recurring ulcers. It was shown in various studies that in the case of contact allergies there was generally an allergy to components such as perubalsam and lanoline in wound ointments, to topical antibiotic such as neomycin, wound dressings, bandages43-49, hydrocolloids and topical anesthetics47,48,50-52, whereby there was a clear relationship between the duration of the ulcers and the occurrence of contact allergies.
One should always consider the possibility of contact allergy when there are indications of slow wound healing. This often manifests itself in the form of eczema.
Conclusions
Level 3 A contact allergy is often present in patients with persistent or recurrent ulcers. Eczema or a slow healing of the wound may indicate this.

C Wilson 199147; Katsarou-Katsari 199848; Lange 199650; Tosti 199651; Schliz 199652
Recommendation 10
The recommendation is to carry out a test with a series of allergens that are present in products for treating wounds and wound dressings in addition to the European standard series in all cases of leg eczema in CVI when contact allergy is suspected.
 
Literature
1.   Callam MJ, Ruckley CV, Dale JJ, Harper DR. Hazards of compression treatment of the leg: an estimate from Scottish surgeons. Br Med J (Clin Res Ed) 1987; 295:1382.
2.   Classification and grading of chronic venous disease of the lower limb: a consensus statement. Phlebology 1995; 10:42-5.
3.   Raju S, Fredericks R. Evaluation of methods for detecting venous reflux. Perspectives in venous insufficiency. Arch Surg 1990; 125:1463-7.
4.   Magnusson M, Kalebo P, Lukes P, Sivertsson R, Risberg B. Colour Doppler ultrasound in diagnosing venous insufficiency. A comparison to descending phlebography. Eur J Vasc Endovasc Surg 1995; 9:437-43.
5.   McMullin GM, Coleridge Smith PD. An evaluation of Doppler ultrasound and photoplethysmography in the investigation of venous insufficiency. Aust N Z J Surg 1992; 62:270-5.
6.   Rautio T, Perala J, Biancari F, Wiik H, Ohtonen P, Haukipuro K, Juvonen T. Accuracy of hand-held Doppler in planning the operation for primary varicose veins. Eur J Vasc Endovasc Surg 2002; 24(5):450-5.
7.   Van Bemmelen P, Bedford G, Beach K, Strandness DE. Quantitative segmental evaluation of venous valvular reflux with duplex ultrasound scanning. J Vasc Surg 1989; 10:425-31.
8.   Haenen JH, van Langen H, Janssen MC, Wollersheim H, van 't Hof MA, van Asten WN, et al. Venous duplex scanning of the leg: range, variability and reproducibility. Clin Sci (Lond) 1999 Mar; 96(3):271-7.
9.   Masuda EM, Kistner RL, Eklof B. Prospective study of duplex scanning for venous reflux: comparison of Valsalva and pneumatic cuff techniques in the reverse Trendelenburg and standing positions. J Vasc Surg 1994; 20(5):711-20.
10.   Baker SR, Burnand KG, Sommerville KM, Thomas ML, Wilson NM, Browse NL. Comparison of venous reflux assessed by duplex scanning and descending phlebography in chronic venous disease. Lancet 1993; 341(8842):400-3.
11.   Masuda EM, Kistner RL. Prospective comparison of duplex scanning and descending venography in the assessment of venous insufficiency. Am J Surg 1992 Sep; 164(3):254-9.
12.   Payne SPK, London NJM, Newland DJ, Thrush AJ, Barrie WW, Bell PRF. Ambulatory venous pressure: correlation with skin condition and role in identifying surgically correctable disease. Eur J Vasc Endovasc Surg 1996; 11:195-200.
13.   Arnoldi CC. Venous pressures: the function of the venous pump in chronic venous insufficiency. J Cardiovasc Surg 1961; 2:116-127.
14.   Kuiper JP. Venous pressure determination (direct method). Dermatologica 1966; 132:206-17.
15.   Whitney RJ. The measurement of volume changes in human limbs. J Physiol 1953; 121:1-27.
16.   Brakkee A, Vendrik A. Strain gauge plethysmography, theoretical and practical notes on a new design. J Appl Physiol. 1966 Mar; 21(2):701-4.
17.   Van Gerwen HJL, Brakkee A, Kuiper JP. Non-invasive measurement of venous muscle pump function in the supine position. Phlebology 1992; 7:146-9.
18.   Janssen MCH, Claassen JA, van Asten WN, Wollersheim H, de Rooij MJ, Thien T. Validation of the supine venous pump function test: a new non-invasive tool in the assessment of deep venous insufficiency. Clin Sci 1996;91-483-8.
19.   Hertzman AB. Photoelectric plethysmography on the fingers and toes in man. Proc Soc Exp Biol (NY) 1937; 37:529-534.
20.   Abramowitz H, Queral LA, Finn WR, Nora PF Jr, Peterson LK, Bergan JJ, et al. The use of photoplethysmography in the assessment of venous insufficiency; a comparison to venous pressure measurements. Surgery 1979; 86:434-41.
21.   Wienert V, Blazek V. Eine neue, apparative nichtinvasive Diagnostik der chronisch-venosen Insuffizienz. Phleb u Prokt 1982; 11:110-3.
22.   Blazek V, Schmitt HJ, Schulz-Ehrenburg U, Kerner J. Digitale Photoplethysmographie (dPPG) fur die Beinvenendiagnostik - medizinisch-technische Grundlagen. Phleb U Prokt 1989; 18:91-7.
23.   Nicolaides AN, Miles C. Photoplethysmography in the assessment of venous insufficiency. J Vasc Surg 1987; 5:405-412.
24.   Van Bemmelen PS, van Ramhorst B, Eikelenboom BC. Photoplethysmography reexamined: lack of correlation with duplex scanning. Surgery 1992; 112:544-8.
25.   Bays RA, Healy DA, Atnip RG, Neumyer M, Thiele BL. Validation of airplethysmography, photoplethysmography and duplex ultrasonography in the evaluation of severe venous stasis. J Vasc Surg 1994; 20:721-7.
26.   Rutgers PH, Kitslaar PJEM, Ermers EJM. Photoplethysmography in the diagnosis of superficial valvular incompetence. Br J Surg 1993; 80:351-3.
27.   Christopoulos D, Nicolaides AN, Szendro G. Venous reflux: quantification and correlation with the severity of venous disease. Br J Surg 1988; 75:352-6.
28.   Thulesius O, Norgren L, Gjores JE. Foot volumetry: a new method for objective assessment of oedema and venous function. VASA 1973; 2:325-9.
29.   Callam MJ, Harper DR, Dale JJ, Ruckley CV. Chronic ulcer of the leg: clinical history. Br Med J (Clin Res Ed) 1987;294: 1389-91.
30.   Magee TR, Stanley PR, al Mufti R, Simpson L, Campbell WB. Should we palpate foot pulses? Ann R Coll Surg Engl 1992; 74:166-8.
31.   Brearley S, Shearman CP, Simms MH. Peripheral pulse palpation: an unreliable physical sign. Ann R Coll Surg Engl 1992; 74:169-71.
32.   Moffat CJ, Oldroyd MI, Greenhalgh, RM, Franks PJ. Palpating ankle pulses is insufficient in detecting arterial insufficiency in patients with leg ulceration. Phlebology 1994;9:170-2.
33.   Stoffers HEJH, Kester ADM, Rinkens PALM, Kitslaar PJEHM, Knottnerus JA. The diagnostic value of the measurement of the ankle-branchial systolic pressure index in primary health care. J Clin Epidemiol 1996; 49:1401-5.
34.   Eriksson G, Eklund AE, Kallings LO. The clinical significance of bacterial growth in venous leg ulcers. Scand J Infect Dis. 1984; 16:175-80.
35.   Hansson C, Hoborn J, Moller A, Swanbeck G. The microbial flora in venous leg ulcers without clinical signs of infection. Repeated culture using a validated standardised microbiological technique. Acta Derm Venereol 1995; 75(1):24-30.
36.   Skene AJ, Smith JM, Dore CJ, Charlett A, Lewis JD. Venous leg ulcers: a prognostic index to predict time to healing. BMJ 1992; 7:1119-21.
37.   Margolis DJ, Berlin JA, Strom BL. Which venous leg ulcers will heal with limb compression bandages? Am J Med 2000; 109(1):15-9.
38.   Madsen SM, Westh H, Danielsen L, Rosdahl VT. Bacterial colonization and healing of venous leg ulcers. APMIS 1996; 104(12):895-9.
39.   Schmidt K, Debus ES, Jessberger ST, Ziegler U, Thiede A. Bacterial population of chronic crural ulcers: is there a difference between the diabetic, the venous, and the arterial ulcer? Vasa 2000; 29(1):62-70.
40.   Alinovi A, Bassissi P, Pini M. Systemic administration of antibiotics in the management of venous ulcers. A randomized clinical trial. J Am Acad Dermatol 1986; 15(2 Pt 1):186-91.
41.   Yang D. Morrison BD, Vandongen YK, Singh A, Stacey MC. Malignancy in chronic leg ulcers. Med J Aust 1996; 164:718-20.
42.   Malten KE, Kuiper JP, van de Staak WJBM. Contact allergic investigations in 100 patients with ulcus cruris. Dermatologica 1973; 147:241-54.
43.   Angelini G, Rantuccio F, Meneghini CL. Contact dermatitis in patients with leg ulcers. Contact Dermatitis 1975; 1:81-7.
44.   Fraki JE, Peltonen L, Hopsu-Hava VK. Allergy to various components of topical preparations in stasis dermatitis and leg ulcer. Contact Dermatitis 1979; 5:97-100.
45.   Kulozik M, Powell SM, Cherry G, Ryan TJ. Contact sensitivity in community-based leg ulcer patients. Clin Exp Dermatol 1988; 13:82-4.