A varicose ulcer is a deep lesion of the skin that results from impaired vein function, blood stasis and tissue inflammation.
Presentation
Typical venous VU are located in the lower leg, preferentially in the lower calves. Ulcers may be rather extensive, but are usually not too deep. Moist granulation tissue that oozes blood upon manipulation may be visible at their base. Borders are irregular. The surrounding, not ulcered skin may show signs of chronic ischemia and dermatitis. Patients with venous VU often report mild pain that can, however, be alleviated by elevating the affected legs.
Of note, there are other types of ulcers that are sometimes deemed VU. In detail, these are arterial, neurotrophic and diabetic ulcers. They differ from venous VU in location and appearance.
- Arterial ulcers usually affect the dorsum of feet and toes. Grayish granulation tissue may be observed at their base. Their borders may be more regular than those of venous VU. Patients report pain to aggravate at night and to subside when the leg is loaded. The surrounding skin is often pale and hairless.
- Neurotrophic ulcers are often observed at the plantar surface the patient's feet, most frequently in close proximity to calluses formed under pressured joints. They have clearly defined borders and are rather deep. Any manipulation provokes bleeding. Adjacent tissues typically show signs of chronic inflammation, but these ulcers are not painful. This apparent contradiction may be explained by the fact that neurotrophic ulcers are developed by patients who suffer from neuropathy and hypesthesia.
- Diabetic ulcers may occur as a combination of any of the aforementioned types of ulcers. Their pathogenesis is not completely understood, but neuropathy and hypesthesia seem to play an important role.
Entire Body System
- Pain
The approach to venous ulcer pain must include an assessment of the cause of pain and the pain characteristics (constant or intermittent). [o-wm.com]
With regard to pain intensity, the mean VAS pain score was 6.70 at baseline, corresponding to severe pain and 0 (no pain) at 8 and 12 months of treatment. [omicsonline.org]
As pain increases to mild or moderate levels, the second step on the pain ladder adds a mild opioid such as codeine. The third step calls for a stronger opioid such as morphine as pain becomes moderate or severe. [woundsresearch.com]
The ulcers are open wounds that can be painful and, if not treated, can become infected. Herbs may help relieve the pain and heal the wound naturally. Consult your health care provider before starting herbal treatment for venous leg ulcer pain. [livestrong.com]
When the compression bandage is first applied to a venous leg ulcer, the patient will usually experience some pain. The vein specialist may prescribe a mild pain medication to keep the patient comfortable. [empirevein.com]
- Swelling
Renal impairment – protein loss from the kidneys causes tissue swelling Liver impairment – decreased production of protein by the liver causes tissue swelling An initial assessment of leg swelling will include a leg ultrasound at Palm Clinic to confirm [palmclinic.co.nz]
Blood then pools in your lower legs, causing your legs to swell. Since the blood can't flow well in your legs, the swelling may be extreme. This extreme swelling can put so much pressure on your skin that venous ulcers form. [hopkinsmedicine.org]
The most common early symptom of venous insufficiency is chronically swollen ankles; the feet and calves may also swell. [bcm.edu]
Treating associated symptom s Swelling in the legs and ankles Venous leg ulcers are often accompanied by swelling of your feet and ankles ( oedema ), which is caused by fluid. This can be controlled by compression bandages. [nhsdirect.wales.nhs.uk]
- Inflammation
It is an ingredient in commercial creams and ointments used for relieving pain and inflammation, and it also helps prevent scars. [livestrong.com]
Non-adherence may be the principal cause of these poor results, but presence of inflammation in people with CVI may be another factor, so a treatment that suppresses inflammation (healing ulcers more quickly) and reduces the frequency of ulcer recurrence [cochrane.org]
A varicose ulcer is a deep lesion of the skin that results from impaired vein function, blood stasis and tissue inflammation. Typical venous VU are located in the lower leg, preferentially in the lower calves. [symptoma.com]
Venous stasis ulcer of lower limb Venous stasis ulcer with edema and inflammation Venous stasis ulcer with edema of lower leg ICD-10-CM L97.909 is grouped within Diagnostic Related Group(s) (MS-DRG v 36.0): 573 Skin graft for skin ulcer or cellulitis [icd10data.com]
These soft cast like dressings help blood flow return to the heart by narrowing the veins, stopping backflow of blood into the legs, and reducing both swelling and inflammation. [schulmanveincenter.com]
- Leg Swelling
Leg Swelling Treatment If you have visible varicose veins, or symptoms of varicose veins (aching, tired or heavy legs when standing) then the most likely reason for the leg swelling is the varicose veins themselves. [palmclinic.co.nz]
This type of ulcer is common in patients with a history of leg swelling or varicose veins. [upmc.com]
Venous stasis (purplish skin) ulcers are common in patients who have a history of leg swelling, varicose veins or a history of blood clots in either the superficial or deep veins of the legs. [premierveincenter.com]
Reduce leg swelling by getting the individual to elevate the leg above the level of the heart as frequently as possible, a minimum of 30 minutes, three times daily. Compression Compression is a mainstay of treatment for stasis ulcers. [dermnetnz.org]
- Falling
If the blood pressure inside your leg veins doesn't fall as you're walking, the condition is called sustained venous hypertension. That increase in blood pressure causes ulcers to form on your ankles. [hopkinsmedicine.org]
In each case, a gradual fall in pressure was recorded - from 42 mmHg at the ankle to 17 mmHg just below the knee. [worldwidewounds.com]
In these cases, the duplex ultrasound scan shows which of the veins have lost their valves and are allowing blood to fall the wrong way down the “hidden varicose veins”. [legulcercharity.org]
Pathophysiology In patients with venous disease or failure, venous pressure in deep system falls less than normal during ambulation and rises in orthostatic position, and this is termed venous hypertension. [intechopen.com]
Gastrointestinal
- Nausea
Gotu kola may cause stomach upset, drowsiness or nausea if used internally. [livestrong.com]
[…] adjunctive treatment for venous ulcers when added to compression therapy. 31, 40 Pentoxifylline may also be useful as monotherapy in patients who are unable to tolerate compression bandaging. 31 The most common adverse effects are gastrointestinal (e.g., nausea [aafp.org]
The main side effects reported were gastrointestinal disturbances such as nausea, indigestion, and diarrhea [ 89, 92, 93 ]. In studies, pentoxifylline has shown to be an effective adjuvant to compression therapy in venous leg ulcers. [intechopen.com]
Cardiovascular
- Thrombosis
Venous/Lymphatic Disorders Deep Vein Thrombosis Deep vein thrombosis is a serious condition that occurs when a blood clot, also known as a thrombus, forms in a vein deep within the body. [cliftonveincarecenter.com]
[…] names separated by a space and hit enter Links Authors Source MeSH Anti-Bacterial Agents Anti-Infective Agents Anti-Infective Agents, Local Antibiotics, Antitubercular Bandages Dermatologic Agents Diet Humans Ointments Phenylbutazone Powders Thiamine Thrombosis [unboundmedicine.com]
Thrombophlebitis and trauma with long-term immobilization predisposing to deep venous thrombosis are important risk factors for CVI and venous ulcer. [ncbi.nlm.nih.gov]
If any of these underlying diseases account for blood stasis or vein thrombosis, the respective patient will suffer from secondary varicose veins. [symptoma.com]
Figure 1: Venous ulcer with obesity as cofactor Figure 2: Large superficial venous ulcer Etiology Any condition that causes blood to pool in the veins of the leg is a potential cause of venous ulcers, including varicose veins, deep vein thrombosis, or [woundsource.com]
- Hypertension
In this line, obesity, hypercholesterolemia, hypertension, heart insufficiency and diabetes mellitus as well as other predisposing conditions should be prevented or accordingly treated. [symptoma.com]
Hypertensive leg ulcer (Ulcus Cruris Hypertonicum Martorell) Hypertensive leg ulcers are extremely painful and commonly located on the distal portion of the lower leg above the lateral malleolus. [intechopen.com]
Skin changes and skin breakdown that result in venous ulcers are triggered by inflammatory mediators when venous hypertension is present. [tnveincenter.com]
Venous leg ulcers develop when persistently high blood pressure in the veins of the legs (venous hypertension) causes damage to the skin, which eventually breaks down and forms an ulcer. 2. [slideshare.net]
The leaking and venous hypertension can cause pain, skin changes (lipodermatosclerosis) and swelling that could lead to open sores, called ulcers, on your legs. [advocatehealth.com]
- Vein Disorder
Vein disorders are hereditary. Inherited factors related to blood clots or clotting disorders are also important, as you could also have inherited the same clotting disorder. [phlebology.org]
More Conservative Management Before seeking out a surgical or non-surgical treatment for varicose veins and other uncomfortable vein disorders, doctors may recommend conservative management techniques for patients. [veincenterofarizona.com]
Musculoskeletal
- Leg Pain
Chronic Wounds can be dangerous, inviting infection and causing pain. When a venous leg ulcer or chronic wounds occur on the legs, it may not heal due to problems with the arteries or veins. [usaveinclinics.com]
Symptoms Aching pain at ulcer site Sensation of limb heaviness Leg Pain increases late in the day Pain relieved with elevating legs VI. [fpnotebook.com]
MRV is useful in some cases because it can help detect causes of leg pain other than vein problems. [bcm.edu]
To help treat a venous ulcer, the high pressure in the leg veins needs to be relieved. Wear compression stockings or bandages every day as instructed. They help prevent blood from pooling, reduce swelling, help with healing, and reduce pain. [medlineplus.gov]
It typically begins with pain, numbness, tingling, burning or weakness in the feet, legs and/or hands, and may progress to more serious conditions such as ulcers, pain and loss of sensation. [cliftonveincarecenter.com]
Skin
- Ulcer
[…] had been present (ulcer duration, also known as ulcer chronicity), and the size of the ulcers. [nejm.org]
Of note, there are other types of ulcers that are sometimes deemed VU. In detail, these are arterial, neurotrophic and diabetic ulcers. They differ from venous VU in location and appearance. [symptoma.com]
[…] of peptic ulcer. gastric ulcer an ulcer of the inner wall of the stomach, one of the two most common kinds of peptic ulcer. [medical-dictionary.thefreedictionary.com]
[…] in infected ulcers. [physiotherapy-treatment.com]
- Skin Ulcer
There are two other types of skin ulcers that can happen on the lower leg or feet. They are different from venous skin ulcers. Arterial skin ulcers are less common than venous skin ulcers. [northshore.org]
Compression Compression therapy is the main treatment for venous skin ulcers. If you have a venous skin ulcer, your doctor may first want to reduce the buildup of fluid in your lower leg. [cigna.com]
Venous skin ulcer is a wound that develops on the skin because the leg veins cannot carry blood effectively back to the heart. [gittervein.com]
Usually, all it takes is a quick examination of the sore and the skin around it to figure out whether you have a venous skin ulcer. [webmd.com]
Skin inflammation (dermatitis) sometimes develops around a venous ulcer. Non-venous skin ulcers are less common. [patient.info]
- Eczema
Failure of the return of venous blood and raised capillary pressure give rise to oedema, eczema, pigmentation, thickening and fibrosis of the skin. These alterations make the skin more liable to break down or fail to repair following minor trauma. [dermis.net]
Treat venous eczema with topical steroids and regular emollients. Medical and surgical treatment Oral medications that affect blood flow, particularly aspirin, provide some benefit in promoting the healing of stasis ulcers. [dermnetnz.org]
Over the years, the inflammation and progressive skin damage causes swelling followed by red skin stains, sometimes with venous eczema, followed by brown stains and finally leg ulceration. [legulcercharity.org]
Signs Medial malleolus most often affected Irregular, flat border Associated findings Dependent Edema Varicose Vein s Purpura Red-brown Skin Discoloration Venous dermatitis ( Eczema tous changes) VII. Differential Diagnosis VIII. [fpnotebook.com]
[…] are recognized as shown on the table below: CEAP classification of chronic venous disease Clinical classification C0 No visible or palpable signs of venous disease C1 Telangiectasies or reticular veins C2 Varicose veins C3 Edema C4a Pigmentation or eczema [sigvaris.com]
- Hyperpigmentation
Hemosiderin Hyperpigmentation gives the appearance of brown veins in the leg. Atrophie Blanche – This term means white areas that are wasting away. [tnveincenter.com]
Aachen-Maastricht, Maastricht, Germany Correspondence to: WB van Gent wbvangent{at}yahoo.com Summary points Venous disease is the most common cause of leg ulcers Signs of venous hypertension include lower extremity varicosities, oedema, venous dermatitis with hyperpigmentation [bmj.com]
[…] arterial disease (PAD) and clinical signs, including irregular shallow ulcers in the ankle region, mid-calf, and medial leg, and above the medial malleolus, swelling of the legs that is worse at the end of the day and that can be relieved by elevation, hyperpigmentation [omicsonline.org]
Other findings include lower extremity varicosities; edema; venous dermatitis associated with hyperpigmentation and hemosiderosis or hemoglobin deposition in the skin; and lipodermatosclerosis associated with thickening and fibrosis of normal adipose [aafp.org]
- Skin Lesion
Patients suffering from varicose veins often report that minimal skin lesions result in poorly healing, painful ulcers. [symptoma.com]
Exclusion criteria were skin lesions other than venous leg ulcers, neuropathic pain detected during the physical examination, ABPI Written informed consent was obtained from all participants prior to their inclusion in the study and after the objectives [omicsonline.org]
Workup
While VU may be diagnosed after clinical examination, a thorough workup is necessary to identify the underlying disease and to evaluate tissue perfusion.
With regards to the former, many VU patients have already been diagnosed with heart insufficiency, diabetes mellitus or any of the afore mentioned diseases that may provoke varicose veins and ulcers. If this is not the case, laboratory analyses of blood samples and possibly imaging techniques may reveal the cause of VU.
There are different diagnostic measures to assess tissue perfusion. Doppler sonography may be applied to detect venous reflex [5]. Sensitivity has been estimated to be > 75%. Ascending venography may provide detailed information regarding vein valve function and potential vessel occlusion.
Furthermore, contrast agents may be used to establish femoral arteriograms that display perfusion of the leg, even of distal parts if deemed necessary. Angiographic images may be obtained using X-rays, computed tomography or magnetic resonance imaging. Magnetic resonance angiography has been found particularly sensitive [6] [7].
Treatment
Ulcer healing may be supported by interactive wound dressings, e.g. interactive hydrocolloid dressings. Other than conventional, passive dressings, these products release growth and migration factors and thus directly promote the healing cascade. Application of platelet-derived growth factor, epidermal growth factor or fibroblast growth factor, among others, aim at enabling the development of healthy granulation tissue and enhanced epithelial cell migration. This may be very valuable in VU patients whose healing process is delayed due to low tissue perfusion. Furthermore, in such a humid environment, formation of rigid eschar is significantly reduced. Of note, interactive hydrocolloid dressings may only be used to accelerate healing of uninfected wounds. Infected wounds require topical if not systemic antibiotic therapy. Silver sulfadiazine is often used to this end. Regular changes of wound dressings decrease the risk for infection [8].
Other therapeutic measures need to be adjusted to the overall condition of the patient and the disease that triggered varicose vein formation. In this context, compression dressings are usually applied to patients suffering from VU due to hypertension [9]. Recently, it has been reported that compression hosiery yields better long-term effects than bandages [10]. Moreover, it has been proposed to treat patients suffering from VU due to lymphedema with intermittent pneumatic compression [11]. It has yet to be shown whether this technique may replace traditional compression methods.
Alternative therapeutic options for VU include low-intensity pulsed ultrasound and hyperbaric oxygen therapy. It could be proven that wound healing improves under ultrasonic stimulation. It has been speculated that ultrasound waves stimulate growth factor production and angiogenesis [12]. According to current knowledge, hyperbaric oxygen therapy only improves wound healing in the short term [13].
Surgical treatment of varicose veins may become necessary if the patient does not respond to wound care and supportive drug therapy.
Prognosis
Etiology of VU, overall condition of the patient and applicable treatment determine prognosis. If adequate treatment can be provided in a timely manner, prognosis for preservation of the affected leg and leg function is good. Prognosis is less favorable if the underlying disease is not curable. VU that are left untreated are likely to become infected and gangrenous. This stage of disease requires amputation.
Relapses are frequent. It has been estimated that half of all VU patients will suffer from recurrences within five years after termination of initial VU treatment.
Etiology
In general, varicose veins develop due to venous insufficiency. This pathological condition, however, may result from a variety of factors and underlying diseases.
There is a genetic component that may predispose certain individuals for varicose veins. Thus, a family history of varicose veins or deep vein thrombosis augments the risk for varicose veins and subsequently VU. If no precise cause for varicose vein development can be identified, primary varicose veins are diagnosed. Moreover, genetic factors may also contribute to systemic diseases like hypercholesterolemia, hypertension, heart insufficiency and diabetes mellitus that render patients more prone to varicose veins. Furthermore, vascular and dermatological disorders, e.g., vasculitis, lupus erythematodes and scleroderma, may accelerate pathophysiological events leading to varicose veins or ulcers. Similar to blood stasis, lymphedema is associated with skin remodelling and susceptibility to injury. In isolated cases, other rare causes have been described [2]. If any of these underlying diseases account for blood stasis or vein thrombosis, the respective patient will suffer from secondary varicose veins.
Patients that are maintained for prolonged periods of time in a lying position may also develop varicose veins and ulcers. Lack of physical activity not only facilitates formation of thrombi, venous blood flow from the legs back to the heart also depends directly on leg muscle activity. Thus, blood pools in leg veins and this condition, unfortunately, makes vein thrombosis even more likely.
Neoplasms are sometimes associated with VU.
Smoking has repeatedly been related to the individual risk for VU.
Epidemiology
Although there are no reliable data regarding the worldwide overall incidence of VU, this is not a rare condition. Approximately 2.5% of patients admitted to long-term care facilities in the United States show VU. In Northern Europe, almost 10% of people aged 70 years and older have suffered from VU at least once in their lives. In Europe and Australia, incidence of leg ulcers in general has been estimated to be around 1% and the vast majority of leg ulcers results from functional impairment of veins [3].
In large parts of the Western world, obesity is a major health problem. Overweight and obesity, in turn, are associated with a series of pathological conditions that facilitate VU development [4]. This applies to hypercholesterolemia, hypertension, heart insufficiency and diabetes mellitus, for instance. Direct intra-abdominal vein compression may further aggravate venous pressure increase in obese patients. It would therefore be expected for VU incidence to diminish if these underlying diseases could be controlled better.
Pathophysiology
VU result from venous insufficiency and varicose veins that may either develop without any identifiable cause or subsequent to underlying, mainly cardiovascular diseases. Independent of their etiology, primary and secondary varicose veins are associated with blood stasis and increased venous pressure. There are different hypotheses regarding pathophysiological events that lead from augmented venous pressure to VU.
It has been shown that dilated veins are unable to prevent fluids from leaking into the surrounding tissue. Even molecules like fibrinogen may pass the damaged vascular wall and reach subcutis and dermis. Fibrinogen may be converted to fibrin and deposit around skin capillaries. This pericapillary cuff literally isolates dependent tissues from nutrient and oxygen supply. Hypoxic injury may then lead to ulceration. Any external lesion would accelerate this process because healing is severely delayed.
Elsewhere, it has been stated that venous wall damage triggers leukocyte activation and release of reactive oxygen species and proteolytic enzymes. These may then pass into the surrounding skin layers, trigger DNA damage and degrade structure proteins. Similar to the above described scenario, internal damage may lead to ulceration and may be exacerbated by external injuries.
Prevention
Prevention of varicose veins and ulcers consists in avoiding risk factors and maintaining an active lifestyle. In this line, obesity, hypercholesterolemia, hypertension, heart insufficiency and diabetes mellitus as well as other predisposing conditions should be prevented or accordingly treated. Regular exercise contributes to weight control and avoids blood stasis. Prolonged periods of siting or standing should be interrupted by small breaks of exercise.
Patients who suffer from varicose veins should carefully avoid skin injuries.
Summary
Venous blood flow largely depends on muscle activity and gravity; venous valves impede reflux inside the veins. However, if these valves do not close correctly due to venous insufficiency, blood will tend to follow gravity and flow back to lower body regions, particularly to feet and legs. The resulting blood stasis evokes elevated pressure on venous walls and triggers remodelling processes. Varicose veins develop.
Varicose veins are superficial and visible as dilated, protruding vessels. Patients suffering from varicose veins often report that minimal skin lesions result in poorly healing, painful ulcers [1]. These varicose ulcers (VU) most commonly affect ankles and calves and are caused by extensive tissue inflammation and reduced oxygen supply to the skin surrounding varicose veins.
Patient Information
Blood is pumped throughout the body by the heart and, to a lesser extent, by arteries. However, reflux to the heart is largely dependent on the pumping action of muscles surrounding veins. In order to avoid blood pooling in the lower parts of the body, particularly in feet and legs, veins possess valves that impede backflow of blood once certain sections have been covered. If these valves do not close correctly, blood will tend to follow gravity and will accumulate in feet and legs. This blood stasis is associated with an increased venous pressure and favors development of varicose veins. Here, fluids are leaking from the intravascular space into the surrounding tissue. Pressure, fluids and its constituents may trigger skin remodelling processes. The latter reduce nutrient and oxygen supply to the skin which thus becomes much more susceptible to injury. Because the skin is deprived of its essential provisions, the healing process is severely slowed down and small lesions may rapidly develop into deep skin defects. These are called varicose ulcers (VU).
Causes
While genetic components play an important role in varicose vein and subsequent ulcer development, comorbidities and lifestyle decisions may further increase the individual risk. In this context, obesity, hypercholesterolemia, hypertension, heart insufficiency and diabetes mellitus as well as vascular and dermatological disorders, smoking and a sedentary lifestyle render patients more susceptible to VU.
Symptoms
Due to gravity, venous varicose veins typically develop in the lower parts of the leg, especially in the lower half of the calf. Here, they become visible as superficial, protruding vessels. The skin surrounding these vessels may turn bluish. Skin injuries take a very long time to heal or do not heal at all and turn into VU. These are extended, but not very deep skin defects. If manipulated, they may start to bleed. Patients often experience mild pain and find relief in elevating their legs.
Diagnosis
Although VU may be diagnosed by means of clinical examinations, additional diagnostic measures will usually be applied to assess the extent of perfusion disturbances and to identify the underlying disease.
In order to visualize tissue perfusion, contrast agents may be injected into veins or arteries before magnetic resonance images are taken. This procedure is called angiography. In some cases, other techniques than magnetic resonance imaging will be utilized.
Analysis of blood samples may reveal valuable information concerning the underlying disease.
Treatment
Intensive wound care is the mainstay of VU therapy. Patients suffering from certain pathological conditions, e.g., hypertension and lymphedema, may benefit from calf compression. Additionally, newer techniques such as low-intensity pulsed ultrasound and hyperbaric oxygen therapy may be applied.
References
- O'Meara S, Al-Kurdi D, Ovington LG. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database Syst Rev. 2008; (1):CD003557.
- Labropoulos N, Manalo D, Patel NP, Tiongson J, Pryor L, Giannoukas AD. Uncommon leg ulcers in the lower extremity. J Vasc Surg. 2007; 45(3):568-573.
- O'Brien JF, Grace PA, Perry IJ, Burke PE. Prevalence and aetiology of leg ulcers in Ireland. Ir J Med Sci. 2000; 169(2):110-112.
- Lane RJ, Cuzzilla ML, Harris RA, Phillips MN. Popliteal vein compression syndrome: obesity, venous disease and the popliteal connection. Phlebology. 2009; 24(5):201-207.
- Neglén P, Raju S. A rational approach to detection of significant reflux with duplex Doppler scanning and air plethysmography. J Vasc Surg. 1993; 17(3):590-595.
- Yucel EK, Dumoulin CL, Waltman AC. MR angiography of lower-extremity arterial disease: preliminary experience. J Magn Reson Imaging. 1992; 2(3):303-309.
- Owen RS, Carpenter JP, Baum RA, Perloff LJ, Cope C. Magnetic resonance imaging of angiographically occult runoff vessels in peripheral arterial occlusive disease. N Engl J Med. 1992; 326(24):1577-1581.
- Edlich RF, Rogers W, Kasper G, Kaufman D, Tsung MS, Wangensteen OH. Studies in the management of the contaminated wound. I. Optimal time for closure of contaminated open wounds. II. Comparison of resistance to infection of open and closed wounds during healing. Am J Surg. 1969; 117(3):323-329.
- van Gent WB, Hop WC, van Praag MC, Mackaay AJ, de Boer EM, Wittens CH. Conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial. J Vasc Surg. 2006; 44(3):563-571.
- Ashby RL, Gabe R, Ali S, et al. VenUS IV (Venous leg Ulcer Study IV) - compression hosiery compared with compression bandaging in the treatment of venous leg ulcers: a randomised controlled trial, mixed-treatment comparison and decision-analytic model. Health Technol Assess. 2014; 18(57):1-293, v-vi.
- Nelson EA, Mani R, Thomas K, Vowden K. Intermittent pneumatic compression for treating venous leg ulcers. Cochrane Database Syst Rev. 2011; (2):CD001899.
- Kavros SJ, Miller JL, Hanna SW. Treatment of ischemic wounds with noncontact, low-frequency ultrasound: the Mayo clinic experience, 2004-2006. Adv Skin Wound Care. 2007; 20(4):221-226.
- Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2012; 4:CD004123.