Intermittent Pneumatic Compression of the Thigh

Clinical Problem: A leg ulcer is defined as the loss of skin below the knee on the leg or the foot, which takes more than two weeks to heal. Leg ulcers are the most common wound type in the community in the UK with a prevalence rate of approximately of 0.45/1000 in men and 0.56/1000 in women, increasing to 8.29/1000 in men and 8.06/1000 in women aged over 85 years old. Leg ulcers of venous origin account for approximately 70% of individuals with leg ulcers, with 10-20% being due to a combination of venous and arterial disease, often referred to as mixed leg ulcers (MLU). Leg ulceration represents a significant source of morbidity with adverse physical, social and psychological sequalae. With appropriate treatment, some ulcers heal successfully within a few weeks, however many persist for months and even several years. The annual cost of managing patients with venous leg ulcers alone in Wales is £7,706 per patient per annum, which translates to an annual cost of over £2 billion when extrapolated to the United Kingdom (UK) population. Current Treatment Compression therapy in the form of graduated, multi-layered bandaging, is widely accepted as the treatment of choice and gold standard therapy for the prevention and management of VLU. Compression therapy can also be recommended for mixed aetiology wounds where vascular assessment has been completed and there is no evidence of severe peripheral arterial disease (PAD) whereby compression therapy would be contraindicated. Patients with mixed etiology ulceration of the lower limb with an ankle brachial pressure index (ABPI) of \>0.5 and an absolute ankle pressure \>60 millimeters of mercury (mmHg) were able to receive inelastic compression up to 40 mmHg without restricting arterial perfusion. Other published guidance suggests a more conservative approach to compression with mixed disease with moderate PAD, utilizing a reduced level delivering approximately 20 - 30 millimeters of mercury compression at the ankle or the use of mild to moderate compression incorporating pressures \<20 millimeters of mercury up to 40 millimeters of mercury. However, a proportion of wounds do not progress towards healing despite receiving this gold standard treatment and furthermore some patients cannot tolerate wearing continual compression bandaging. A study showed that of 440 patients with VLUs who were in gold standard compression, 48% had not healed within 12 months. Comparable healing rates between VLU and MLU treated with reduced compression have been previously demonstrated. Physiological Effects of IPC Application of IPC to the limb affects underlying subcutaneous tissue, muscle and blood vessels resulting in a range of physiological effects including alterations in blood flow dynamics and the release of biochemical mediators that affect the circulatory system. The effects of IPC are documented as: * Increasing venous blood flow: When IPC is applied to the lower limb, or part of, the application of cyclical intermittent compression causes a pulsatile flow to move proximally. This drains the blood at the compression site and increases venous flow, simulating the action of the calf muscle pump. This can also facilitate clearance within the venous valve sinuses. Venous hypertension is reduced and there is a decrease in local oedema that in turn increases capillary perfusion. * Increasing arterial blood flow: If arterial compression is applied at sufficient pressure to occlude arterial blood flow, ischemia will occur and on release of the compression, a reactive hyperemia ensues. This reactive hyperemia also occurs at lower pressures when the veins are compressed, and several mechanisms have been suggested as to why this occurs. By increasing venous flow, there is a corresponding increase in the arterio-venous pressure gradient that in turn causes an increase in arterial blood flow. Additional hypotheses include suspension of the veno-arteriolar reflex, and a myogenic mechanism. The veno-arteriolar response to an increase in venous pressure is neurally controlled. It has been suggested that the reduced venous pressure produced by mechanical compression, suppresses the veno-arteriolar reflex; allowing arterioles to dilate, and enabling a hyperemia to ensue. The proposed myogenic mechanism is a vascular response to alterations in intravascular pressures. Arteriolar smooth muscle is believed to respond directly to the increased distension that arises as a result of raised intravascular pressure by constricting; and conversely, a loss in vascular tone and hence dilation occurring in response to a decrease in intravascular pressure. * The act of compression also increases mechanical stress on the endothelial lined wall of the artery causing a release of biochemical substances with anti-thrombotic, pro-fibrinolytic and vasodilatory properties. Hematological studies have demonstrated that patients with chronic venous insufficiency have a reduced plasma fibrinolytic activity. IPC increases tissue plasminogen activator (tPA) and urokinase-plasminogen activator (UPA) with a corresponding decrease in plasminogen activator inhibitor-1 (PAI-1). These actions have the overall effect of suppressing pro-coagulant activity whilst enhancing the fibrinolytic mechanism. Evidence of effectiveness of IPC in the treatment of venous and mixed leg ulceration In 2014, a Cochrane review found that there was some limited evidence that showed that IPC may improve healing of venous leg ulcers when added to compression bandaging. Five trials compared IPC plus compression with compression alone. Two of these found increased healing with IPC than with compression alone. The remaining three trials (122 people) found no evidence of a benefit of IPC plus compression compared with compression alone. However, all of these trials were noted as being at high risk of bias as a result of inadequate randomization procedures, allocation concealment and blinded outcome assessments. Additional research, undertaken after this review, is limited and is confined to case report series. Another study found that IPC combined with negative pressure wound treatment appeared to promote healing and reduce associated chronic pain in 11 patients with venous leg ulcers. More recent studies have also demonstrated that IPC can improve the symptoms of arterial insufficiency and reduce oedema. Further high-quality trials are therefore required to determine whether IPC increases the healing of venous and mixed etiology leg ulcers when used in modern practice where compression therapy is widely used. Thigh-administered IPC IPC devices usually apply relatively high intermittent pressure over a wound site, which may cause concern to patients and clinicians, may interfere with existing treatments, and may not always be tolerated. A novel IPC device (the WoundExpress, Huntleigh Healthcare) has recently become available on the UK market which could address this issue; the device applies compression to the thigh of the afflicted leg (proximal compression), away from the actual leg ulcer sites which are, by definition, situated below the knee. The device consists of a 3-chamber thigh garment and pneumatic compression pump which delivers a 4-minute compression cycle consisting of a 2-minute venous emptying phase followed by a 2-minute rest phase; it is used for 2 hours per day in a hospital, community or home setting. A study examined how this thigh IPC device affected distal arterial and venous blood flow in 20 healthy volunteers and 14 patients of leg ulcers of various etiologies. They found that arterial blood flow velocity increased in the dorsalis pedis artery after periods of compression, and that venous blood flow velocity increased when the lower chambers of the cuff deflated; these effects were similar in the healthy volunteers and the patients with leg ulcers. Hence, these results demonstrated that the device resulted in positive effects on venous and arterial blood flow distal to the compression site, but proximal to wound sites. Further to this, another study conducted a prospective observational pilot study which involved 21 recruited patients with hard to heal wounds utilizing the same thigh administered IPC device for two hours a day for an eight-week period in addition to their standard wound care (hard to heal was defined as failure of the wound to progress in the opinion of the treating clinician and a wound that was observed for an 8 week period prior to recruitment). 95.24% of participants progressed towards healing and pain scores decreased in 83.33%. Most participants felt that the thigh IPC was comfortable and easy to apply and remove in the setting of their own homes. However, this was not a controlled trial with a potential for selection bias. The IPCOTT study therefore aims to further evaluate the effectiveness of thigh IPC for the treatment of lower limb wounds using gold standard RCT methodology. Design: The IPCOTT study is a global, multicenter, pragmatic, open, randomised controlled trial (RCT) of IPC (2hrs daily) plus standard wound care vs. standard wound care alone. One hundred and sixty participants will be recruited across eleven sites which provide wound care in a clinic environment- Aneurin Bevan University Heatlh Board, Cardiff \& Vale University Health Board Cwm Taf Morgannwg University Health Board, Wales; Accelerate CIC, London, England; St. Maria Hilf Krankenhaus, Bochum, Germany; Clinique Pasteur, Toulouse, France; Northumbria Healthcare National Health Service Foundation Trust, England; SerenaGroup Monroeville, US), Mid Yorkshire Hospitals National Health Service Trust, England. Setting: Eligible patients attending wound clinic appointments at each of the eleven study sites, or patients who have been referred for screening for entry into the study who are found to be eligible, will be invited to participate. Recruitment, consent and all study assessments and data collection will take place in the respective clinics or by a member of the study team visiting the patient in their own home. Duration of the study: 18 weeks; includes a 2-week run in period followed by 16-week intervention period.