Intermittent cycles of remote ischemic preconditioning augment diabetic foot ulcer healing

Abstract

The morbidity and mortality caused by diabetic foot ulcer (DFU) are still significant. Conservative treatment of DFU is often ineffective. Treatment modalities using stem cells directly into the DFU or systematically have been introduced recently. Ischemic preconditioning (IPC) has been proved to be a cheap, simple, and safe method which can augment stem cells number in the peripheral blood circulation. This study's purpose was to test whether IPC can improve DFU healing. Forty diabetic patients were enrolled and divided into study and control groups. All patients received their regular treatment. The study group patients received in addition brief, transient cycles of IPC while the control group patients received a sham procedure only. The procedure was repeated every 2 weeks to complete a follow-up period of 6 weeks. The ulcers were photographed to measure wound area, and the degree of granulation tissue was assessed. No serious adverse events were noted. Twenty-two patients from the study group and 12 from the control group completed the entire follow-up. The ratio of patients who reached complete healing of their ulcer was 9/22 (41%) in the study group compared with 0/12 (0%) in the control group, p = 0.01. Furthermore, the mean remaining ulcer area at the end of the follow-up was significantly smaller in the study group, 25 ± 6% of the initial area vs. 61 ± 10% in the control group, p = 0.007. The degree of granulation increased after one cycle of treatment in 8/24 (33%) study patients compared to 3/16 (19%) in the control group, p = 0.47. Remote, repeated IPC significantly improves the healing of DFU. This simple, safe, inexpensive treatment method should be considered to be routinely applied to diabetic patients with DFU in addition to other regular treatment modalities.

Repeated ischaemic preconditioning: a novel therapeutic intervention and potential underlying mechanisms

“…In that study, significant protection against stroke recurrence was observed after 180 days of twice daily RIPC in symptomatic intracranial arterial stenosis patients (Meng et al 2015). Another recent study examined the impact of repeated RIPC on diabetic wound healing in patients with diabetes mellitus type 1 or type 2 (Shaked et al 2015). Patients with foot ulcers were randomized to 6 weeks of bilateral repeated RIPC (upper limbs) or a control intervention.…”

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

“…There has been considerable variation in the timeframe of administration, ranging from one bout of 5 cycles of 5 min of ischaemia and reperfusion applied once or twice daily [43], to three 5 min cycles applied once per fortnight [44]. The period of intervention has ranged from 1 week of application of RRIC [45] to 300 days of RRIC [43].…”

“…Although often termed repeat, regular or intermittent remote ischaemic pre conditioning, intervention studies utilising this method are generally applied to a chronic condition (such as heart failure [188], endothelial dysfunction [189], stroke recurrence [43] or chronic wounds [44]) or following an acute ischaemic episode (such as in a lower limb [190], post-myocardial infarction [191] or cerebrovascular accident [43]). Depending on the context, the chronicity of pathological ischaemia in the cohort, and endpoints studied, this would more accurately represent combinations of pre, per and post-conditioning, reflected in the term repeat remote ischaemic conditioning (RRIC).…”

“…It is therefore unexpected that a recent study showed diabetic patients with refractory lower leg ulcers had significant improvement following repeat RIC [44]. In Shaked et al’s double-blinded randomised study with sham control, 22 patients received 3 fortnightly cycles of RRIC to both arms, in addition to standard wound care.…”

“…In Shaked et al’s double-blinded randomised study with sham control, 22 patients received 3 fortnightly cycles of RRIC to both arms, in addition to standard wound care. At the completion of the 6 week study, 9/22 (41 %) of the study group had complete healing of their ulcer compared to 0/12 of the control group [44]. Questionably, only one participant in each group was reported as having “neuropathy”, even though this was not listed in the exclusion criteria for the study.…”