Randomized prospective controlled trial of recombinant granulocyte colony-stimulating factor as adjunctive therapy for limb-threatening diabetic foot infection. Evaluation of granulocyte-colony stimulating factor (Filgrastim) in infected diabetic foot ulcers. Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Effects of granulocyte-colony stimulating factor in the treatment of diabetic foot infection. Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Prospective randomized controlled study of Hydrofiber dressing containing ionic silver or calcium alginate dressings in non-ischaemic diabetic foot ulcers. Total contact casting in treatment of diabetic plantar ulcers. Controlled clinical trial. Sodium carboxyl-methyl-cellulose dressings in the management of deep ulcerations of diabetic foot.
Adult diabetic patients admitted to our Diabetes Center from September 1996 to January 1998 for severe, limb-threatening foot infection were consecutively enrolled in a prospective, randomized, controlled clinical study aimed at assessing the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) (lenograstim) as an adjunctive therapy for the standard treatment of diabetic foot infection. Forty patients, all of whom displayed evidence of osteomyelitis and long-standing ulcer infection, were randomized 1:1 to receive either conventional treatment (i.e., antimicrobial therapy plus local treatment) or conventional therapy plus 263 microg of G-CSF subcutaneously daily for 21 days. The empiric antibiotic treatment (a combination of ciprofloxacin plus clindamycin) was further adjusted, when necessary, according to the results of cultures and sensitivity testing. Microbiologic assessment of foot ulcers was performed by both deep-tissue biopsy and swab cultures, performed at enrollment and on days 7 and 21 thereafter. Patients were monitored for 6 months; the major endpoints (i.e., cure, improvement, failure, and amputation) were blindly assessed at weeks 3 and 9. At enrollment, both patient groups were comparable in terms of both demographic and clinical data. None of the G-CSF-treated patients experienced either local or systemic adverse effects. At the 3- and 9-week assessments, no significant differences between the two groups could be observed concerning the number of patients either cured or improved, the number of patients displaying therapeutic failure, or the species and number of microorganisms previously yielded from cultures at day 7 and day 21. Conversely, among this small series of patients the cumulative number of amputations observed after 9 weeks of treatment appeared to be lower in the G-CSF arm; in fact, only three patients (15%) in this group had required amputation, whereas nine patients (45%) in the other group had required amputation (P = 0.038). In conclusion, the administration of G-CSF for 3 weeks as an adjunctive therapy for limb-threatening diabetic foot infection was associated with a lower rate of amputation within 9 weeks after the commencement of standard treatment. Further clinical studies aimed at precisely defining the role of this approach to this serious complication of diabetes mellitus appear to be justified. To re-evaluate the use of Granulocyte-Colony Stimulating Factor (G-CSF) in the treatment of infected diabetic foot ulcers.
                Thirty-seven diabetic subjects were randomised to Granulocyte-Colony Stimulating Factor (G-CSF) (n=20) or placebo (n=17). The primary endpoint was resolution of cellulitis, which was evaluated clinically and with an infection summary score. Patients were hospitalised for 10 days and received subcutaneously either 5 microg/kg G-CSF or placebo daily. Ulcers were treated with a standard wound protocol and the patients were instructed to stay in bed. All subjects received antibiotics (clindamycin and ciprofloxacin) intravenously until the inflammation had subsided.
                Patients who received G-CSF did not have an earlier resolution of clinically defined cellulitis (p=0.57). The infection summary score declined, but comparably, in both groups (G-CSF: 29.5+/-18.4 to 6.7+/-6.3 p<0.001, placebo: 24.2+/-16.9 to 8.9+/-7.2 p<0.001). The ulcer volume, which was not greater among placebo patients, was reduced by 59% in G-CSF and by 35% in placebo patients.
                We conclude that antibiotic and non weight-bearing therapy (bed rest) accelerated the resolution of cellulitis in infected foot ulcers. Additional treatment with G-CSF had no further beneficial effect. Diabetic foot infections cause substantial morbidity and mortality. Neutrophil superoxide generation, a crucial part of neutrophil bactericidal activity, is impaired in diabetes. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil function. We assessed G-CSF as adjuvant therapy for the treatment of severe foot infections in diabetic patients.
                40 diabetic patients with foot infections were enrolled in a double-blind placebo-controlled study. On admission, patients were randomly assigned G-CSF (filgrastim) therapy (n = 20) or placebo (n = 20) for 7 days. Both groups received similar antibiotic and insulin treatment. Neutrophils from the peripheral blood of these participants and from healthy controls were stimulated with opsonised zymosan, and superoxide production was measured by a spectrophotometric assay (reduction of ferricytochrome C).
                G-CSF therapy was associated with earlier eradication of pathogens from the infected ulcer (median 4 [range 2-10] vs 8 [2-79] days in the placebo group; p = 0.02), quicker resolution of cellulitis (7 [5-20] vs 12 [5-93] days; p = 0.03), shorter hospital stay (10 [7-31] vs 17.5 [9-100] days; p = 0.02), and a shorter duration of intravenous antibiotic treatment (8.5 [5-30] vs 14.5 [8-63] days; p = 0.02). No G-CSF-treated patient needed surgery, whereas two placebo recipients underwent to amputation and two had extensive debridement under anaesthesia. After 7 days' treatment, neutrophil superoxide production was significantly higher in the G-CSF group than in the placebo group (16.1 [4.2-24.2] vs 7.3 [2.1-11.5] nmol per 10(6) neutrophils in 30 min; p < 0.0001). G-CSF therapy was generally well tolerated.
                G-CSF treatment was associated with improved clinical outcome of foot infection in diabetic patients. This improvement may be related to an increase in neutrophil superoxide production. Foot infections and the subsequent amputation of a lower extremity are the most common cause of hospitalization among patients with diabetes mellitus. Although there are several reasons for susceptibility to infection in diabetic patients, white blood cell dysfunction is considered to be an important cause for this tendency. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil functions. Based on this knowledge, the aim of the present study was to investigate the effects of addition of G-CSF to the treatment of foot infections in diabetic patients.
                Thirty diabetic patients with foot infection were included in the study. Fifteen of the patients received standard treatment consisting of local wound care and antibiotics (standard group), and the other 15 patients received G-CSF besides standard treatment (G-CSF group). The objectives of this study were to determine the time to resolution of infection, time to hospital discharge, need for surgical intervention, and the effects of G-CSF on phagocytosis and respiratory burst of neutrophils.
                Treatment with G-CSF led to significantly higher neutrophil counts on the 5th and 10th days, and at the end of treatment in the G-CSF treated group compared to the standard group. Respiratory burst of neutrophils increased significantly in both the G-CSF group (from 1.6 +/- 0.3 to 2.3 +/- 0.5, p = 0.001) and the standard group (from 2.0 +/- 0.4 to 2.3 +/- 0.4, p = 0.02) with treatment. But, while phagocytosis of neutrophils increased significantly in the G-CSF group (from 70.4 +/- 2.0 to 74.5 +/- 1.9, p = 0.004), it did not change significantly in the standard group (from 68.1 +/- 0.2 to 69.4 +/- 1.9, p = 0.3) with treatment. Duration of hospitalization (26.9 +/- 2.0 vs. 28.3 days, p < 0.05), duration of parenteral antibiotic administration (22.9 +/- 2.0 vs. 23.3 +/- 1.9 days, p < 0.05), time to resolution of infection (23.6 +/- 1.8 vs. 22.3 +/- 1.7 days, p < 0.05), and need for amputation (13.3% vs. 20%, p > 0.05) were similar between the G-CSF and the standard groups.
                Although G-CSF improves neutrophil function as well as increasing the absolute numbers, this improvement is not associated with shortening of duration of antibiotic administration, duration of hospital stay or need for amputation in diabetic foot infection. To test the efficacy of surgical treatment of non-infected neuropathic foot ulcers compared to conventional non-surgical management, a group of diabetic outpatients attending our diabetic foot clinic were studied. All patients who came to the clinic for the first time from January to December 1995 inclusive with an uncomplicated neuropathic ulcer were randomized into two groups. Group A received conservative treatment, consisting of relief of weight-bearing, regular dressings; group B underwent surgical excision, eventual debridement or removal of bone segments underlying the lesion and surgical closure. Healing rate, healing time, prevalence of infection, relapse during a 6-month period following intervention and subjective discomfort were assessed. Twenty-four ulcers in 21 patients were treated in group A (17 Type 2 DM/3 Type 1 DM, age 63.24 +/- 13.46 yr, duration of diabetes 18.2 +/- 8.41 yr, HbA1c 9.5 +/- 3.8%) and 22 ulcers in 21 patients in group B (19 Type 2 DM/2 Type 1 DM, age 65.53 +/- 9.87yr, duration of diabetes 16.84 +/- 10.61 yr; HbA1c 8.9 +/- 2.2%). Healing rate was lower (79.2% = 19/24 ulcers) in group A than in group B (95.5% = 21/22 ulcers; p < 0.05), and healing time was longer (128.9 +/- 86.60 days vs 46.73 +/- 38.94 days; p < 0.001). Infective complications occurred significantly more often in group A patients (3/24, 12.5% vs 1/22, 4.5%; p < 0.05), as did relapses of ulcerations (8 vs 3; p < 0.01). There were only two minor perioperative complications in group B patients. Patients reported a higher degree of satisfaction in group B (p < 0.01) as well as lower discomfort (p < 0.05) and restrictions (p < 0.05). Thus surgical treatment of neuropathic foot ulcers in diabetic patients proved to be an effective approach compared to conventional treatment in terms of healing time, complications, and relapses, and can be safely performed in an outpatient setting. Nonhealing diabetic foot ulcers are a common cause of amputation. Emerging cellular therapies such as platelet-rich plasma gel provide ulcer management options to avoid loss of limb. The purpose of this prospective, randomized, controlled, blinded, multicenter clinical study was to evaluate the safety and efficacy of autologous platelet-rich plasma gel for the treatment of nonhealing diabetic foot ulcers. One hundred, twenty-nine (129) patients were screened; 72 completed a 7-day screening period and met the study inclusion criteria. Patients were randomized into two groups - the standard care with platelet-rich plasma gel or control (saline gel) dressing group - and evaluated biweekly for 12 weeks or until healing. Healing was confirmed 1 week following closure and monitored for another 11 weeks. An independent audit led to the exclusion of 32 patients from the final per-protocol analysis because of protocol violations and failure to complete treatment. In this group, 13 out of 19 (68.4%) of the platelet-rich plasma gel and nine out of 21 (42.9%) of the control wounds healed. After adjusting for wound size outliers (n = 5), significantly more platelet-rich plasma gel (13 out of 16, 81.3%) than control gel (eight out of 19, 42.1%) treated wounds healed (P = 0.036, Fisher's exact test). Kaplan-Meier time-to-healing also was significantly different between groups (log-rank, P = 0.0177). No treatment-related serious adverse events were reported and bovine thrombin used in the preparation of PRP did not cause Factor V inhibition. When used with good standards of care, the majority of nonhealing diabetic foot ulcers treated with autologous platelet-rich plasma gel can be expected to heal. Diabetic foot ulcers (DFUs) are at risk of infection and impaired healing, placing patients at risk of lower extremity amputation. DFU care requires debridement and dressings. A prospective, multicentre study compared clinical efficacy and safety of AQUACEL Hydrofiber dressings containing ionic silver (AQAg) with those of Algosteril calcium alginate (CA) dressings in managing out-patients with Type 1 or 2 diabetes mellitus and non-ischaemic Wagner Grade 1 or 2 DFUs.
                Patients stratified by antibiotic use on enrolment were randomly assigned to similar protocols including off-loading, AQAg (n = 67) or CA (n = 67) primary dressings and secondary foam dressings for 8 weeks or until healing. Clinical efficacy measures were healing outcomes and primarily healing speed. Adverse events were recorded.
                AQAg and CA groups were comparable at baseline. All ulcer healing outcomes improved in both groups. The mean time to healing was 53 days for AQAg ulcers and 58 days for CA ulcers (P = 0.34). AQAg-treated ulcers reduced in depth nearly twice as much as CA-treated ulcers (0.25 cm vs. 0.13 cm; P = 0.04). There was more overall ulcer improvement and less deterioration in AQAg subjects (P = 0.058), particularly in the subset initially using antibiotics (P = 0.02). Safety profiles of both groups were similar.
                When added to standard care with appropriate off-loading, AQAg silver dressings were associated with favourable clinical outcomes compared with CA dressings, specifically in ulcer depth reduction and in infected ulcers requiring antibiotic treatment. This study reports the first significant clinical effects of a primary wound dressing containing silver on DFU healing. This study compared the treatment of total contact casting (TCC) with traditional dressing treatment (TDT) in the management of diabetic plantar ulcers. Forty patients with diabetes mellitus and a plantar ulcer but with no gross infection, osteomyelitis, or gangrene were randomly assigned to the TCC group (n = 21) or TDT group (n = 19). Age, sex, ratio of insulin-dependent diabetes mellitus to non-insulin-dependent diabetes mellitus, duration of diabetes mellitus, vascular status, size and duration of ulcer, and sensation were not significantly different between groups (P greater than .05). In the experimental group, TCC was applied on the initial visit, and subjects were instructed to limit ambulation to approximately 33% of their usual activity. Subjects in the control group were prescribed dressing changes and accommodative footwear and were instructed to avoid bearing weight on the involved extremity. Ulcers were considered healed if they showed complete skin closure with no drainage. Ulcers were considered not healed if they showed no decrease in size by 6 wk or if infection developed that required hospitalization. In the TCC group, 19 of 21 ulcers healed in 42 +/- 29 days; in the TDT group, 6 of 19 ulcers healed in 65 +/- 29 days. Significantly more ulcers healed (chi 2 = 12.4, P less than .05) and fewer infections developed (chi 2 = 4.1, P less than .05) in the TCC group. We conclude TCC is a successful method of treating diabetic plantar ulcers but requires careful application, close follow-up, and patient compliance with scheduled appointments to minimize complications. To test the safety and effectiveness of carboxyl-methyl-cellulose dressing (Aquacel; ConvaTec, UK) in the management of deep diabetic foot ulcers, a group of consecutive out-patients attending the foot clinic of the Department of Metabolic Diseases was studied.
                Patients were selected according to the following inclusion criteria: a foot ulcer deeper than 1 cm for > 3 weeks, good peripheral blood supply (palpable peripheral pulses or ABPI > 0.9). Exclusion criteria were as follows: active infection, as evident from clinical signs (purulent discharge, redness, swelling, tenderness) and confirmed by culture exams, plasma creatinine > 2 mg/dl, recent episodes of ketoacidosis, malignancies, and any therapy or pathology which might interfere with the healing process. Twenty patients were enrolled in the study and having obtained their informed consent, their lesions were surgically debrided with the complete elimination of all necrotic tissue and debris up to the bleeding healthy tissue; then ulcers were staged and measured, and patients were randomly assigned to two different treatment groups. Patients in group A were dressed with saline-moistened gauze, while patients in group B were dressed with Aquacel according to the manufacturer's instructions. All patients in both groups received special post-operative shoes (Podiabetes; Zeno Buratto, Treviso, Italy) and crutches until complete re-epithelialization. Ulcers were all left to heal by secondary intent. After 8 weeks patients were blindly evaluated for: the rate of reduction of lesional volume (RLV), rate of granulation tissue (GT), number of infective complications (IC). Intralesional (ILTC) and perilesional (PLTC) temperatures were also recorded with a thermocouple surface digital thermometer, and the difference between the two values (Delta TC) was calculated. Healing time (HT, days), was then compared between the two groups. Data were compared by analysis of variance (ANOVA), linear regression, Kaplan-Meier survival analysis and Fisher's exact test.
                HT was significantly shorter in Group B than in Group A (P < 0.001). RLV was significantly (P < 0.01) higher in Group B patients compared with Group A, as well as GT (P < 0.05). IC were in 1/10 Group B and in 3/10 Group A (P = 0.582). In addition, both ILTC and Delta TC were higher in Group B compared with Group A ones (P < 0.01).
                Carboxyl-methyl-cellulose dressings were shown to be safe, effective and well tolerated in the management of non-ischaemic, non-infected deep diabetic foot ulcers.
The available evidence is limited, but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection, including infected ulcers, does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer. However, it does appear to reduce the need for surgical interventions, especially amputations, and the duration of hospitalisation. Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections, especially in patients with a limb-threatening infection, but it is not clear which patients might benefit.