Healing Of Ischemic Ulcers Research Articles

Transcutaneous oxygen tension: a useful predictor of ulcer healing in critical limb ischaemia

To investigate the threshold of transcutaneous oxygen tension (TcPO(2)) values in predicting ulcer healing in patients with critical limb ischaemia in a prospective study. 50 patients suffering from critical limb ischaemia with chronic ischemic ulcers or gangrenous toes were enrolled in this study between January and December 2008. Their demographic data and ankle brachial pressure index (ABPI) were collected. Baseline ulcers were measured with a wound measurement system (Visitrak, Smith & Nephew). TcPO(2) was measured at rest in the supine position and with 30 degrees leg elevation. The patients with infective and ischemic ulcers underwent debridement and gangrenous toes were amputated. Ulcer outcome was classified as either: (1) A healing ulcer, showing good epithelialisation or granulation at both base and edges, or a decrease in ulcer area during the study; or (2) A non-healing ulcer, showing poor granulation tissue formation or a pale base and necrotic edges, or deterioration in an ischaemic ulcer. The mean age of the patients was 67.6 + or - 10.8 years. The most common risk factor was hypertension (90%). Mean ABPI was 0.75 + or - 0.39. 13 patients (26%) had a TcPO(2) of less than 20 mmHg, of which none showed any improvement in ulcer healing (p<0.001). 15 patients (30%) had a TcPO(2) of more than 40 mmHg, of which all progressed to complete ulcer healing (p<0.001). In the borderline group (20-40 mmHg, 22 patients, 44%), 10 patients (45%) had a TcPO2 drop of <10 mmHg with 30 degrees leg elevation, of which 8 achieved complete ulcer healing (p<0.001). 12 patients (55%) had a TcPO(2) drop of >10 mmHg with 30 degrees leg elevation, of which 11 showed no ulcer healing (p<0.001). TcPO(2) measurement is an accurate, non-invasive, and good predictor of ischemic ulcer healing, for cut-off TcPO(2) values of less than 20 mmHg and more than 40 mmHg. In addition, the leg elevation method for TcPO(2) might provide an important adjunct in the assessment of patients with borderline values.

Células-tronco de medula óssea em isquemia crítica de membros

Os autores discutem aspectos clínicos e de tratamento convencional da isquemia critica dos membros inferiores e consideram a possibilidade de tratamento com células- -tronco autógenas de medula óssea para os pacientes que já esgotaram, sem sucesso, todos os meios de tratamento conhecidos. Comentam sobre o histórico, as fontes, as experiências animais e clínicas e, finalmente, apresentam sua experiência inicial com seis pacientes, todos com indicação de amputação maior ou menor. Em apenas um paciente não foi possível evitar a amputação. Além de ótimos resultados, quanto à supressão da dor e cicatrização de lesões isquêmicas, pode-se notar a ausência de quaisquer efeitos colaterais deletérios, sugerindo que a terapia celular é eficiente e segura, demandando, porém, mais pesquisas e estudos randomizados para se tornar uma terapia de uso corrente.

Abstract 6054: Immersing Feet in CO 2 -Rich Water-Bath Improves Ulcer Healing on Ischemic Limb after Infrainguinal Bypass Surgery

Background : We have shown that immersion of feet in warmed water enriched with carbon dioxide (CO 2 immersion) improves subcutaneous microcirculation in critical limb ischemia (CLI) with ischemic ulcer/gangrene. Using an animal model, other group has reported that the CO 2 immersion enhances collateral blood flow in ischemic limb via mobilization of endothelial progenitor cells and activation of NO-cGMP system. For CLI patients with ulcer/gangrene, infrainguinal bypass surgery is the standard therapy. However, ulcer healing and prevention of amputation still remain suboptimal. In order to know whether the CO 2 immersion improves the clinical efficacy, here we performed the CO 2 immersion after infrainguinal bypass surgery. Methods : This study was designed as a prospective controlled trial. Fifty-five patients with ischemic ulcer/gangrene underwent the standard care including successful infrainguinal bypass surgery were enrolled and were randomly divided into the two groups; patients underwent standard care added CO 2 immersion (CO 2 group, 27 patients with 30 limbs) and patients received standard care alone (control group, 28 patients with 30 limbs). The patients in the CO 2 group immersed their feet in CO 2 enriched water (depth of 20 –30 cm, 37–38°C, duration for 10 minutes) twice a day. Primary endpoint was defined as complete healing of ischemic ulcers. Results : Baseline demographical data, traditional risk factors, surgical procedure, ankle pressure and transcutaneous oxygen pressure (tcPO 2 ) were comparable between the two groups. Rate of the complete ulcer healing after 1-year was much higher in the CO 2 group than in the control group (43.3% vs. 20.0%, HR 2.72, 95%CI 1.03–7.17, p=0.043). Cox multivariate analysis revealed that CO 2 immersion (HR 4.13, 95%CI 1.09 –15.75, p=0.038), diabetes (HR 0.020, 95%CI 0.01–.303, p=0.005) and tcPO 2 (HR 1.04, 95%CI 1.00 –1.09, p=0.050) were independent predictors for complete ulcer healing. In contrast, rates of 1-year mortality, graft patency and limbs salvage showed no significant differences between 2 groups (p=0.55, p=0.47 and p=0.16, respectively). Conclusion : The CO 2 immersion after infrainguinal bypass surgery provided additional benefit for the ulcer healing in CLI patients with ulcer/gangrene.

Significance of Phlebosclerosis in Non-healing Ischaemic Foot Ulcers of End-stage Renal Disease

Objectives To determine the influence of haemodialysis on the poor healing of ischaemic ulcers in end-stage renal failure patients regardless of successful revascularization. Materials and methods We investigated the microscopic findings of subcutaneous small vessels in the amputated limbs of 78 patients (27 diabetic/haemodialysis, 26 diabetic/non-haemodialysis and 25 non-diabetic/non-haemodialysis patients) who underwent foot/toe or limb amputation because of ischaemic foot ulcers in the period between 1998 and 2006. All the haemodialysis patients were diabetic. Multivariate logistic analysis was conducted to identify important clinical factors related to the histological findings. Results Marked medial thickening was observed in both small veins and arteries in diabetic patients compared with non-diabetic patients. In diabetics, there was significant medial thickening of small veins, which was greater in haemodialysis patients than in non-haemodialysis patients (Dunnett test, P < 0.05). Multivariate analysis indicated that haemodialysis treatment (odds ratio 14.12, P < 0.01), ABI value (odds ratio 5.41, P < 0.01) and poor stump wound healing (odds ratio 6.19, P = 0.03) were important factors related to medial thickening of small veins. Conclusions Our data suggest that medial thickening of small veins, or phlebosclerosis, might affect the healing of ischaemic ulcers in end-stage renal failure, although the strong influence of diabetes cannot be ignored.

Spinal cord stimulation for lower limb ischemic pain treatment

Spinal cord stimulation (SCS) was proposed many years ago for pain treatment but healing of ischemic ulcers opened a new treatment indication. The aim of this review was to assess the efficacy of SCS. studies regarding ischemic pain, limb ischemia and SCS reported on Pubmed have been reviewed, including randomized controlled trials (RCTs), clinical trials, Cochrane library review, neurophysiological studies and microcirculatory evaluations. Five RCTs, three multicenter studies and many clinical trials and reports of series have documented the clinical efficacy of SCS in the treatment of ischemic pain, particularly in patients with post-implantation increased blood flow. Pain relief, ulcer healing and limb salvage seems to be greater in non-diabetic patients, in diabetic without autonomic neuropathy, and in patients with rest pain or ulcer more than in patients with gangrene. A pain reduction of 75% was reported in the 3 RCTs; pain relief was significantly greater than in control group. Another study reported a lower use of analgesic in the SCS group. Moreover, pain relief obtained with SCS is maintained at follow-up while relief after medical treatment disappears quickly. The three multicenter studies showed a total pain relief between 41% and 43% and a cumulative pain reduction of 75% in 64.8% of cases. The clinical trials reported a pain reduction in up to 91% of patients. Based on six studies, the Cochrane reviewers found evidence to favor SCS over standard conservative treatment to improve limb salvage and clinical situation in patients with non-reconstructable critical limb ischemia (CLI). The mechanism of action of SCS is not completely clarified. the endovascular approach reduced the number of patients unsuitable for revascularization, however, some patients cannot be treated by angioplasty or open surgery; moreover, some are unfit for surgery, and others have persistent distal ischemia and pain with a functioning revascularization. In these cases SCS (alone or associated with prostanoids) can be indicated on the basis of the more recent evidences. A trial period with external stimulator, associated with a microcirculatory evaluation, is currently utilized to select patients that can derive benefit from this treatment, reducing costs.

Does infection affect amputation rate in chronic critical leg ischemia?

Aim was to analyze the association between local infection and amputation rate in patients with chronic critical limb ischemia (CLI) with or without successful revascularization. We performed a retrospective analysis of 56 consecutive patients with 57 critically ischemic legs seen at the University Hospital Bern. Patients with CLI were selected if ischemic lesions and follow-up of more than 2 months were documented. Infection was suggested when 2 of the following criterion were present: temperature > 37 degrees C, C-reactive protein > 50 mg/L, leukocytes > 10 x 10(3)/microliter ("2 of 3" criterion), or a putrid secretion was documented ("secretion" criterion). In patients with successful revascularization (n = 39), there was a significant shift from 10.3% major to 33.3% minor amputations (Chi Square p value = 0.014) as compared to patients without or with failed revascularization (n = 18) with 44.4% and 11.1% (Chi Square p value = 0.008), respectively. An infection was suggested in 22 of 53 limbs (41.5%) according to the "2 of 3" criterion, and 30 of 57 limbs (52.6%) satisfying the "secretion" criterion. Both criteria, were significantly more common in patients undergoing amputation as compared to patients without amputation (p = 0.001). Multiple lesions were more common in patients with major amputations (p = 0.026). Successful revascularization effectively reduces major amputations and leads to healing of ischemic ulcers. Secondary foot infections are frequent. Infections are associated with a significantly higher rate of minor and major amputations, also in patients with successful revascularization, and should be treated adequately as well as in time with antibiotics.

Pedicled omental transfer for limb salvage in Buerger’s disease

We performed pedicled omental transfer in 62 patients with Buerger’s disease at the Department of Surgery, J.L.N. Hospital, Ajmer between January 1990 and December 1996. All were male and had evidence of limb ischaemia. Post-operative results in these patients consisted of relief of intermittent claudication in 92%, disappearance of rest pain in 94%, disappearance of limb coldness in 83%, disappearance of discolouration in 82%, and healing of ischaemic ulcers in 83%. Tissue oxygen saturation in the affected limb improved from a mean of 84.8±3.6% in the preoperative period, to 89±1.5% at 12 h, 93.1±1.8% at 72 h and 96±1.2% at the end of 2 months of follow-up. Claudication distance improved from a mean of 75±20 m in the pre-operative period to 1000±110 m at 2 months of follow-up in 57 of 62 patients. Major amputations were not required in any patient, thus conserving the limb. We conclude that pedicled omental transfer offers promising results in patients with limb ischaemia due to Buerger’s disease.

Vascular imaging and intervention in peripheral arteries in the diabetic patient.

Diabetic patients are four times more likely to develop peripheral vascular disease than the general population. This disease is likely to be more aggressive, with five times more patients developing critical limb ischaemia. Early diagnosis and treatment allows up to 80% of these patients to have some form of surgical or endovascular re-vascularisation. The primary imaging modalities to be used should be duplex ultrasound followed by angiography. Magnetic resonance angiography, however, holds out promise for the future as being a good method of non-invasive imaging. Endovascular (interventional radiological) procedures have a major role to play in treatment of vascular stenoses and occlusions. Thrombolytic agents can be used to dissolve thrombus within occluded vessels and so restore patency. Percutaneous transluminal angioplasty is of value in dilating the stenotic lesions within the vessels and so restoring normal blood flow. Endovascular stents may be inserted to ensure longer term patency. There is indirect evidence to suggest that the outcomes of endovascular procedures in the diabetic patient are less good than those in the general population, but nevertheless such procedures may save the diabetic patient from primary amputation and allow healing of ischaemic ulcers.

Arterial gene transfer for therapeutic angiogenesis in patients with peripheral artery disease.

The age-adjusted prevalence of peripheral arterial disease (PAD) in the U.S. population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease (PAD) include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may be used to successfully revascularize the limbs of certain patients with PAD. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and/or healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients. The purpose of this clinical protocol is to document the safety of therapeutic angiogenesis achieved in this case by percutaneous catheter-based delivery of the gene encoding vascular endothelial growth factor (VEGF) in patients with PAD; and, as secondary objectives, investigate the bioactivity of this strategy to relieve rest pain and heal ischemic ulcers of the lower extremities. The rationale for this human protocol is based upon preclinical studies performed in a rabbit model of hindlimb ischemia. These studies are described in detail below and in the manuscripts enclosed in the Appendix to this proposal. In brief, a single intra-arterial bolus of VEGF recombinant human protein, delivered percutaneously to the ischemic limb via an intravascular catheter, resulted in angiographic, hemodynamic, physiologic, and histologic evidence of augmented collateral artery development. Subsequently, similar results were achieved using an angioplasty catheter with a hydrogel-coated balloon to deliver 400 micrograms of a plasmid containing the cDNA for VEGF to the internal iliac artery in the same animal model. Accordingly, we propose to administer arterial gene (VEGF) therapy to patients with rest pain and/or ischemic leg ulcers considered not to be candidates for conventional revascularization techniques. The dose of plasmid to be administered will be progressively escalated beginning with 500 micrograms for the first four patients, 1000 micrograms for the following six patients, 2000 micrograms for the third group of six patients, and 400 micrograms for the fourth group of six patients.

Topical hydrogen peroxide treatment of ischemic ulcers in the guinea pig: Blood recruitment in multiple skin sites

Background: Oxygen deficit is a key factor associated with delayed healing of ischemic wounds in human beings. Topical oxygen-releasing compounds such as hydrogen peroxide or tetrachlorodecaoxide have been suggested as therapy for ischemic tissue. Objective: Our purpose was to monitor the effect of hydrogen peroxide cream on the process of ischemic ulcer healing with a model for ischemic ulcers in the guinea pig. Methods: Measurement of vascular perfusion with a laser Doppler velocimeter and gross observations of percentage of nonnecrotic wound surface were made on ischemic wounds in guinea pigs after treatment with either a hydrogen peroxide cream or a placebo cream. Results: Visual evaluations of the percentage of nonnecrotic wound surface showed no statistically significant differences among the treatments. In contrast, vascular perfusion measurements resulted in statistically significant differences. Blood flow was significantly higher up to day 15 in ulcers treated with 2% hydrogen peroxide cream than in those treated with placebo cream. Vascular perfusion was significantly higher in ulcers treated with 3.5% hydrogen peroxide cream than in ulcers treated with either 1.5% hydrogen peroxide cream or placebo. Adjacent control sites in guinea pigs whose ulcers were treated with hydrogen peroxide cream showed increased vascular perfusion compared with corresponding sites in animals whose ulcers were treated with placebo. Even distant flank control sites of ulcers treated with 3.5% hydrogen peroxide cream showed increased vascular perfusion. Conclusion: Treatment of ischemia-induced ulcers with hydrogen peroxide cream enhanced cutaneous blood recruitment not only to ulcers and adjacent sites, but also to distant sites.

Epidural Spinal Electrical Stimulation in Peripheral Vascular Disease

Epidural spinal electrical stimulation (ESES) has been valuable in the control of pain arising from peripheral vascular disease. Thirty-two of 34 patients experience some relief of pain and 12 of 24 patients showed healing of ischemic ulcers. This technique may prove to be useful in preventing or delaying amputation of ischemic limbs. A prospective randomized study has been undertaken to assess whether this form of electrical stimulation can save limbs.

Prostacyclin for ischemic ulcers in peripheral arterial disease. A random assignment, placebo controlled study

A 72 h infusion of prostacyclin or placebo was given into femoral artery as a treatment for ischemic ulcers in 30 patients with peripheral arterial disease. Patients were well matched for age, sex, type and localization of disease, rest pain, number and area of ulcers, calf blood flow and previous sympathectomies. They had no diabetes mellitus, gangrene or marked aorto-iliac involvement. Six weeks after the infusion there was a significant difference in ulcer area between the two groups /p< 0.02, t unpaired test/: mean ulcer area decreased /p< 0.02, t paired test/ in the prostacyclin-treated group, but not in the placebo group /p >0.05, t paired test/. Thus, intra-arterial infusion of prostacyclin promotes healing of ischemic ulcers in non-diabetic patients with peripheral arterial disease without gangrene.

Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease: Results of a prospective randomized, double-blind, multicenter clinical trial

Most previous reports suggesting beneficial effects of prostaglandin E1 (PGE1) have been retrospective and uncontrolled. Therefore, this study was undertaken to assess the efficacy of PGE1 in the treatment of ischemic ulcers in patients with peripheral vascular occlusive disease (PVOD). One hundred twenty patients with one to three ischemic ulcers not healing for 3 weeks with standard care were randomized to receive either PGE1 (20 ng/kg/min) or a placebo for 72 hours through a central venous catheter. Ulcers were measured and photographed, and the rest pain was evaluated before and after infusion and at 1- and 2-month follow-up intervals. Fifty-seven patients with 95 ulcers received PGE1. Seventeen ulcers healed (18%); 22 ulcers decreased in size (23%); 37 ulcers remained unchanged or increased in size (39%); five new ulcers developed during the study (5%); and 14 ulcers had inadequate follow-up (15%). Sixty-three patients with 115 ulcers received a placebo. Nineteen ulcers healed (16%); 38 ulcers decreased in size (33%); 45 ulcers remained unchanged or increased in size (39%); three new ulcers developed during the study (3%); and 10 ulcers had inadequate follow-up (9%). None of the above differences between the drug-treated group and the placebo-treated group was statistically significant. This study did not demonstrate efficacy for intravenously administered PGE1 in the healing of ischemic ulcers in patients with PVOD.

A controlled study showing significant short term effect of prostaglandin e l in healing of ischaemic ulcers of the lower limb in man

The effect on healing of ischaemic leg ulcers was tested in a double blind study in twenty-two patients given prostaglandin E 1 intravenously. Ulcer shapes were determined regularly by stereophotogrammetry. A significant healing effect was found during the first weeks after prostaglandin E 1 but not after placebo. After two months no significant difference was noted in ulcer size between the two groups which both had a wide range of ulcer size and type. In subjects receiving placebo 40 percent of the ulcers diminished. It is concluded that controlled studies are necessary because of the large variability in the development of ischaemic ulcers. Furthermore prostaglandin El must probably be given in higher dose and/or for longer time and/or more frequently than in the present study in order to show definite benefit over placebo.

A randomized, placebo controlled trial of prostacyclin (PGI 2) in peripheral arterial disease

Observational studies suggest that short term infusion of prostacyclin (PGI 2) may be of rapid and prolonged benefit in peripheral arterial disease. 10 patients with peripheral arterial disease received 72 hour intravenous infusions of PGI 2 and saline alone. The administration was randomized and single blind and 7 days separated the infusions. Calf muscle blood flow did not alter during PGI 2 or control infusions. Reactive hyperaemia improved slightly after PGI 2 but not significantly more so than after the control infusion. Leg pain improved during both infusions, but more so during PGI 2 infusion. Systolic pressure in the cubital, posterior tibial and dorsal pedal arteries was unaltered by PGI 2 infusion. Both the inhibition of spontaneous platelet aggregability and the aggregation response to ADP had returned to baseline 72 hours after PGI 2, although platelet adhesion remained impaired. Coagulation, fibrinolysis and apparent viscosity were unaltered by PGI 2 infusion. Healing of ischaemic ulcers was not observed within 7 days of either infusion. However, within 8 weeks, 6 patients had undergone ulcer healing and 3 had progressed to amputation.

The effect of intravenous prostacyclin on resting pains and healing of ischaemic ulcers in peripheral artery disease

Prostacyclin (PGI 2) was given intravenously in doses of 1 to 5 ng/kg/min to eight consecutive patients with end stage peripheral arteriosclerosis and ischaemic ulcers. Seven patients had intense ischaemic pains. Complete or partial healing of ulcers were seen in six cases (complete in three). In those whose ulcers healed (complete or partially) relief of ulcer pain was remarkable. Acute studies of the effect of prostacyclin on skin temperature of ischaemic areas showed no correlation with clinical effects. Seven patients had more or less pronounced subjective side effects, most often flushing, nausea, headache and uneasiness. As we previously have seen equally good healing and pain relieving effects by the administration of prostaglandin E 1 without these side effects the latter compound is so far preferred in the treatment of severe peripheral artery disease. Controlled studies of the effect are needed.

Successful Treatment of Raynaud's Syndrome with Prostacyclin

There is evidence to suggest that platelet activation occurs in Raynaud's syndrome. We evaluated the effect of prostacyclin (PGI2) a potent antiplatelet and vasodilator agent in 5 female patients with Raynaud's syndrome. Outpatient visits were made at weekly intervals for 4 weeks. At the first visit buffer solution (Wellcome Laboratories) was infused intravenously for 5 hrs, thereafter three five hr infusions of PGI2 at a peak dose of 10 ng/Kg/min were given. Six weeks after the infusions patients were reviewed. Symptomatic improvement, including healing of ischaemic ulcers, occurred in 4 out of 5 patients. Thermography confirmed an increase in hand temperature after PCI2. Subjective and objective improvement has persisted for at least 6 weeks after the last treatment.

Prostacyclin therapy in peripheral arterial disease.

Abstract Thirty patients with advanced peripheral arterial disease of lower extremities were treated with a single or multiple courses of prostacyclin /2–10 ng/kg/min intraarterially or intravenously for about 72 hours/. The observation period ranged from 2 to 15 months. The sustained improvement, as evidenced by alleviation of rest pain and healing of ischemic ulcers, occurred in 40 per cent of patients. Severity of local symptoms and arteriographic localization of the lesions are of essential prognostic value for the efficacy of prostacyclin therapy, however, they do not comprise all of the factors which determine responsiveness to prostacyclin. Platelet activity as assessed by several in vitro and in vivo methods was suppressed during the therapy, and returned to normal shortly after termination of the infusions. These short-lasting anti-platelet as well as vasodilatory effects of prostacyclin are in contrast with persistance of the clinical improvement which occurred in a substantial number of patients.

Healing of ischaemic ulcers by intravenous prostaglandin E1 in a woman with thrombangitis obliterans

Abstract is not available

Failure of Dimethyl Sulfoxide in the Treatment of Scleroderma

Nineteen patients with systemic scleroderma and five with localized scleroderma were treated with topical dimethyl sulfoxide by painting and immersion techniques. Partial control was obtained by using a very low concentration (5%) on one side when involvement was symmetrical. Duration of treatment ranged from 3 to 15 months. Topical dimethyl sulfoxide did not improve the skin induration, range of motion, or Raynaud's phenomenon in the scleroderma patients. No substantial beneficial effect was noted on the healing of ischemic ulcers, and the continuous application of dimethyl sulfoxide did not prevent new ulceratins from developing. Relief of pain was noted in ten of 16 patients, probably due to the local analgesic effect of dimethyl sulfoxide.