In chapter 1 we provide a general introduction of this thesis. Chronic venous disease (CVD) is a common medical condition that affects 2-64% of the worldwide population and leads to leg ulcers in 1% of the Western population. Venous leg ulceration (VLU) has an unfavorable prognosis with regard to non-healing and recurrence rates. Annually 6% of the total healthcare costs are spent on the treatment of venous diseases. CVD results from ambulatory venous hypertension and is the consequence of valvular incompetence, venous outflow obstruction, or a combination of both, and may be divided in primary CVD and secondary CVD. However, the venous microcirculation is very complex and multifactorial. CVD is associated with multiple and subjective symptoms and objective clinical signs. Nowadays the diagnosis CVD is made by duplex ultrasound and in special situations other diagnostic tools may be used. Compression therapy is the cornerstone in the treatment of CVD, as treatment modality as well as supplement to another treatment. We end this introduction by stating the aims of this thesis. In chapter 2 we investigate the effect of light medical elastic compression stockings (light MECS) (Proleg®) on leg symptoms in a choir after a standing rehearsal. We performed a case-control study, in which the cases wore light MECS during the rehearsal, and the controls did not wear any MECS. Preceding the rehearsal all the subjects filled in a questionnaire. After the rehearsal the effect of the stockings was evaluated by a second questionnaire. A part of the questions was answered by visual analogue scores. Wearing light MECS led to significant improvement of symptoms of leg fatigue (P < 0.01). Improvement of symptoms of leg swelling, leg cramp, and restless legs was demonstrated, but this improvement was not significant. In conclusion, light MECS are very effective in preventing symptoms of leg fatigue during sustained standing. Moreover they reduce symptoms of restless legs, leg swelling, and leg cramp. In chapter 3 we investigate the use of compression ulcer stockings with regard to reduction of the capillary filtration rate (CFR). We used plethysmography to measure the CFR in both legs of 17 subjects, 6 with chronic venous insufficiency and 11 healthy subjects. The CFR was measured with both (day and night) stockings, only the night stocking and without stockings. The reduction of the CFR was significant (P < 0.0001) for the total population in the group wearing two stockings versus one stocking (CFR = 0.019 vs. 0.084 ml/100ml/min), one stocking versus no stockings (CFR = 0.149 vs. 0.084 ml/100ml/min) and two stockings versus no stockings (CFR = 0.019 vs. 0.149 ml/100ml/min). In conclusion, compression ulcer stockings are highly effective in reducing the CFR and thus reducing edema formation, which leads to improved healing of venous ulcers. Ambulatory venous pressure (AVP) measurement has never been fully standardised. In chapter 4 we invite experts on AVP measurement to discuss this investigation and reach consensus on AVP measurement. After committing to participate to the consensus meeting during the UIP World Congress in Monaco 2009, each expert received statements and questions concerning the pitfalls in standardising AVP measurement by email. They also received the protocol of AVP measurement of the department of dermatology in Rotterdam, the Netherlands. From here, this protocol was revised. A list of questions was sent out beforehand based on which several proposals for future evaluations of venous pressure curves were formulated at the meeting. The most important change of the previous non-standardised protocol on AVP measurement is that AVP measurement should be performed on a treadmill at a speed of 2 km/h and with an elevation of 8˚. If no treadmill is available tiptoe or knee bending exercises may be used. It is proposed to define AVP as mean AVP [(systolic venous pressure + 2 x diastolic venous pressure)/ 3]. Venous refill time (RT) should not be routinely used as outcome measure. The conclusion of AVP measurement may be: normal (no venous hypertension), intermediate ambulatory venous hypertension or severe venous hypertension. The related pressure ranges obtained by the proposed mode of evaluation should be validated in future studies. AVP measurement is the “gold standard” to quantify the severity of hemodynamic abnormality of CVD in the lower extremity. Several proposals concerning a standardized evaluation of venous pressure measurements have been formulated. In chapter 5 we investigate the association between CEAP clinical classification and AVP measurement and ACP measurement, and the correlation between AVP measurement and ACP measurement. In a retrospective descriptive study, patients with various causes and at various clinical stages of CVD were examined. Severity of venous disease was scored by the CEAP clinical classification and patients were investigated by AVP measurement and ACP measurement. In total 163 legs were investigated in 89 patients (median age 44 years, range 16-79). These were classified as 90 female and 73 male legs. The legs were categorized in accordance with CEAP clinical classification: C0 n = 33; C1 n = 8; C2 n = 15; C3 n = 27; C4 n = 47; C5 n = 21; C6 n = 12. Statistically significant differences between the seven groups of CEAP clinical classification compared with AVP measurement (p < 0.001), for both AVP and RT were demonstrated. No significant relation was demonstrated between CEAP clinical classification and supine ACP (p = 0.165) or standing ACP (p = 0.148). A poor correlation was found between AVP measurement and ACP measurement (r < 0.10). In conclusion, patients with severe CVD as scored with CEAP clinical classification have significantly higher AVP and shorter RT. No relations were observed between CEAP clinical classification and ACP measurement, as well as between AVP measurement and ACP measurement, presuming that AVP and ACP represent different stages and/or complications of CVD. Replacement of AVP measurement in daily practice by CEAP clinical classification is justified. However in special situations where quantification of CVD is required, i.e. in post-thrombotic syndrome, AVP measurement is still practical. If chronic venous compartment syndrome (CVCS) is suspected by the patients’ symptoms, ACP measurement may be used irrespective of CEAP clinical classification and AVP. However the correlation between high ACP and chronic venous hypertension determined by as well CEAP clinical classification as high AVP could not be proved. This lack of correlation between CVD and CVCS may be explained by the fact that tissue interaction by the decompensated microcirculation leading to fibrosis seems to be different in the skin, the subcutaneous tissue and the compartment. Up to now we have no predictable criterion for the development of CVCS in relation to CVD. In chapter 6 we discuss the use of the CEAP-classification. Since the introduction of the CEAP-classification in 1994 most published phlebological literature only mention the CEAP clinical classification (indicated by the C in the CEAP-classification), which is a clinical appraisal of the physician and not an interpretation of duplex ultrasound. The CEAP-classification was introduced in an era when the hand-held-Doppler was the phlebologist’s most important investigative tool and clinical appraisal was done by sight alone. Nowadays duplex ultrasound is common in every phlebological practice and mandatory to perform in every patient before an intervention takes place. The decision to treat patients should be based on the expectation to recover the disturbed venous haemodynamics. The use of just the CEAP clinical classification may lead to misinterpretation of the function of the saphenous veins because the CEAP clinical classification only comprises visible clinical signs. We therefore proposed to adjust the CEAP clinical classification by dividing C2 into two subclasses: C2a (minor reflux) and C2b (major reflux) just as was done with C4. In chapter 7 we perform a systematic search to summarize the evidence-based literature with regard to VLU recurrence, because of the large variation in published VLU recurrence rates. A review of published data was performed using the MEDLINE OvidSP, EMBASE, Web-of-Science, PubMed publisher and Cochrane Library with the Medical Subject Headings (MeSH) varicose ulcer and recurrence. To be included, studies needed to fulfil the following criteria: prospective study design; diagnosis made by CEAP-classification and/or by using duplex ultrasound; and leg ulcer recurrence expressed as recurrence at a certain time. Our data demonstrated VLU recurrence rates ranging from 0% at 6 months to 56% at 54 months. Two studies mention VLU recurrence at 60 months, with VLU recurrence rates of 19 and 48% respectively. Only three studies are comparable with regard to treatment and demonstrate VLU recurrence of 17, 17 and 25% respectively at 12 months. This was the first study summarising high-level evidence with regard to VLU recurrence demonstrating a tendency that even after several years recurrence rates still increase. A more systematic approach of organising the evidence of VLU recurrence might lead to the final answer. The results of this study, high recurrence rates indicate the need for new strategies after a VLU has healed. In chapter 8 we execute an internet survey to get insight into the frequency of VLU in the Dutch dermatologic practice, and into how this profession treats this disease. To all Dutch dermatologists and residents dermatology an email was sent in October 2008, with an online link to a questionnaire on venous leg ulcers. The overall response to the internet survey was 30%. All responders are familiar with the Dutch guideline on Venous Leg Ulcer. 83.5% of the doctors usually treat their patients according to this guideline. The dermatologic practice consists on average of 73 patients (range 0-500; SD 93) with leg ulceration, and yearly 54 new leg ulcer patients (range 0-300; SD 50) are seen. 65% of the patients are women, 80% is over 45 years of age and 55% is over 65. Of all ulcers, 77% has a venous aetiology, of which 59% has a primary cause. Supplementary examination is performed in almost every patient. The outpatient treatment in all cases consists of ambulatory compression therapy. Mean time to heal is 74 days (range 4-200; SD 39). Per year, dermatologists admit on average 7 patients (range 0-50; SD 11) because of leg ulceration. A majority of the admitted patients (59%) are confined to bed, and half of these patients are treated by vacuum-assisted closure (VAC®) therapy. Eventually, 47% of the admitted patients are treated by skin transplantation. We conclude that this questionnaire gives a good insight in the epidemiology, and the diagnostic and therapeutic regimen for patients with VLU in Dutch dermatologic practice. In chapter 9 we perform a prospective open study to investigate VLU healing in a Dutch population using the existing guideline on VLU. The study was performed in patients with VLU receiving outpatient treatment at the dermatology department in one of the five contributing hospitals. In the course of five months, patients were examined by taking a photograph of the ulcerated area, digital planimetry was performed to obtain an initial ulcer size and after 12 weeks ulcers were classified as healed or unhealed. A total of 56 patients were included, with a median age of 71.38 years (SD 13.8) and the group consisting of 23 (41.1%) males and 33 (58.9%) females. The median initial ulcer size was calculated to be 2.82 cm2 (± 11.16). The twelve-week healing rate was 51.8% (n = 29), with a median closure time of 38.0 days (± 35.68). The initial ulcer size was significantly smaller in the healed ulcers compared with the unhealed ulcers (p = 0.001). We concluded that the results of this study correspond with the existing literature with regard to 3-month ulcer healing and application of the existing guideline is possible in the dermatological practice and will fulfil the expectations in optimising evidence-based healthcare. Besides, initial ulcer size is an indicator for healing. In chapter 10 we investigate time to VLU recurrence after in-hospital treatment of VLU in a multicentre, retrospective cohort study of patients admitted for leg ulceration between 1996 and 2007. Of 107 patients data could be collected. Of these, 27 patients had a conservative treatment (bed rest, local wound care, pain management) and 48 patients underwent surgical ulcer treatment with (n = 19) or without (n = 29) initial VAC treatment. Treatment method was ‘miscellaneous’ in the remaining 32 patients. Median admission time was 30 days, median percentage of closure at discharge was 95 %, and median time to ulcer recurrence 60 days. Mann-Whitney U-test showed significant differences between the conservative group and the surgery group, the latter having a longer length of hospital stay (P < 0.0001) and a higher percentage of ulcer closure (P < 0.0001) but there was no difference in time to ulcer recurrence (P = 0.273). Comparable differences were demonstrated between the conservative group and the VAC plus surgery group. No significant differences could be demonstrated between the surgically treated patients and those treated by VAC and surgery. In conclusion, hospital stay was significantly shorter in case of surgical treatment of recalcitrant VLU. Most ulcers recurred within 2 months after hospital discharge. Recurrence of VLU after hospital admission is independent of method of treatment and cause of ulceration. VLU may be divided into three categories: uncomplicated, recurrent and recalcitrant. In general four particular causes of recalcitrant venous leg ulcers may be distinguished: foot pump insufficiency, lipodermatosclerosis, chronic venous compartment syndrome and non-recanalized popliteal vein thrombosis. In chapter 11 we review the literature and describe the four main causes of recalcitrant venous leg ulceration and their specific treatment besides wearing lifelong MECS with a high stiffness. Foot pump insufficiency arises when the plantar foot veins are not able to empty, as a consequence treatment should consist of physical therapy, a mechanic foot pump device and an insole. Lipodermatosclerosis may be treated by excision and split-thickness skin grafting (Vigoni procedure). Chronic venous compartment syndrome is usually caused by post-thrombotic syndrome, which may result in increased pressure. Treatment consists of decompression through a fasciectomy. Patients with non-recanalized popliteal vein thrombosis may be supported by intermittent pneumatic compression, walking exercises, alternating standing and walking with lying down. Only a few patients will be suitable for venous stenting. We may conclude that patients with recalcitrant venous leg ulceration are challenging, with regard to diagnosis as well as to treatment. More specific treatment will heal more of those ulcers. In chapter 12 the main findings from studies presented in this thesis are discussed and placed into a broader perspective.

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H.A.M. Neumann (Martino)
Erasmus University Rotterdam
Medi, Bauerfeind, Lohman & rauscher, Varodem, Juzo, LEO Pharma BV, Galderma Benelux BV, Roche Nederland BV, Fagron BV, AbbVie BV, Mediq i.s.m. Pierre Fabre Dermo-Cosmétique, Beiersdorf NV, BAP Medical Nederland BV, Oldekamp Medisch BV, biolitec biomedical technology GmbH, ChipSoft BV, Bo Medical Technologies BV, Dalton Medical BV, Esaote Benelux BV, NV Varitex, La Roche-Posay
Erasmus MC: University Medical Center Rotterdam

Reeder, S.W.I. (2013, September 25). Chronic Venous Disease under pressure. Erasmus University Rotterdam. Retrieved from