Remote ischaemic conditioning in the context of type 2 diabetes and neuropathy: the case for repeat application as a novel therapy for lower extremity ulceration

Abstract

An emerging treatment modality for reducing damage caused by ischaemia–reperfusion injury is ischaemic conditioning. This technique induces short periods of ischaemia that have been found to protect against a more significant ischaemic insult. Remote ischaemic conditioning (RIC) can be administered more conveniently and safely, by inflation of a pneumatic blood pressure cuff to a suprasystolic pressure on a limb. Protection is then transferred to a remote organ via humoral and neural pathways. The diabetic state is particularly vulnerable to ischaemia–reperfusion injury, and ischaemia is a significant cause of many diabetic complications, including the diabetic foot. Despite this, studies utilising ischaemic conditioning and RIC in type 2 diabetes have often been disappointing. A newer strategy, repeat RIC, involves the repeated application of short periods of limb ischaemia over days or weeks. It has been demonstrated that this improves endothelial function, skin microcirculation, and modulates the systemic inflammatory response. Repeat RIC was recently shown to be beneficial for healing in lower extremity diabetic ulcers. This article summarises the mechanisms of RIC, and the impact that type 2 diabetes may have upon these, with the role of neural mechanisms in the context of diabetic neuropathy a focus. Repeat RIC may show more promise than RIC in type 2 diabetes, and its potential mechanisms and applications will also be explored. Considering the high costs, rates of chronicity and serious complications resulting from diabetic lower extremity ulceration, repeat RIC has the potential to be an effective novel advanced therapy for this condition.

Short‐Term Glucocorticoid Treatment Normalizes the Microcirculatory Response to Remote Ischemic Conditioning in Early Complex Regional Pain Syndrome

“…RIC has been shown to confer protection against hypoxia and ischemia–reperfusion injuries and has been successfully applied in animal models in limb, gut, mesenteric, kidney, and skeletal muscle and reduced myocardial infarct size . Furthermore, RIC has been shown to have a protective effect in flap surgery and has shown promising results in the therapy of lower extremity ulceration in diabetes mellitus …”

Hyperbaric oxygen therapy and intermittent ischaemia in the treatment of chronic wounds

“…[1][2][3] There is emerging, contradictory evidence of the benefits of ischaemic preconditioning in these wounds. 4,5 A review of the literature found over 20 reviews, 7 systematic reviews and 3 systematic reviews of randomised controlled trials for HBOT in chronic wounds. Whilst they all concur that there is evidence supporting the use of HBTO in chronic wounds, the quality of the evidence remains low.…”

“…2,3 There is emerging evidence that intermittent cycles of remote ischaemic preconditioning augment diabetic ulcer healing. 4,5 As hypoxia is one of the causes of chronic wound healing, the concept appears counterintuitive, and the exact mechanisms remain unknown. The idea of ischaemic conditioning was first noted in 1986 by Murry et al They found that intermittent cycles of complete coronary artery occlusion, followed by reperfusion, decreased the size of a subsequent induced myocardial infarction by up to 75%.…”

“…The idea of ischaemic conditioning was first noted in 1986 by Murry et al They found that intermittent cycles of complete coronary artery occlusion, followed by reperfusion, decreased the size of a subsequent induced myocardial infarction by up to 75%. 5 This has been found to protect against a more significant ischaemic insult and end-organ damage, which is not limited to skin and wounds. 4,5 The treatment is inexpensive with few noted complications.…”

“…5 This has been found to protect against a more significant ischaemic insult and end-organ damage, which is not limited to skin and wounds. 4,5 The treatment is inexpensive with few noted complications. This concept is a novel and promising treatment option moving from bench to bedside.…”