Original Article
The distribution and extent of reflux and obstruction in patients with active venous ulceration
Phlebology 2015, Vol. 30(5) 350–356 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355514530277 phl.sagepub.com
Aditi M Kanth, Sami U Khan, Antonis Gasparis and Nicos Labropoulos
Abstract Objectives: This study was performed to precisely define the underlying pathophysiology in patients with active venous ulcers. Methods: A PubMed search was conducted from 1991 to 2013 to select papers reporting the anatomic and physiologic etiology of ulceration in CEAP Class 6 patients. Studies which did not decipher between active and healed ulcers, did not use clear definitions, or did not give detailed accounts on the distribution/extent of venous pathology were excluded. Using the PRISMA guidelines, 12 studies were selected for further analysis. Results: Primary insufficiency was reportedly the most common etiology of ulcers. Reflux most frequently occurred in the superficial system, either isolated or in conjunction with perforating and/or deep systems. Combined superficial and deep disease was observed in a median of 11.6% of limbs (range of 0–48%). Triple system disease was seen in a median of 31.6% of limbs (range of 22–52%). Isolated deep reflux was infrequently reported (2.1–28.4% of limbs). Previous deep venous thrombosis, reported in a median of 33% of patients, is likely underreported as it may resolve without detectable damage. Conclusion: There is a lack of data in the literature regarding the etiology of chronic active venous ulcers. Insufficiency of the superficial venous system from the micro- to the macro-vasculature has been frequently implicated in the development of venous ulceration. A prospective randomized controlled study is required for more conclusive results.
Keywords Venous ulceration, venous reflux, venous obstruction
Introduction Venous ulceration of the lower extremities from chronic insufficiency is a pathology that affects up to 1% of the Western population, resulting in disability and impaired quality of life.1 Those who suffer from leg ulcers experience not only discomfort and disability but also social embarrassment.2 Moreover, the management and treatment of chronic leg ulcers impart a significant socioeconomic burden. Recent estimates suggest that more than 1 billion dollars are spent in the United States annually to treat venous ulcers,3 and around 2 million workdays are lost per year as a result of this disease. The advent of the venous duplex ultrasound has allowed more accurate examination of the veins in the lower extremities. With this modality, it is possible to carefully examine the superficial, deep, and perforating veins to determine the cause of ulceration.
By identifying the most common patterns and processes of venous disease in patients with venous ulcers, more targeted clinical decisions can be made in order to provide the most cost-effective treatment. While multiple papers have been published to date on the etiology of venous ulceration, the information presented in these papers is generally incomplete. For example, certain studies report data combining healed and active ulcers.4 Other studies did not report all types of venous pathology5 or did not examine the entire limb. Although other review articles have been published, none used accurate definitions to precisely
Department of Surgery, Division of Vascular Surgery, SUNY at Stony Brook, Stony Brook, NY, USA Corresponding author: Aditi Kanth, 20 Old School House Ct., Roslyn, NY 11576, USA. Email: [email protected]
Downloaded from phl.sagepub.com at University of Otago Library on October 22, 2015
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describe the venous pathology of the highlighted studies in a systematic manner. In an effort to address this, our study was designed to select papers using strict criteria in order to more precisely define the pathology in patients presenting with active venous ulceration.
Materials and methods A PubMed search from 1991 to 2013 was performed by the authors to select papers discussing the impact of venous pathology in patient with leg ulcers (CEAP Class 6). The goal of the study was to examine venous pathology in active ulcers and exclude venous pathology in healed ulcers or in other disease processes such as varicose veins. The search year started at 1991 as the first paper using ultrasound in patients with venous ulceration was published giving enough
information to fulfill our criteria. The terms used to conduct the search were venous reflux, incompetence, and insufficiency in combination with ulcer, leg ulcer, ulceration, lower limb, post-phlebitic, obstruction, chronic thrombosis, and post-thrombotic limbs. An extensive manual search was also performed on the reference list of relevant papers. Papers were selected for patients with active ulcers that were not healed at the time of the study with exploration of reflux and/or obstruction in the lower extremity veins. Studies which did not decipher between active and healed ulcers, did not use clear definitions, or did not give a detailed account on the distribution and extent of venous pathology were excluded. Using the search terms listed above a PRISMA diagram was made (Figure 1). A primary search resulted in 282 articles regarding venous pathology and ulceration.
Figure 1. PRISMA diagram.
Downloaded from phl.sagepub.com at University of Otago Library on October 22, 2015
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Careful examination of the abstracts with application of the inclusion and exclusion criteria listed above resulted in the exclusion of 241 papers, leaving 41 studies for full paper screening. Of the 41 studies, 13 had mixed data of CEAP Classes 5 and 6 and were thus excluded. Three additional studies were excluded because they did not differentiate the distribution of reflux in the superficial, deep, and perforator veins. In four papers, only the superficial venous system was studied, and in another two, there was combined arterial and venous insufficiency. One paper had a significant number of patients used in earlier study and therefore was excluded. After these papers were removed, 12 of the 41 studies were selected for further analysis.
Results Duplex ultrasound was used in 12 studies6–17 to examine the anatomical and physiologic changes of the venous system in the lower extremities of patients with CEAP 6 venous disease. Venous reflux, rather than obstruction, was found to be the most common pathophysiology underlying venous ulcers with primary insufficiency identified more frequently than postthrombotic disease.12,13 Ulceration has been linked to localized venous hemodynamic abnormality, with reflux found anatomically close to the ulceration in up to 86% of cases.10 Most, but not all, of the 12 papers clarified that pathologic reflux, when assessed by Doppler, was defined as reflux time greater than 0.5 s with the exception of common femoral, femoral, and popliteal veins in which the cutoff of 1 s was used. Perforator reflux, when defined, was identified by the presence of bidirectional flow on the Doppler.
The papers which evaluated for obstruction did not describe in detail the criteria used to identify it with the venous duplex. Disorder of the superficial venous system has been frequently implicated as a common cause of venous ulcers. Involvement of the superficial system has been reported in up to 98% of ulcers,15,16,18 with exclusive superficial disease in 63% of limbs.12 In the 12 papers examined for this study, isolated superficial disease was found in a median of 22.9% of ulcerated limbs, with a range from 3%13 to 72%9 (Table 1). The combination of superficial and deep venous reflux was frequently implicated as the cause of leg ulceration in these studies, ranged from 7% to 42%.7,17 Reflux isolated to the deep veins was rarely reported, with a range from 1% to 19%.7,12 The data from the six papers which specifically examined the perforator veins in addition to deep and superficial veins revealed triple system disease in a median of 31.6% of limbs with a range of 22–52% of ulcerated limbs.14,17 It is evident from Table 2 that most authors in the 12 papers examined also investigated the presence or absence of deep venous thrombosis (DVT) in the patient’s clinical history. Nine of the 12 authors reported history of DVT in patients with active venous ulceration, ranging from 22% to 51% of patients.14,16 Labropoulos et al.15 reported that a previously documented DVT was significantly associated with skin changes, and thus, worsening venous disease. They later found a significant association between previous DVTs and ulcer non-healing, and reported that patients with non-healing ulcers had more than a five times greater odds of history of DVTs compared to patients with ulcers that healed.17
Table 1. Anatomic distribution of reflux found on ultrasound in CEAP 6 patients.
References
Superficial only, %
Perforator only, %
Hanrahan et al.6
16.8
8.4
Weingarten et al.7 Shami et al.8
16.9 53
NR NR
Van Rij et al.9
72.3
NR
Labropoulos et al.10
23.2
2.7
Grabs et al.11
54.3
NR
Scriven et al.12
63
NR
Deep only, %
No incompetence, %
Superficial and deep, %
18.9
11.6
NR NR
42 32
NR NR
NR NR
7.6
NR
20.2
NR
NR
0
119
6.3
20.5
11.6
27.7
3.6
112
5.7
NR
40
NR
NR
0
105
1
NR
35
NR
NR
8.7
104
2.1 19 15
Perforator and deep, %
Superficial perforator and deep, %
Superficial and perforator, %
4.2
4.5
31.6
6.3 44 0
Total limbs 95 192 79
Danielsson et al.13
3
3
4
19
11
6
51
1
98
Obermayer et al.14
5
4
NR
27
NR
10
52
0
173
1.4 NR
36.2 43
10.1 0
1.4 0.5
23.2 44.5
7.2 1.6
69 182
3.2
40.8
7
0.64
21.7
1.3
153
Labropoulos et al.15 Obermayer and Garzon16
20.3 11
NR 1.6
Labropoulos et al.17
22.9
0
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Table 2. History of DVT and post-thrombotic changes found on ultrasound.
References
History of DVT, %
Post-thrombotic changes found on ultrasound, %
Hanrahan et al.6 Weingarten et al.7 Labropoulos et al.10 Grabs et al.11 Scriven et al.12 Danielsson et al.13 Obermayer et al.14 Obermayer and Garzon16 Labropoulos et al.17
NR 22 50 15 23 23 51 39 37
33 NR NR 14 11 NR NR NR NR
Discussion Venous ulceration results from chronic venous hypertension. The cause of elevated venous pressure in the lower extremities can be broken down into valvular dysfunction of the superficial veins, valvular dysfunction of the deep veins, venous outflow obstruction, and calf muscle pump failure.6,19,20 Our study focused on chronic reflux, obstruction, or a combination of the two. It was once believed that the most common cause of venous ulcers was damage to the deep venous system after an episode of DVT. In the current analysis, it was instead found that primary venous insufficiency is by far the most common etiology of active ulcers. Specifically, our findings highlight the extensive involvement of superficial venous reflux in the development of leg ulceration. Isolated superficial reflux was observed in a median of 21.6% of limbs with a wide range from 3% to 72%.9,13 The lower end of the range can be partially explained by the fact that 24 limbs out of the 92 examined by Danielsson et al.13 had previously underwent superficial surgical treatment. The upper limit of the range is likely falsely elevated because these studies did not specifically report data on perforator reflux, so those limbs with combined superficial and perforator reflux were likely included in the count. Identification of superficial disease is important because such patients would greatly benefit from surgical intervention. Barwell et al.5 compared outcomes from superficial venous surgery with conservative ulcer management to outcomes of conservative management alone. While there was no significant difference in ulcer healing rates at six months, there was significant reduction in ulcer recurrence at the 12month period.21 Gohel et al.22 reported that, for patients with isolated superficial reflux, 51% of ulcers
treated with compression therapy recurred, compared to 27% of ulcers treated with compression and surgery. Furthermore, compression in combination with surgery results in a lower incidence of non-healing in four years as well as 7% more of that time ulcer-free.22 This finding is supported by Obermayer and Garzon,16 who found that the healing rate after superficial and perforator surgery was 87%, having only a 5% recurrence at five years. Simultaneous involvement of the superficial and deep venous systems was frequently reported, and triple system disease was cited as the most common cause of ulceration in most papers that examined all three systems. Isolated deep venous reflux, caused by either primary insufficiency or post-thrombotic syndrome, was infrequently reported with numbers ranging from 2.1% to 19%6,7 of ulcerated limbs. In fact, Obermayer and Garzon16 and Obermayer et al.14 did not report a single instance of isolated deep venous reflux in both of his papers. This should not, however, undermine the significant role played by deep venous reflux in ulcer development, as it is commonly found in conjunction with reflux in other systems. Combined insufficiency has been found to impart a greater risk of ulcer recurrence after surgical intervention.21 Information about perforating veins was examined in only six of the papers analyzed in this study. In those papers, isolated perforator reflux was found in a median of 2.85% of limbs. It is very unlikely that such reflux occurred in the perforator veins without reflux in the local superficial veins.23 Often it is erroneously thought that, because the treatment of the perforator may heal the ulcer, reflux in perforator veins can exist alone. Like deep venous reflux, reflux in the perforator veins was often found in conjunction with reflux in other systems. Currently, evidence does not support perforator surgery in the management of venous ulceration.24–26 History of DVT is a major risk factor for venous ulceration. A previously documented episode of DVT was reported in a median of 33% of ulcerated limbs. The papers reported a range of 22–51%. The prevalence of previous DVT in ulcerated limbs is likely underestimated, as a small number of veins with previous DVTs may fully recanalize without leaving detectable damage to the vessel other than pathophysiologic reflux. Furthermore, many patients may unknowingly have a DVT without clinical history of it. Most of the papers did not report on post-thrombotic luminal changes and did not use these findings as a record of previous DVT. It is also known that many patients with DVT may have superficial vein thrombosis as well and therefore some of the superficial vein reflux is attributable to thrombosis. This was not described in the majority of the papers.
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The mechanism of chronic venous insufficiency actually leading to skin changes is due to presence of localized reflux within the general area of ulceration.10 It has been further suggested that the presence of reflux in microvenous valves of the superficial system results in ulceration via venous hypertension and, thus, endorgan skin damage. Such reflux is not readily identifiable by ultrasound and may be interpreted as normal venous function. Vincent et al. demonstrated using retrograde resin venography that the competence of these microvalves is an important factor in the progression of skin changes when superficial reflux is present in the great saphenous vein. Using light microscopy, valves were identified from the great saphenous vein up to the sixth-generation tributaries, with the highest density of valves found at the third generation. They also found that, in limbs with venous ulcers, there was extensive incompetence to resin flow with distended microvalves and tortuous microvasculature identified by scanning electron microscopy.27 The study provided evidence that the microcirculation, in addition to the macrocirculation, is responsible for skin changes seen in venous disease. As stated earlier, calf muscle pump overload and failure secondary to inflammatory or neuropathic conditions is a concept that has also been linked to ulceration in limbs with isolated superficial venous disease. It has been shown that perforator veins of the calf have been can regain competence after superficial venous surgery, which is a finding consistent with the picture of global venous hypertension of the extremity. Bello et al.24 also used this concept to explain that patients with great saphenous vein incompetence and short saphenous vein incompetence did not necessarily present with ulcers anatomically along the distribution of the incompetent vein. The goals of treatment for chronic venous ulcers are to heal the lesion, reduce pain, relieve edema, and prevent recurrence by relieving the underlying venous hypertension. While compression and elevation remain the gold standard of treatment, compliance is a major limiting factor. Surgical treatment aids in the reduction of venous hypertension and treatment of CEAP Class 6 ulcers. Surgical ablation of perforator reflux has been shown to hasten healing and prevent recurrence when used in combination with compression techniques. Recent papers have shown that, in order to maximize ulcer healing and minimize recurrence rates, treatment should address not only the underlying reflux but also central obstruction when present. For example, iliac venous obstruction has been demonstrated in 25% of ulcerated limbs,4 and its associated symptoms have been shown to improve with percutaneous stenting. An ulcer healing rate of 64% with substantial relief of pain and swelling was found at four-year follow-up after
percutaneous iliofemoral stenting and superficial venous ablation.28 At this time, there is not enough data on the subject to draw definite conclusions, as few studies have specifically addressed the treatment of simultaneous reflux and obstruction in venous ulceration. In fact, the actual prevalence of obstruction in patients with active ulceration is not known. Recent data have been published on minimally invasive techniques, a middle ground between surgical and conservative management, to treat active ulcers. These modalities include radiofrequency ablation, endovenous laser ablation, and ultrasound guided foam sclerotherapy (UGFS). A recent comparison UGFS and thermal ablation to compression alone demonstrated faster healing times and decreased recurrences at oneyear follow-up for the groups undergoing minimally invasive procedures. These minimally invasive procedures are not only cost effective but also an excellent alternative to surgery. Analysis of the current literature regarding active ulceration has yielded interesting findings regarding the distribution of disease and implications for treatment. This study has several limitations, however. Due to the quality of the papers, enough data were not available to perform a true meta-analysis. As stated earlier, the definition of pathologic reflux was not consistent among the papers. Hanrahan et al.6 simply defined reflux as bidirectional flow, and others defined pathologic reflux as reflux time exceeding 0.5 s,8,13 or greater than 1 s for common femoral, femoral, and popliteal and greater than 0.5 s for all other veins.10,14,15 A precise study on the reflux definition for all lower extremity vein was produced from our group in 2003 and has been adopted by most centers.29–31 Our paper did not delve into great detail about proximal venous obstruction and its associated implications as there is limited information available. Obstruction was rarely investigated in the studies analyzed in this paper, and in the instances when obstruction was reported, the severity was not clarified. This could be due to the difficulty in identifying obstruction using the Doppler as the modality for investigation. Another problem was that the patient population in the papers examined varied greatly and there was insufficient information provided about their status at the time of the study. For example, common risk factors such as obesity, recent immobilization, and history of leg trauma were not addressed and likely not controlled for in many of the papers examined. Furthermore, it is possible that the centers in which each paper received its data had different levels of expertise, variable number of referrals, and different patient populations. Finally, it can be argued that, as the papers examined spanned at least two decades, there may be variability in the quality of information obtained from venous duplex in earlier
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studies due to the inevitable evolution of equipment. In this retrospective paper, specific criteria were created so that the papers analyzed were similar enough in order to draw the most accurate conclusions about venous reflux and obstruction. The ideal way to control patient factors, what information is obtained from the venous Doppler, and differences in operator skill would be through a prospective randomized controlled study. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Reeder S, de Roos KP, de Maeseneer M, et al. Ulcer recurrence after in-hospital treatment for recalcitrant venous ulceration. Br J Dermatol 2013; 168: 999–1002. 2. Ruckley CV. Socioeconomic impact of chronic venous insufficiency and leg ulcers. Angiology 1997; 48: :67–69. 3. Simka M and Majewski E. The social and economic burden of venous leg ulcers: focus on the role of micronized purified flavonoid fraction adjuvant therapy. Am J Dermatol 2003; 4: 573–581. 4. Marston W, Fish D, Unger J, et al. Incidence of and risk factors for iliocaval venous obstruction in patients with active or healed venous leg ulcers. J Vasc Surg 2011; 53: 1303–1308. 5. Barwell JR, Taylor M, Deacon J, et al. Surgical correction of isolated superficial venous reflux reduces longterm recurrence rate in chronic venous leg ulcers. Eur J Endovasc Surg 2000; 20: 363–368. 6. Hanrahan L, Araki C, Rodriguez A, et al. Distribution of valvular incompetence in patients with venous stasis ulceration. J Vasc Surg 1991; 13: 805–812. 7. Weingarten M, Branas C, Czeredarczuk M, et al. Distribution and quantification of venous reflux in lower extremity chronic venous stasis disease with duplex scanning. J Vasc Surg 1993; 18: 753–759. 8. Shami SK, Sarin S, Cheatle TR, et al. Venous ulcers and the superficial venous system. J Vasc Surg 1993; 17: 487–490. 9. Van Rij A, Solomon C and Christie R. Anatomic and physiologic characteristics of venous ulceration. J Vasc Surg 1994; 20: 759–764. 10. Labropoulos N, Giannoukas A, Nicolaides A, et al. New insights into the pathophysiologic condition of venous ulceration with color flow duplex imaging: indications for treatment? J Vasc Surg 1995; 22: 45–50. 11. Grabs AJ, Wakely MC, Nyamekye I, et al. Color duplex ultrasonography in the rational management of chronic venous leg ulcers. Br J Surg 1996; 83: 1380–1382. 12. Scriven JM, Hartshorne T, Bell P, et al. Single visit venous ulcer assessment clinic: the first year. Br J Surg 1997; 84: 334–336.
13. Danielsson G, Arfvidsson B, Eklof B, et al. Reflux from thigh to calf in chronic venous ulcer disease: surgery indicated in the majority of patients. Vasc Endovasc Surg 2004; 38: 209–219. 14. Obermayer A, Gostl K, Walli G, et al. Chronic venous ulcers benefit from surgery: long term results in 173 legs. J Vasc Surg 2006; 44: 572–579. 15. Labropoulos N, Patel P, Tiongson J, et al. Patterns of venous reflux and obstruction in patients with skin damage due to chronic venous disease. Vasc Endovasc Surg 2007; 41: 33–40. 16. Obermayer A and Garzon K. Identifying the source of superficial reflux in venous leg ulcers using duplex ultrasound. J Vasc Surg 2010; 52: 1255–1261. 17. Labropoulos N, Wang E, Lanier S, et al. Factors associated with poor healing and recurrence of venous ulceration. Plast Reconstr Surg 2012; 129: 179–186. 18. Magnusson M, Nelzen O, Risberg B, et al. A color doppler ultrasoun in patients with chronic leg ulcers. Eur J Vasc Endovasc Surg 2001; 21: 353–360. 19. Valencia I, Falabella A, Kirsner R, et al. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol 2001; 44: 401–421. 20. Malleti O and Perrin M. Reconstructive surgery in the lower limbs: techniques, results, and indications. Eur J Vasc Endovasc Surg 2011; 41: 837–848. 21. Barwell J, Davies C, Deacon J, et al. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised trial. Lancet 2004; 363: 1854–1859. 22. Gohel M, Barwell J, Taylor M, et al. Long term results of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised trial. Br Med J 2007; 335: 83–86. 23. Labropoulos N, Tassiopoulos AK, Bhatti AF, et al. Development of reflux in the perforator veins in limbs with primary venous disease. J Vasc Surg 2006; 43: 558–562. 24. Bello M, Scriven M, Hartshorne T, et al. Role of superficial surgery in treatment of venous ulceration. Br J Surg 1999; 86: 755–759. 25. Van Gent WB, Hop WC, van Praag MC, et al. Conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial. J Vasc Surg 2006; 44: 563–571. 26. Nelze´n O and Fransson I. Swedish SEPS study group. Early results from a randomized trial of saphenous surgery with or without subfascial endoscopic perforator surgery in patients with a venous ulcer. Br J Surg 2011; 98: 495–500. 27. Vincent J, Jones GT, Hill G, et al. Failure of microvenous valves in small superficial veins is a key to the skin changes of venous insufficiency. J Vasc Surg 2011; 54: 62S–69S. 28. Neglen P, Hollis K and Raju S. Combined saphenous ablation and iliac stent placement for complex severe chronic venous disease. J Vasc Surg 2006; 44: 828–833.
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29. Neglen P, Hollis K, Olivier J, et al. Stenting of the venous outflow in chronic venous disease: long-term stent-related outcome, clinical, and hemodynamic result. J Vasc Surg 2007; 46: 979–990. 30. Alden PB, Lips EM, Zimmerman KP, et al. Chronic venous ulcer: minimally invasive treatment of superficial
axial and perforator vein reflux speeds healing and reduces recurrence. Ann Vasc Surg 2013; 27: 75–83. 31. Labropoulos N, Tiongson J, Pryor L, et al. Definition of reflux in lower extremity veins. J Vasc Surg 2003; 38: 793–798.
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The distribution and extent of reflux and obstruction in patients with active venous ulceration
Phlebology 2015, Vol. 30(5) 350–356 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355514530277 phl.sagepub.com
Aditi M Kanth, Sami U Khan, Antonis Gasparis and Nicos Labropoulos
Abstract Objectives: This study was performed to precisely define the underlying pathophysiology in patients with active venous ulcers. Methods: A PubMed search was conducted from 1991 to 2013 to select papers reporting the anatomic and physiologic etiology of ulceration in CEAP Class 6 patients. Studies which did not decipher between active and healed ulcers, did not use clear definitions, or did not give detailed accounts on the distribution/extent of venous pathology were excluded. Using the PRISMA guidelines, 12 studies were selected for further analysis. Results: Primary insufficiency was reportedly the most common etiology of ulcers. Reflux most frequently occurred in the superficial system, either isolated or in conjunction with perforating and/or deep systems. Combined superficial and deep disease was observed in a median of 11.6% of limbs (range of 0–48%). Triple system disease was seen in a median of 31.6% of limbs (range of 22–52%). Isolated deep reflux was infrequently reported (2.1–28.4% of limbs). Previous deep venous thrombosis, reported in a median of 33% of patients, is likely underreported as it may resolve without detectable damage. Conclusion: There is a lack of data in the literature regarding the etiology of chronic active venous ulcers. Insufficiency of the superficial venous system from the micro- to the macro-vasculature has been frequently implicated in the development of venous ulceration. A prospective randomized controlled study is required for more conclusive results.
Keywords Venous ulceration, venous reflux, venous obstruction
Introduction Venous ulceration of the lower extremities from chronic insufficiency is a pathology that affects up to 1% of the Western population, resulting in disability and impaired quality of life.1 Those who suffer from leg ulcers experience not only discomfort and disability but also social embarrassment.2 Moreover, the management and treatment of chronic leg ulcers impart a significant socioeconomic burden. Recent estimates suggest that more than 1 billion dollars are spent in the United States annually to treat venous ulcers,3 and around 2 million workdays are lost per year as a result of this disease. The advent of the venous duplex ultrasound has allowed more accurate examination of the veins in the lower extremities. With this modality, it is possible to carefully examine the superficial, deep, and perforating veins to determine the cause of ulceration.
By identifying the most common patterns and processes of venous disease in patients with venous ulcers, more targeted clinical decisions can be made in order to provide the most cost-effective treatment. While multiple papers have been published to date on the etiology of venous ulceration, the information presented in these papers is generally incomplete. For example, certain studies report data combining healed and active ulcers.4 Other studies did not report all types of venous pathology5 or did not examine the entire limb. Although other review articles have been published, none used accurate definitions to precisely
Department of Surgery, Division of Vascular Surgery, SUNY at Stony Brook, Stony Brook, NY, USA Corresponding author: Aditi Kanth, 20 Old School House Ct., Roslyn, NY 11576, USA. Email: [email protected]
Downloaded from phl.sagepub.com at University of Otago Library on October 22, 2015
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describe the venous pathology of the highlighted studies in a systematic manner. In an effort to address this, our study was designed to select papers using strict criteria in order to more precisely define the pathology in patients presenting with active venous ulceration.
Materials and methods A PubMed search from 1991 to 2013 was performed by the authors to select papers discussing the impact of venous pathology in patient with leg ulcers (CEAP Class 6). The goal of the study was to examine venous pathology in active ulcers and exclude venous pathology in healed ulcers or in other disease processes such as varicose veins. The search year started at 1991 as the first paper using ultrasound in patients with venous ulceration was published giving enough
information to fulfill our criteria. The terms used to conduct the search were venous reflux, incompetence, and insufficiency in combination with ulcer, leg ulcer, ulceration, lower limb, post-phlebitic, obstruction, chronic thrombosis, and post-thrombotic limbs. An extensive manual search was also performed on the reference list of relevant papers. Papers were selected for patients with active ulcers that were not healed at the time of the study with exploration of reflux and/or obstruction in the lower extremity veins. Studies which did not decipher between active and healed ulcers, did not use clear definitions, or did not give a detailed account on the distribution and extent of venous pathology were excluded. Using the search terms listed above a PRISMA diagram was made (Figure 1). A primary search resulted in 282 articles regarding venous pathology and ulceration.
Figure 1. PRISMA diagram.
Downloaded from phl.sagepub.com at University of Otago Library on October 22, 2015
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Careful examination of the abstracts with application of the inclusion and exclusion criteria listed above resulted in the exclusion of 241 papers, leaving 41 studies for full paper screening. Of the 41 studies, 13 had mixed data of CEAP Classes 5 and 6 and were thus excluded. Three additional studies were excluded because they did not differentiate the distribution of reflux in the superficial, deep, and perforator veins. In four papers, only the superficial venous system was studied, and in another two, there was combined arterial and venous insufficiency. One paper had a significant number of patients used in earlier study and therefore was excluded. After these papers were removed, 12 of the 41 studies were selected for further analysis.
Results Duplex ultrasound was used in 12 studies6–17 to examine the anatomical and physiologic changes of the venous system in the lower extremities of patients with CEAP 6 venous disease. Venous reflux, rather than obstruction, was found to be the most common pathophysiology underlying venous ulcers with primary insufficiency identified more frequently than postthrombotic disease.12,13 Ulceration has been linked to localized venous hemodynamic abnormality, with reflux found anatomically close to the ulceration in up to 86% of cases.10 Most, but not all, of the 12 papers clarified that pathologic reflux, when assessed by Doppler, was defined as reflux time greater than 0.5 s with the exception of common femoral, femoral, and popliteal veins in which the cutoff of 1 s was used. Perforator reflux, when defined, was identified by the presence of bidirectional flow on the Doppler.
The papers which evaluated for obstruction did not describe in detail the criteria used to identify it with the venous duplex. Disorder of the superficial venous system has been frequently implicated as a common cause of venous ulcers. Involvement of the superficial system has been reported in up to 98% of ulcers,15,16,18 with exclusive superficial disease in 63% of limbs.12 In the 12 papers examined for this study, isolated superficial disease was found in a median of 22.9% of ulcerated limbs, with a range from 3%13 to 72%9 (Table 1). The combination of superficial and deep venous reflux was frequently implicated as the cause of leg ulceration in these studies, ranged from 7% to 42%.7,17 Reflux isolated to the deep veins was rarely reported, with a range from 1% to 19%.7,12 The data from the six papers which specifically examined the perforator veins in addition to deep and superficial veins revealed triple system disease in a median of 31.6% of limbs with a range of 22–52% of ulcerated limbs.14,17 It is evident from Table 2 that most authors in the 12 papers examined also investigated the presence or absence of deep venous thrombosis (DVT) in the patient’s clinical history. Nine of the 12 authors reported history of DVT in patients with active venous ulceration, ranging from 22% to 51% of patients.14,16 Labropoulos et al.15 reported that a previously documented DVT was significantly associated with skin changes, and thus, worsening venous disease. They later found a significant association between previous DVTs and ulcer non-healing, and reported that patients with non-healing ulcers had more than a five times greater odds of history of DVTs compared to patients with ulcers that healed.17
Table 1. Anatomic distribution of reflux found on ultrasound in CEAP 6 patients.
References
Superficial only, %
Perforator only, %
Hanrahan et al.6
16.8
8.4
Weingarten et al.7 Shami et al.8
16.9 53
NR NR
Van Rij et al.9
72.3
NR
Labropoulos et al.10
23.2
2.7
Grabs et al.11
54.3
NR
Scriven et al.12
63
NR
Deep only, %
No incompetence, %
Superficial and deep, %
18.9
11.6
NR NR
42 32
NR NR
NR NR
7.6
NR
20.2
NR
NR
0
119
6.3
20.5
11.6
27.7
3.6
112
5.7
NR
40
NR
NR
0
105
1
NR
35
NR
NR
8.7
104
2.1 19 15
Perforator and deep, %
Superficial perforator and deep, %
Superficial and perforator, %
4.2
4.5
31.6
6.3 44 0
Total limbs 95 192 79
Danielsson et al.13
3
3
4
19
11
6
51
1
98
Obermayer et al.14
5
4
NR
27
NR
10
52
0
173
1.4 NR
36.2 43
10.1 0
1.4 0.5
23.2 44.5
7.2 1.6
69 182
3.2
40.8
7
0.64
21.7
1.3
153
Labropoulos et al.15 Obermayer and Garzon16
20.3 11
NR 1.6
Labropoulos et al.17
22.9
0
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Table 2. History of DVT and post-thrombotic changes found on ultrasound.
References
History of DVT, %
Post-thrombotic changes found on ultrasound, %
Hanrahan et al.6 Weingarten et al.7 Labropoulos et al.10 Grabs et al.11 Scriven et al.12 Danielsson et al.13 Obermayer et al.14 Obermayer and Garzon16 Labropoulos et al.17
NR 22 50 15 23 23 51 39 37
33 NR NR 14 11 NR NR NR NR
Discussion Venous ulceration results from chronic venous hypertension. The cause of elevated venous pressure in the lower extremities can be broken down into valvular dysfunction of the superficial veins, valvular dysfunction of the deep veins, venous outflow obstruction, and calf muscle pump failure.6,19,20 Our study focused on chronic reflux, obstruction, or a combination of the two. It was once believed that the most common cause of venous ulcers was damage to the deep venous system after an episode of DVT. In the current analysis, it was instead found that primary venous insufficiency is by far the most common etiology of active ulcers. Specifically, our findings highlight the extensive involvement of superficial venous reflux in the development of leg ulceration. Isolated superficial reflux was observed in a median of 21.6% of limbs with a wide range from 3% to 72%.9,13 The lower end of the range can be partially explained by the fact that 24 limbs out of the 92 examined by Danielsson et al.13 had previously underwent superficial surgical treatment. The upper limit of the range is likely falsely elevated because these studies did not specifically report data on perforator reflux, so those limbs with combined superficial and perforator reflux were likely included in the count. Identification of superficial disease is important because such patients would greatly benefit from surgical intervention. Barwell et al.5 compared outcomes from superficial venous surgery with conservative ulcer management to outcomes of conservative management alone. While there was no significant difference in ulcer healing rates at six months, there was significant reduction in ulcer recurrence at the 12month period.21 Gohel et al.22 reported that, for patients with isolated superficial reflux, 51% of ulcers
treated with compression therapy recurred, compared to 27% of ulcers treated with compression and surgery. Furthermore, compression in combination with surgery results in a lower incidence of non-healing in four years as well as 7% more of that time ulcer-free.22 This finding is supported by Obermayer and Garzon,16 who found that the healing rate after superficial and perforator surgery was 87%, having only a 5% recurrence at five years. Simultaneous involvement of the superficial and deep venous systems was frequently reported, and triple system disease was cited as the most common cause of ulceration in most papers that examined all three systems. Isolated deep venous reflux, caused by either primary insufficiency or post-thrombotic syndrome, was infrequently reported with numbers ranging from 2.1% to 19%6,7 of ulcerated limbs. In fact, Obermayer and Garzon16 and Obermayer et al.14 did not report a single instance of isolated deep venous reflux in both of his papers. This should not, however, undermine the significant role played by deep venous reflux in ulcer development, as it is commonly found in conjunction with reflux in other systems. Combined insufficiency has been found to impart a greater risk of ulcer recurrence after surgical intervention.21 Information about perforating veins was examined in only six of the papers analyzed in this study. In those papers, isolated perforator reflux was found in a median of 2.85% of limbs. It is very unlikely that such reflux occurred in the perforator veins without reflux in the local superficial veins.23 Often it is erroneously thought that, because the treatment of the perforator may heal the ulcer, reflux in perforator veins can exist alone. Like deep venous reflux, reflux in the perforator veins was often found in conjunction with reflux in other systems. Currently, evidence does not support perforator surgery in the management of venous ulceration.24–26 History of DVT is a major risk factor for venous ulceration. A previously documented episode of DVT was reported in a median of 33% of ulcerated limbs. The papers reported a range of 22–51%. The prevalence of previous DVT in ulcerated limbs is likely underestimated, as a small number of veins with previous DVTs may fully recanalize without leaving detectable damage to the vessel other than pathophysiologic reflux. Furthermore, many patients may unknowingly have a DVT without clinical history of it. Most of the papers did not report on post-thrombotic luminal changes and did not use these findings as a record of previous DVT. It is also known that many patients with DVT may have superficial vein thrombosis as well and therefore some of the superficial vein reflux is attributable to thrombosis. This was not described in the majority of the papers.
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The mechanism of chronic venous insufficiency actually leading to skin changes is due to presence of localized reflux within the general area of ulceration.10 It has been further suggested that the presence of reflux in microvenous valves of the superficial system results in ulceration via venous hypertension and, thus, endorgan skin damage. Such reflux is not readily identifiable by ultrasound and may be interpreted as normal venous function. Vincent et al. demonstrated using retrograde resin venography that the competence of these microvalves is an important factor in the progression of skin changes when superficial reflux is present in the great saphenous vein. Using light microscopy, valves were identified from the great saphenous vein up to the sixth-generation tributaries, with the highest density of valves found at the third generation. They also found that, in limbs with venous ulcers, there was extensive incompetence to resin flow with distended microvalves and tortuous microvasculature identified by scanning electron microscopy.27 The study provided evidence that the microcirculation, in addition to the macrocirculation, is responsible for skin changes seen in venous disease. As stated earlier, calf muscle pump overload and failure secondary to inflammatory or neuropathic conditions is a concept that has also been linked to ulceration in limbs with isolated superficial venous disease. It has been shown that perforator veins of the calf have been can regain competence after superficial venous surgery, which is a finding consistent with the picture of global venous hypertension of the extremity. Bello et al.24 also used this concept to explain that patients with great saphenous vein incompetence and short saphenous vein incompetence did not necessarily present with ulcers anatomically along the distribution of the incompetent vein. The goals of treatment for chronic venous ulcers are to heal the lesion, reduce pain, relieve edema, and prevent recurrence by relieving the underlying venous hypertension. While compression and elevation remain the gold standard of treatment, compliance is a major limiting factor. Surgical treatment aids in the reduction of venous hypertension and treatment of CEAP Class 6 ulcers. Surgical ablation of perforator reflux has been shown to hasten healing and prevent recurrence when used in combination with compression techniques. Recent papers have shown that, in order to maximize ulcer healing and minimize recurrence rates, treatment should address not only the underlying reflux but also central obstruction when present. For example, iliac venous obstruction has been demonstrated in 25% of ulcerated limbs,4 and its associated symptoms have been shown to improve with percutaneous stenting. An ulcer healing rate of 64% with substantial relief of pain and swelling was found at four-year follow-up after
percutaneous iliofemoral stenting and superficial venous ablation.28 At this time, there is not enough data on the subject to draw definite conclusions, as few studies have specifically addressed the treatment of simultaneous reflux and obstruction in venous ulceration. In fact, the actual prevalence of obstruction in patients with active ulceration is not known. Recent data have been published on minimally invasive techniques, a middle ground between surgical and conservative management, to treat active ulcers. These modalities include radiofrequency ablation, endovenous laser ablation, and ultrasound guided foam sclerotherapy (UGFS). A recent comparison UGFS and thermal ablation to compression alone demonstrated faster healing times and decreased recurrences at oneyear follow-up for the groups undergoing minimally invasive procedures. These minimally invasive procedures are not only cost effective but also an excellent alternative to surgery. Analysis of the current literature regarding active ulceration has yielded interesting findings regarding the distribution of disease and implications for treatment. This study has several limitations, however. Due to the quality of the papers, enough data were not available to perform a true meta-analysis. As stated earlier, the definition of pathologic reflux was not consistent among the papers. Hanrahan et al.6 simply defined reflux as bidirectional flow, and others defined pathologic reflux as reflux time exceeding 0.5 s,8,13 or greater than 1 s for common femoral, femoral, and popliteal and greater than 0.5 s for all other veins.10,14,15 A precise study on the reflux definition for all lower extremity vein was produced from our group in 2003 and has been adopted by most centers.29–31 Our paper did not delve into great detail about proximal venous obstruction and its associated implications as there is limited information available. Obstruction was rarely investigated in the studies analyzed in this paper, and in the instances when obstruction was reported, the severity was not clarified. This could be due to the difficulty in identifying obstruction using the Doppler as the modality for investigation. Another problem was that the patient population in the papers examined varied greatly and there was insufficient information provided about their status at the time of the study. For example, common risk factors such as obesity, recent immobilization, and history of leg trauma were not addressed and likely not controlled for in many of the papers examined. Furthermore, it is possible that the centers in which each paper received its data had different levels of expertise, variable number of referrals, and different patient populations. Finally, it can be argued that, as the papers examined spanned at least two decades, there may be variability in the quality of information obtained from venous duplex in earlier
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studies due to the inevitable evolution of equipment. In this retrospective paper, specific criteria were created so that the papers analyzed were similar enough in order to draw the most accurate conclusions about venous reflux and obstruction. The ideal way to control patient factors, what information is obtained from the venous Doppler, and differences in operator skill would be through a prospective randomized controlled study. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
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