Ezio Faglia

Adjunctive Systemic Hyperbaric Oxygen Therapy in Treatment of Severe Prevalently Ischemic Diabetic Foot Ulcer: A randomized study

OBJECTIVE To evaluate the effectiveness of systemic hyperbaric oxygen therapy (s HBOT) in addition to a comprehensive protocol in decreasing major amputation rate in diabetic patients hospitalized for severe foot ulcer. RESEARCH DESIGN AND METHODS From August 1993 to August 1995, 70 diabetic subjects were consecutively admitted into our diabetologic unit for foot ulcers. All the subjects underwent our diagnostic-therapeutic protocol and were randomized to undergo s-HBOT. Two subjects, one in the arm of the treated group and one in the arm of nontreated group, did not complete the protocol and were therefore excluded from the analysis of the results. Finally, 35 subjects received s-HBOT and another 33 did not. RESULTS Of the treated group (mean session = 38.8 ± 8), three subjects (8.6%) underwent major amputation: two below the knee and one above the knee. In the nontreated group, 11 subjects (33.3%) underwent major amputation: 7 below the knee and 4 above the knee. The difference is statistically significant (P = 0.016). The relative risk for the treated group was 0.26 (95% CI 0.08–0.84). The transcutaneous oxygen tension measured on the dorsum of the foot significantly increased in subjects treated with hyperbaric oxygen therapy: 14.0 ± 11.8 mmHg in treated group, 5.0 ± 5.4 mmHg in nontreated group (P = 0.0002). Multivariate analysis of major amputation on all the considered variables confirmed the protective role of s-HBOT (odds ratio 0.084, P = 0.033, 95% CI 0.008–0.821) and indicated as negative prognostic determinants low ankle-brachial index values (odds ratio 1.715, P = 0.013, 95% CI 1.121–2.626) and high Wagner grade (odds ratio 11.199, P = 0.022, 95% CI 1.406–89.146). CONCLUSIONS s-HBOT, in conjunction with an aggressive multidisciplinary therapeutic protocol, is effective in decreasing major amputations in diabetic patients with severe prevalently ischemic foot ulcers.

Manufactured Shoes in the Prevention of Diabetic Foot Ulcers

OBJECTIVE To evaluate the efficacy of manufactured shoes specially designed for diabetic patients (Podiabetes by Buratto Italy) to prevent relapses of foot ulcerations. RESEARCH DESIGN AND METHODS A prospective multicenter randomized follow-up study of patients with previous foot ulcerations was conducted. Patients were alternatively assigned to wear either their own shoes (control group, C; n = 36) or therapeutic shoes (Podiabetes group, P; n = 33). The number of ulcer relapses was recorded during 1-year follow-up. RESULTS Both C and P groups had similar risk factors for foot ulceration (i.e., previous foot ulceration, mean vibratory perception threshold > 25 mV). After 1 year, the foot ulcer relapses were significantly lower in P than in C (27.7 vs. 58.3%; P = 0.009; odds ratio 0.26 [0.2–1.54]). In a multiple regression analysis, the use of therapeutic shoes was negatively associated with foot ulcer relapses (coefficient of variation = −0.315; 95% confidence interval = −0.54 to −0.08; P = 0.009). CONCLUSIONS The use of specially designed shoes is effective in preventing relapses in diabetic patients with previous ulceration.

Hyperbaric Oxygen in Diabetic Gangrene Treatment

We treated a group of 18 hospitalized adult diabetic patients (all with retinopathy, 17 with symptomatic neuropathy, and 6 with macroangiopathy) presenting with gangrenous lesions of the foot by a combined regime consisting of strict metabolic control, daily debridement of necrotic tissues, and daily hyperbaric oxygen (HBO) treatments given in a multiplace oxygen chamber. Another group of 10 adult subjects with comparable foot lesions (all with retinopathy, 9 with symptomatic neuropathy, and 4 with macroangiopathy) was treated in exactly the same way except for HBO. In the test treatment group, 16 patients were healed, and the remaining 2 showed no improvement and later underwent amputation. The number of HBO treatments required for healing was significantly related to the size of gangrenous lesions. In the non-HBO-treated group, only 1 patient improved, 5 of 10 showed no change, and 4 of 10 worsened until leg amputation was unavoidable. Comparison of the two groups by X2-test revealed a highly significant difference (P = .001). In practical terms, HBO treatment drastically reduced leg amputations in patients so treated in the last 3 yr compared with earlier and current figures for patients not receiving HBO treatment.

Angiographic evaluation of peripheral arterial occlusive disease and its role as a prognostic determinant for major amputation in diabetic subjects with foot ulcers

OBJECTIVE To evaluate in diabetic patients with foot ulcers the angiographic findings of peripheral occlusive arterial disease and their role as a prognostic determinant for major amputation. RESEARCH DESIGN AND METHODS From 1993 to 1995, 104 diabetic inpatients with foot ulcers underwent arteriography on the ulcerated limb. Stenoses in the iliac trunk, the superficial femoral artery, the profunda femoral artery, the popliteal artery, the anterior tibial artery, the posterior tibial artery, and the peroneal artery were scored on the basis of vessel lumen reduction: 0 if stenoses involved a reduction in the vessel lumen of <50%, 1 if stenoses involved 50 to <75% reduction, 2 if stenoses involved 75 to <100% reduction, and 3 if total occlusion was present. The sum of the points assigned to each of these arteries was called the angiographic score. RESULTS Stenoses causing a vessel lumen reduction ≥50% were detected in 103 patients (99%). Stenoses were also detected in subjects with palpable foot pulses, ankle-brachial indexes ≥1, or transcutaneous oxygen tension ≥50 mmHg. The risk of major amputation was increased significantly when total occlusion was present in the popliteal and infrapopliteal arteries (x2 for trend = 50.57, P < 0.001). No major amputation was carried out in patients with angiographic scores <10; major amputation was carried out in all the patients with scores >14. Multivariate analysis indicated a high angiographic score as an independent risk factor for major amputation (odds ratio 2.32, P = 0.001, CI 1.40–3.84). CONCLUSIONS Angiography permits an exact detection of occlusive arterial disease in subjects with normal results for noninvasive vascular procedures. A score that has a relevant prognostic value for major amputation can be obtained from the evaluation of the extent and diffusion of the stenoses.

Long-Term Prognosis of Diabetic Patients With Critical Limb Ischemia: A population-based cohort study

OBJECTIVE To evaluate the long-term prognosis of critical limb ischemia (CLI) in diabetic patients. RESEARCH DESIGN AND METHODS A total of 564 consecutive diabetic patients were hospitalized for CLI from January 1999 to December 2003; 554 were followed until December 2007. RESULTS The mean follow-up was 5.93 ± 1.28 years. Peripheral angioplasty (PTA) was performed in 420 (74.5%) and bypass graft (BPG) in 117 (20.6%) patients. Neither PTA nor BPG were possible in 27 (4.9%) patients. Major amputations were performed in 74 (13.4%) patients: 34 (8.2%) in PTA, 24 (21.1%) in BPG, and 16 (59.2%) in a group that received no revascularization. Restenosis occurred in 94 patients, bypass failures in 36 patients, and recurrent ulcers in 71 patients. CLI was observed in the contralateral limb of 225 (39.9%) patients; of these, 15 (6.7%) required major amputations (rate in contralateral compared with initial limb, P = 0.007). At total of 276 (49.82%) patients died. The Cox model showed significant hazard ratios (HRs) for mortality with age (1.05 for 1 year [95% CI 1.03–1.07]), unfeasible revascularization (3.06 [1.40–6.70]), dialysis (3.00 [1.63–5.53]), cardiac disease history (1.37 [1.05–1.79]), and impaired ejection fraction (1.08 for 1% point [1.05–1.09]). CONCLUSIONS Diabetic patients with CLI have high risks of amputation and death. In a dedicated diabetic foot center, the major amputation, ulcer recurrence, and major contralateral limb amputation rates were low. Coronary artery disease (CAD) is the leading cause of death, and in patients with CAD history the impaired ejection fraction is the major independent prognostic factor.

Change in Major Amputation Rate in a Center Dedicated to Diabetic Foot Care During the 1980s: Prognostic Determinants for Major Amputation

From 1990 to 1993, 115 diabetic patients were consecutively hospitalized in our diabetologic unit for foot ulcer and 27 (23.5%) major amputations were carried out. The major amputation rate of this series of cases was compared with that occurring in diabetic subjects taken into our hospital for foot ulcer in two previous periods: 1979-1981 (17 major amputations in 42 inpatients or 40.5%) and 1986-1989 (26 major amputations in 78 inpatients or 33.3%). The comparison shows a progressive reduction in major amputation rate [Odds ratio 0.66, 95% confidence interval (CI) 0.46-0.96]. Univariate and multivariate analysis, carried out in the population of the 1990-1993 period, in order to detect the independent factors associated with major amputation show the following prognostic determinants of major amputation: Wagner grade (odds ratio 7.69, CI 1.58-37.53), prior stroke (odds ratio 35.05, CI 3.14-390.53), prior major amputation (odds ratio 3.49, CI 1.26-9.38), transcutaneous oxygen level (odds ratio 1.06, CI 1.01-1.12), and ankle-brachial blood pressure index (odds ratio 4.35, CI 1.58-12.05), while an independent protective role was attributed to hyperbaric oxygen treatment (odds ratio 0.15, CI 0.03-0.64). In accordance with other studies, we, therefore, conclude that a comprehensive protocol as well as a multidisciplinary approach in a dedicated center can assure a decrease in major amputation rate. The parameters of limb perfusion were the modifiable prognostic determinants most strongly predictive for amputation.

MicroRNA-15a and MicroRNA-16 Impair Human Circulating Proangiogenic Cell Functions and Are Increased in the Proangiogenic Cells and Serum of Patients With Critical Limb Ischemia

Rationale: Circulating proangiogenic cells (PACs) support postischemic neovascularization. Cardiovascular disease and diabetes mellitus impair PAC regenerative capacities via molecular mechanisms that are not fully known. We hypothesize a role for microRNAs (miRs). Circulating miRs are currently investigated as potential diagnostic and prognostic biomarkers. Objective: The objectives were the following: (1) to profile miR expression in PACs from critical limb ischemia (CLI) patients; (2) to demonstrate that miR-15a and miR-16 regulate PAC functions; and (3) to characterize circulating miR-15a and miR-16 and to investigate their potential biomarker value. Methods and Results: Twenty-eight miRs potentially able to modulate angiogenesis were measured in PACs from CLI patients with and without diabetes mellitus and controls. miR-15a and miR-16 were further analyzed. CLI-PACs expressed higher level of mature miR-15a and miR-16 and of the primary transcript pri–miR-15a/16-1. miR-15a/16 overexpression impaired healthy PAC survival and migration. Conversely, miR-15a/16 inhibition improved CLI-PAC–defective migration. Vascular endothelial growth factor-A and AKT-3 were validated as direct targets of the 2 miRs, and their protein levels were reduced in miR-15a/16–overexpressing healthy PACs and in CLI-PACs. Transplantation of healthy PACs ex vivo–engineered with anti–miR-15a/16 improved postischemic blood flow recovery and muscular arteriole density in immunodeficient mice. miR-15a and miR-16 were present in human blood, including conjugated to argonaute-2 and in exosomes. Both miRs were increased in the serum of CLI patients and positively correlated with amputation after restenosis at 12 months postrevascularization of CLI type 2 diabetes mellitus patients. Serum miR-15a additionally correlated with restenosis at follow-up. Conclusions: Ex vivo miR-15a/16 inhibition enhances PAC therapeutic potential, and circulating miR-15a and miR-16 deserves further investigation as a prognostic biomarker in CLI patients undergoing revascularization.

MicroRNA-15a and MicroRNA-16 Impair Human Circulating Pro-Angiogenic Cell (PAC) Functions and are Increased in the PACs and Serum of Patients with Critical Limb Ischemia

Rationale: Circulating proangiogenic cells (PACs) support postischemic neovascularization. Cardiovascular disease and diabetes mellitus impair PAC regenerative capacities via molecular mechanisms that are not fully known. We hypothesize a role for microRNAs (miRs). Circulating miRs are currently investigated as potential diagnostic and prognostic biomarkers. Objective: The objectives were the following: (1) to profile miR expression in PACs from critical limb ischemia (CLI) patients; (2) to demonstrate that miR-15a and miR-16 regulate PAC functions; and (3) to characterize circulating miR-15a and miR-16 and to investigate their potential biomarker value. Methods and Results: Twenty-eight miRs potentially able to modulate angiogenesis were measured in PACs from CLI patients with and without diabetes mellitus and controls. miR-15a and miR-16 were further analyzed. CLI-PACs expressed higher level of mature miR-15a and miR-16 and of the primary transcript pri–miR-15a/16-1. miR-15a/16 overexpression impaired healthy PAC survival and migration. Conversely, miR-15a/16 inhibition improved CLI-PAC–defective migration. Vascular endothelial growth factor-A and AKT-3 were validated as direct targets of the 2 miRs, and their protein levels were reduced in miR-15a/16–overexpressing healthy PACs and in CLI-PACs. Transplantation of healthy PACs ex vivo–engineered with anti–miR-15a/16 improved postischemic blood flow recovery and muscular arteriole density in immunodeficient mice. miR-15a and miR-16 were present in human blood, including conjugated to argonaute-2 and in exosomes. Both miRs were increased in the serum of CLI patients and positively correlated with amputation after restenosis at 12 months postrevascularization of CLI type 2 diabetes mellitus patients. Serum miR-15a additionally correlated with restenosis at follow-up. Conclusions: Ex vivo miR-15a/16 inhibition enhances PAC therapeutic potential, and circulating miR-15a and miR-16 deserves further investigation as a prognostic biomarker in CLI patients undergoing revascularization.

When is a technically successful peripheral angioplasty effective in preventing above-the-ankle amputation in diabetic patients with critical limb ischaemia?

Aim  To determine parameters predictive of avoidance of major (above‐the‐ankle) amputation after a technically successful peripheral angioplasty (PTA) in patients with diabetes with critical limb ischaemia.

Effectiveness of Removable Walker Cast Versus Nonremovable Fiberglass Off-Bearing Cast in the Healing of Diabetic Plantar Foot Ulcer A randomized controlled trial

OBJECTIVE To evaluate the efficacy of a removable cast walker compared with that of a nonremovable fiberglass off-bearing cast in the treatment of diabetic plantar foot ulcer. RESEARCH DESIGN AND METHODS Forty-five adult diabetic patients with nonischemic, noninfected neuropathic plantar ulcer were randomly assigned for treatment with a nonremovable fiberglass off-bearing cast (total contact cast [TCC] group) or walker cast (Stabil-D group). Treatment duration was 90 days. Percent reduction in ulcer surface area and total healing rates were evaluated after treatment. RESULTS A total of 48 patients were screened; however, 2 patients in the TCC group and 1 patient in the Stabil-D group did not complete the study and were considered dropouts. There were no significant differences in demographic and clinic characteristics of the 45 patients completing the study. Ulcer surface decreased from 1.41 to 0.21 cm2 (P < 0.001) in the TCC group and from 2.18 to 0.45 cm2 (P < 0.001) in the Stabil-D group, with no significant differences between groups (P = 0.722). Seventeen patients (73.9%) in the TCC group and 16 patients (72.7%) in the Stabil-D group achieved healing (P = 0.794). Average healing time was 35.3 ± 3.1 and 39.7 ± 4.2 days in the TCC and Stabil-D group, respectively (P = 0.708). CONCLUSIONS The Stabil-D cast walker, although removable, was equivalent in efficacy to the TCC in terms of ulcer size reduction and total healing rate. The easier use of Stabil-D may help increase the use of off-loading devices in the management of plantar neuropathic diabetic foot ulcers.