Oxygen Therapy to Enhance Wound Healing After Revascularization.

Oxygen is one of the important factors for wound healing and infection control. The revascularization procedure is amended to correct the tissue hypoxia problem by increasing the blood flow to obtain an adequate amount of oxygen. Hypoxic wounds are still the issue in the cases of unsuccessful or incomplete revascularization. The issue needs to be clarified and confirmed by proper methods for management to achieve wound healing and prevent limb loss. Oxygen therapy may benefit in the case of remaining hypoxia or wound infection in postrevascularization.

Diabetic Foot Ulcers: Contemporary Assessment And Management.

Diabetic foot ulcer disease is the combination of vasculopathy, neuropathy and infection. It is important to identify the main aetiology and to treat it for optimal ulcer healing so that limb amputation may be prevented. A literature review spanning five years (2018-2021) was performed to assess the current understanding of these aetiologies and management options for their treatment. Peripheral artery disease is prevalent in patients with diabetes. Before performing any amputations, whether minor or major, vascular supply in these patients needs to be evaluated and, if needed, improved. Diabetic neuropathy is a long-term complication of uncontrolled diabetes. Patients' education is very important with respect to selfcare and prevention of foot complications arising out of minor trauma in diabetic population. Better foot care and regular use of off-loading shoe wear can prevent neuropathic diabetic foot ulcers. Infection in diabetic patients is mostly polymicrobial and it can present as superficial or deep infections. Early diagnosis, use of broad-spectrum antibiotics, and aggressive debridement, when needed, is advocated to prevent foot amputation. Contemporary treatment armamentarium provides many options for treating diabetic foot ulcers. Nevertheless, one must exhaust all preventive strategies to avoid ulcers in the first place. Once an ulcer has developed, it should be managed aggressively with appropriate soft tissue and, if required, with bony procedures. The current narrative review was planned to explore the current understanding about the main aetiologies of diabetic foot ulcers and about the available treatment options.

The use of innovative targeted angiogenic therapies for ischemic diabetic foot ulcer repair: From nanomedicine and microRNAs toward hyperbaric oxygen therapy.

Diabetes mellitus is a metabolic disease that has a high prevalence worldwide and is characterized by chronic hyperglycemia leading to the development of vascular or nonvascular complications. It is these complications that result in huge mortality rates in patients with diabetes, especially vascular ones. This work focuses on diabetic foot ulcers (DFUs), which are one of the most common complications of type 2 diabetes mellitus (T2DM) and cause significant morbidity, mortality, and healthcare costs. The healing of DFUs is hindered by deregulation of nearly all phases of this process because of the hyperglycemic environment. Although therapies currently exist to treat a patient with DFU, they are proving inadequate. In the present work, angiogenesis is highlighted as part of the proliferative phase, which, when diminished, plays an important role in the impaired healing of DFU and other chronic wounds. Therefore, the search for new therapeutic strategies targeting angiogenesis is of great interest. In this study, we provide an overview of molecular targets with therapeutic potential and therapies that act on angiogenesis. To this end, a search of articles in PubMed and Scopus databases from 2018 to 2021 was performed to review angiogenesis as a therapeutic target for DFU. Growth factors, microRNAs, and signaling pathways were investigated as molecular targets, and negative pressure, hyperbaric oxygen therapy, and the use of nanomedicine were explored as therapies.

The burden of costs on health services by patients with neuro-ischaemic ulcers in Singapore.

The economic burden of neuro-ischaemic ulcers (NIU) is expected to increase because of rising prevalence of comorbidities in an aging population. We aim to estimate healthcare resources consumed by NIU patients, and to quantify the extent to which factors explain variation in cost-related outcomes. We analysed retrospective patient-level cohort data for NIU patients from a tertiary hospital registry in Singapore, from 2013 to 2017, using generalised linear regression models. The outcome variables were the length of stay per admission; inpatient and outpatient bill per admission; and, if they had an Emergency Department visit. Cost outcomes were reported in Singapore dollars (S$). A total of 1682 patients were included, and the mean age was 69.9 years (±13.0). An average patient incurred a length of stay of 38.7 days, 7.9 inpatient dressing sessions, an inpatient bill of S$33 096, 11.3 outpatient dressing sessions, and an outpatient bill of S$8780. Inpatient services per patient cost 73.5% higher than outpatient services. NIU patients with multiple (>3) comorbid conditions, peripheral artery disease, or chronic kidney disease incurred longer hospitalisation and higher inpatient bill. Patients with diabetes mellitus and coronary artery disease had higher odds of incurring an ED visit. Patients with coronary artery disease, hyperlipidaemia, kidney complications, or obesity incurred higher outpatient bills. NIU treatment imposes a significant economic burden, especially with inpatient services.

A Systematic Review on the Outcomes of the Fillet Flap in Treating Diabetic and Ischemic Forefoot Ulcers.

BACKGROUND: Diabetic and ischemic foot ulcers are difficult to heal, and the mastering of numerous treatment methods is imperative to achieve healing. One of these methods is the fillet toe flap used to cover specific diabetic wounds of the forefoot associated with toe osteomyelitis. Instead of amputating the infected toe, phalanges are removed while keeping the viable surrounding soft tissue. METHODS: A systematic review was performed searching electronic databases up to October 2019 to identify relevant articles reporting the outcomes of the fillet flap in forefoot ulcers of patients with diabetes or peripheral artery disease. All study designs were included. The healing rate was the primary outcome. Secondary outcomes were the time to heal, ulcer recurrence, and complication rates of such infection, partial necrosis, and total necrosis. RESULTS: The 8 studies that met the inclusion criteria were all case series or case reports, with a total of 28 patients including 29 flaps. The mean healing rate was 92.8% (2/29); in both cases, total necrosis was due to infection (7.2%). No ulcer recurrence or partial necrosis was noted. CONCLUSIONS: Though having limited indications, the fillet flap illustrates the full optimization of the available resources for wound coverage. The consistent presence of an axial vessel makes the fillet flap a reliable local flap to be used in specific circumstances where the loss of a toe is unavoidable. Further research is needed with large prospective controlled trials to support the findings of the review.

HISTORIQUE: Les ulcères diabétiques et ischémiques du pied sont difficiles à guérir. Il est impératif de maîtriser de multiples méthodes thérapeutiques pour qu'ils cicatrisent. Le lambeau en filet de l'orteil, utilisé pour couvrir des plaies diabétiques précises de l'avant-pied associées à l'ostéomyélite de l'orteil, fait partie de ces méthodes. Au lieu d'amputer l'orteil infecté, les phalanges sont retirées, mais les tissus mous viables avoisinants sont conservés. MÉTHODOLOGIE: Les chercheurs ont effectué une analyse systématique des bases de données électroniques jusqu'en octobre 2019 pour extraire les articles appropriés sur les résultats des lambeaux en filet pour les ulcères de l'avant-pied des patients atteints du diabète ou d'une maladie artérielle périphérique. Toutes les méthodologies d'étude étaient incluses. Le taux de guérison était le résultat clinique primaire, et le temps de guérison, la récurrence des ulcères, le taux de complications de cette infection et, la nécrose partielle et totale, les résultats cliniques secondaires. RÉSULTATS: Les huit études qui respectaient les critères d'inclusion étaient toutes des séries ou des rapports de cas, pour un total de 28 patients qui avaient reçu 29 lambeaux. Le taux de guérison moyen s'élevait à 92,8 % (deux sur 29). Dans les deux cas, la nécrose totale était causée par l'infection (7,2 %). Aucune récurrence d'ulcère ni nécrose partielle n'a été observée. CONCLUSIONS: Même si les indications sont limitées, le lambeau en filet fait appel à l'optimisation totale des ressources disponibles pour couvrir les plaies. Grâce à la présence continue d'un vaisseau axial, le lambeau en filet est un lambeau local fiable à utiliser dans des situations particulières, lorsqu'il est impossible d'éviter de perdre un orteil. Il faudra réaliser la présence d'importants essais prospectifs contrôlés pour soutenir les observations de l'analyse.

Outcome after Hybrid Outflow Interventions for Chronic Limb-threatening Ischemia.

BACKGROUND AND AIMS: Because chronic limb-threatening ischemia (CLTI) is often associated with multilevel arterial disease, it usually requires revascularization at different sites of the limb vasculature. We aim to assess the outcome of the hybrid interventions including open surgical revascularization together with outflow segment percutaneous transluminal angioplasty (PTA) in patients with chronic limb-threatening ischemia. MATERIAL AND METHODS: This study included all hybrid outflow-PTA interventions (n = 80) on patients suffering from CLTI performed in Helsinki University Hospital between 2003 and 2015. Follow-up ended on 31 December 2019. Patient data were prospectively collected into our vascular registry and scrutinized retrospectively. Thirty-one patients (39%) suffered from rest pain (Rutherford category IV) and 49 patients (61%) had ischemic ulcers (Rutherford category V-VI). The most common open surgical procedure was femoral endarterectomy (n = 63, 79%) and the most common endovascular procedure was superficial femoral artery percutaneous transluminal angioplasty (n = 65, 81%). Mean follow-up time was 56 months (range: 4 days-183 months). RESULTS: Limb salvage was at 30 days-92%, at 1 year-91%, and at 5 and 10 years-86%. Survival and amputation-free survival were at 30 days-93% and 86%, at 1 year-80% and 76%, at 5 years-51% and 48%, and at 10 years-21% and 21%. Wound healing at 3, 6, and 12 months was 48%, 71%, and 87%. Freedom from target lesion revascularization was at 30 days-97%, at 1 year-88%, at 5 years-72%, and at 10 years-66%. CONCLUSION: Hybrid outflow revascularization is an important tool in the vascular surgeon's armamentarium for treatment of patients with multilevel arterial disease causing chronic limb-threatening ischemia.

Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients With Peripheral Artery Disease (STOP-PAD) Trial: Six-Month Results.

Purpose: To present the 6-month results of the Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Peripheral Artery Disease (STOP-PAD) trial. The trial was an attempt to alter the course of chronic limb-threatening ischemia (CLTI) with a biological agent vs placebo after successful arterial revascularization at or below the knee. Materials and Methods: The multicenter, randomized, double-blinded, placebo-controlled, phase 2B STOP-PAD trial (ClinicalTrials.gov identifier NCT02544204) randomized 109 patients (mean age 71 years; 68 men) with Rutherford category 5 or 6 CLTI and evidence of persistent impaired forefoot perfusion following recent successful revascularization to 8- (n=34) or 16-mg (n=36) intramuscular injections of a non-viral DNA plasmid-based treatment vs placebo (n=34). The primary efficacy outcome was the 6-month wound healing score evaluated by an independent wound core laboratory; the primary safety endpoint was major adverse limb events (MALE), a composite of major amputation plus clinically-driven target lesion revascularization at 6 months. Results: Only one-third of the patients had complete wound healing at 6 months in the placebo (31%), 8-mg injection (33%), and 16-mg injection (33%) groups. In addition, the observed increase in the toe-brachial index from baseline to 6 months was statistically significant in each group; however, this did not result in lower rates of MALE at 6 months (24% in the placebo, 29% in the 8-mg injection, and 11% in the 16-mg injection groups). During the 6-month period, 6 patients (6%) died, and 24 patients (23%) had an amputation [only 4 (4%) major]. Conclusion: Combining revascularization and biological therapy failed to improve outcomes in CLTI at 6 months. STOP-PAD has provided insights for future trials to evaluate biological therapy.

Substance P accelerates wound repair by promoting neovascularization and preventing inflammation in an ischemia mouse model.

AIMS: Arterial insufficiency ulcers are frequent complications of peripheral artery disease and infection or long-term neglect of the ulcer can eventually lead to amputation of the affected body part. An ischemic environment, caused by interrupted blood flow, affects the supply of nutrients and elongates the inflammation period, inducing tissue degeneration. Thus, the modulation of neovascularization and inflammation could be an ideal therapeutic strategy for ischemic wound healing. This study aimed to elucidate whether systemically administered substance P (SP) could promote ischemic wound repair in mice by restoring blood perfusion and suppressing inflammation. MAIN METHODS: The effects of SP were assessed by analyzing wound size, blood flow, epidermal and dermal layer regeneration, vessel formation, and the inflammatory cytokine profiles in a hind-limb ischemia non-clinical mouse model. KEY FINDINGS: SP-treated mice exhibited dramatically rapid wound healing and restoration of blood flow within the ischemic zone, compared with saline-treated mice. Notably, SP-treated mice showed enhanced pericyte-covered vasculature compared to saline-treated mice. Moreover, anti-inflammatory effects were detected in mice in the SP-treated group, including suppression of inflammation-mediated spleen enlargement, reduction of tumor necrosis factor-alpha, and promotion of circulatory interleukin-10 levels. SIGNIFICANCE: These results suggest that SP could be a possible therapeutic candidate for patients with peripheral artery disease, including those with ischemic ulcers.

Endovascular Distal Plantar Vein Arterialization in Dialysis Patients With No-Option Critical Limb Ischemia and Posterior Tibial Artery Occlusion: A Technique for Limb Salvage in a Challenging Patient Subset.

PURPOSE: To detail a percutaneous technique for distal plantar venous arterialization in diabetic, end-stage renal disease (ESRD) patients with no-option critical limb ischemia (CLI). TECHNIQUE: After failure of standard intraluminal recanalization attempts, a subintimal approach through the posterior tibial artery (PTA) is begun using a 0.014-inch, 190- or 300-cm-long guidewire supported by a 2-×20-mm, low-profile balloon catheter positioned a short distance behind the narrow "U-shaped" loop in the guidewire. Typically, heavy calcification in the distal tortuous segment of the PTA prevents reentry to the arterial true lumen; however, an entry in the distal lateral or medial plantar vein from a subintimal channel in the plantar artery can be intentionally pursued as a bailout technique, pointing the tip of the guidewire opposite to the arterial wall calcifications. Venous access is confirmed by contrast injection through the balloon catheter. Once the guidewire is advanced in the distal lateral or medial plantar vein and a plantar arteriovenous fistula (AVF) has been created, the AV anastomosis and the occluded PTA segment are dilated with 0.014-inch balloon catheters. The technique has been attempted in 9 consecutive diabetic, ESRD patients (mean age 69 years; 5 men) with no-option CLI; an AVF was created between the PTA and plantar vein in 7 patients. The mean TcPO2 at 1 month was 30±17 mm Hg (vs 7.3±2.2 at baseline). Six ulcers healed over an average of 21±4 weeks. Three of the 9 patients had below-knee amputations. CONCLUSION: Although further investigations are required, distal plantar venous arterialization may represent a promising technique to improve recanalization rates and limb salvage in diabetic ESRD patients with extremely calcified PTA occlusions.

Successful Treatment of Burn-Induced Digital Ischemic Ulcer with Stellate Ganglion Block: Case Report

The Stellate ganglion block (SGB) could be used to treat sympathetic dependent circulatory insufficiency. We report a 36-year-old female patient with burn-induced refractory ischemic ulcer in distal phalanges. The patient admitted in department of plastic surgery for second degree burn wound in the right second through fifth fingertips. Continuous dressing treatment was conducted. However digital burn wounds were not healed but seems to be refractory. The upper extremity angiography revealed decreased perfusion and the fingertip wounds were diagnosed as ischemic ulcer. Despite of botulinum toxin injection into the perineural tissue and aspirin prescription, burn wounds showed ulcerative necrotic change. The SGBs were performed twice a week for 3 weeks to restore vasoconstriction of the upper extremity arteries. The follow-up angiography showed significant improvement of fingertip perfusion. Consequently, wounds were completely healed. In conclusion, SGB could be a rational option to overcome burn-induced digital ischemia refractory to other medical therapy.

Ischemic Ulcer Pain Is Both Nociceptive and Neuropathic Pain Based on a Discriminant Function Analysis Using the McGill Pain Questionnaire.

The McGill Pain Questionnaire (MPQ) is composed of 78 words reflecting the mechanisms underlying chronic pain conditions. Ischemic ulcer pain is generally regarded as a nociceptive and inflammatory pain condition. However, it is sometimes refractory to nonsteroidal anti-inflammatory drug (NSAID) and opioid treatment. We categorized ischemic pain into nociceptive/inflammatory pain (NocP) or neuropathic pain (NeP), on the basis of patients' descriptions of their pain using the MPQ. We investigated pain characteristics of 365 patients with NeP and 124 with NocP using the 78 words of the MPQ. We thereby developed a discriminant function, which efficiently discriminates descriptions of NocP from those of NeP. We applied this function to 18 ischemic pain patients (before and after peripheral revascularization) and categorized their pain as either NocP or NeP. The discriminant probability of the function was 72.8% (P <.05), suggesting relatively accurate discrimination of NocP from NeP. Among the 78 words, only "annoying" was not utilized for the function. On the basis of this function, 9 of the 18 ischemic pain patients' complaints were classified as NeP. Ten patients received revascularization and after revascularization, 7 of 10 patients' complaints were still NeP. Our results suggest that ischemic ulcer pain should be regarded as a mixed pain condition composed of both NocP and NeP and that it might be treated with medications for NeP (e.g., pregabalin, duloxetine) in combination with NSAIDs and opioids.

Clinical Evaluation of Beraprost Sodium (TRK-100, PGI2 derivatives) in the Treatment of Chronic Occlusive Arterial Disease

The main object of treatment in chronic occlusive arterial disease is to increase blood flow for ischemic limb. In case of severe symptoms and signs such as rest pain, ischemic ulcer and gangrene with poor angiographic distal run-off, conservative medical treatment is recommended. Beraprost sodium(TRK-100) is the oral preparation of a prostaglandin I2,that has known to increase blood flow, prevent secondary thrombi formation, suppress platelet aggregation,increase oxygen perfusion pressure, increase deformability of erythrocyte, and protect endothelial cell from ischemia and inflammation. From September 1995 to January 1997, 23 patients among 42 patients with severe ischemic ulcer and poor angiographic distal run-off underwent Beraprost oral treatment in the Department of Surgery, Ulsan-chungang and Yeungnam University Hospital: Buerger's disease(TAO) in 14 and arteriosclerosis obliterans(ASO) in 9 cases. Daily dose was 120microgram(6 tablets #3) and medicated for consecutive 6 weeks. To detect the changes of symptoms, signs & ischemic ulcer size and occurrence of side reactions, inquiries, photography and laboratory tests were checked at prior to medication and 2, 4 & 6 weeks after medication. The results were as follows. There were 21 men and 2 women, ranging in age from 23 to 77 years old with mean of 44 years old and in body weight from 43 to 75kg with mean of 61kg. Forteen cases(60.9%) were improved but 2 cases(6.2%) were aggravated on rest pain and coldness. Improval rate on ischemic ulcer & granulation size was 70%(16 cases) and 82.6%(19 cases) respectively. There noted infection in 7 cases(30.4%). Overall improval rates were 70.0%(16 cases), general safety rates were 95.7%(22 cases), and usefulness of the drug was shown in 16 cases(70.0%). One case(3.2%) of indigestion was reported as side reaction. There noted no significant hematologic, urinary or biochemical abnormalities. In conclusion, Beraprost treatment for severe ischemic limb had a beneficial effect on relieving pain and ulcer healing and proved safety in its use.