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Diabetic foot disease (DFD) is a common and serious complication for diabetes and is characterized with impaired angiogenesis. In addition to the well-defined role of vascular endothelial growth factor (VEGF) -A and its defect in the pathogenesis of DFD, another VEGF family member, placental growth factor (PlGF), was also recently found to alter expression pattern in the DFD patients with undetermined mechanisms. This question was thus addressed in the current study. We detected attenuated PlGF upregulation in a mouse DFD model. In addition, the major cell types at the wound to express the unique PlGF receptor, VEGF receptor 1 (VEGFR1), were macrophages and endothelial cells. To assess how PlGF regulates DFD-associated angiogenesis, we injected recombinant PlGF and depleted VEGF1R specifically in macrophages by local injection of an adeno-associated virus (AAV) carrying siRNA for VEGFR1 under a macrophage-specific CD68 promoter. We found that the angiogenesis and recovery of the DFD were both improved by PlGF injection. The PlGF-induced improvement in angiogenesis and the recovery of skin injury were largely attenuated by macrophage-specific depletion of VEGF1R, likely resulting from reduced macrophage number and reduced M2 polarization. Together, our data suggest that reduced PlGF compromises angiogenesis in DFD at least partially through macrophages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhu, Qian, Jiang, Yang, Duan and Xiao.)

Background: Computed tomography angiography (CTA) has become a widely used imaging modality in vascular surgery. The first web arterial branches of the foot are significant for surgical planning of the donor site for thumb reconstruction., Methods: We retrospectively analysed 30 thumb reconstructions with free second toe/great toe wrap-around flap transfer, performed between January 2016 and January 2019. The mean patient age was 30 (2-45) years. The causes of hand injury were: 20 machine strangulation injuries, 6 heavy weight smash injuries, and 4 crush injuries. Patients with iodine allergy were excluded preoperatively. We evaluated the effectiveness of CTA in visualizing first web arterial branches and compared it with intraoperative findings. Surgical plan for donor sites was prepared based on the classification of the first web arterial branches., Results: The arterial branches of the patients were classified based on CTA findings as follows: (1) fork type: 24 patients (48 feet, 80%); (2) main trunk type: four patients (8 feet, 13.33%); and (3) side branch type: one patient (2 feet, 3.33%). One case of poor vascular continuity and artifacts in CTA underwent thumb reconstruction with free great toe wrap-around flap transfer. Tissue survival was achieved in all reconstructed thumbs. During the follow-up period (average, 12 months), all reconstructed thumbs exhibited good outcomes. The donor sites on the feet of all patients recovered well., Conclusion: CTA allows preoperative assessment of blood supply and planning of donor site. Our results can serve as a reference for surgical planning of the donor site while reducing the occurrence of adverse events., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: To emerge hypoperfusion of lower limbs in patients with critical limb ischemia (CLI) using Intravoxel Incoherent Motion microperfusion magnetic resonance imaging (IVIM-MRI). Moreover to examine the ability of IVIM-MRI to differentiate patients with severe peripheral arterial disease (PAD) from normal subjects and evaluate the percutaneous transluminal angioplasty (PTA) results in patients with CLI., Methods: Eight patients who presented with CLI and six healthy volunteers were examined. The patients underwent IVIM-MRI of lower extremity before and following PTA. The imaging protocol included sagittal diffusion-weighted (DW) sequences. DW images were analyzed and color parametric maps of the micro-circulation of blood inside the capillary network (D*) were constructed. The studies were evaluated by two observers to define interobserver reproducibility., Results: Technical success was achieved in all patients (8/8). The mean ankle-brachial index increased from 0.35 ± 0.2 to 0.76 ± 0.25 ( p < 0.05). Successful revascularization improved IVIM microperfusion. Mean D* increased from 279.88 ± 13.47 10 -5 mm 2 /s to 331.51 ± 31 10 -5 mm 2 /s, following PTA, p < 0.05. Moreover, PAD patients presented lower D* values as compared to healthy individuals (279.88 ± 13.47 10 -5 mm 2 /s vs 332.47 ± 22.95 10 -5 mm 2 /s, p < 0.05, respectively). Good interobserver agreement was obtained with an ICC = 0.84 (95% CI 0.64-0.93)., Conclusions: IVIM-MRI can detect differences in microperfusion between patients with PAD and healthy individuals. Moreover, significant restitution of IVIM microperfusion is found following successful PTA., Advances in Knowledge: IVIM-MRI is a safe, reproducible and effective modality for evaluation of lower limb hypoperfusion in patients with PAD. It seems also to be a helpful tool to detect changes of tissue perfusion in patients with CLI following revascularization.

Background: In the setting of Peripheral Arterial Disease (PAD), pedal arch interrogation by ultrasound has not been well described. Patients with noncompressible vessels and/or open wounds of the foot may preclude the use of ankle-brachial indices, toe pressure measurements, or TcPO2, respectively. We propose that pedal artery interrogations with Pedal Acceleration Time (PAT) can be a predictor for limb salvage in patients with Chronic Limb-Threatening Ischemia (CLTI)., Methods: A retrospective review of a prospectively kept database was performed from 2018 to 2019. Patients with pending amputation due to severe infection (WIFI infection class 2 and 3) were excluded from the study. We identified 73 limbs with CLTI that fit the inclusion criteria. Data included WIFI classification, age, gender, cardiovascular risk factors, PAT, ABI, and TBI when reliable, were collected. PAT measurements were categorized into 4 classifications; 1 (40-120 msec), 2 (121-180 msec), 3 (181-224 msec), and 4 (Greater than 225 msec). Statistical analyses were performed., Results: Seventy-three limbs with CLTI were included in our study. All patients underwent arterial revascularization with either percutaneous technique or arterial bypass. Limb salvage was achieved in 59 (81%) of the 73 limbs. All 59 limbs had a 2-classification improvement in their PAT following interventions. A total of 14 (19%) limbs without improvement in their PAT underwent above ankle level amputations. An improvement in PAT classes to class 1 or 2 is associated with limb salvage., Conclusions: Patients with noncompressible ankle pressures or nonobtainable toe pressures poses a challenge in the complete assessment of WIFI classification. Our group has shown that PAT can be used in the scoring system for severity of ischemia in conjunction with current WIFI classification. Our data suggests that limb salvage correlates with post procedure PAT in category 1 and 2. Therefore we propose that PAT be added as part of the WIFI classification., (Copyright © 2021. Published by Elsevier Inc.)

Summary: Adequate arterial inflow is mandatory for a successful free tissue transfer. Maximizing this inflow appears to be especially important during distal lower extremity reconstruction, where perfusion pressures can be significantly lower than in the trunk or head and neck. In the current study, the authors used color and pulsed-wave Doppler ultrasonography to analyze blood flow volumes in the foot in accordance with the ankle position. Twenty feet of 10 healthy subjects were included in the analyses. All subjects were examined by Doppler ultrasonography at three different ankle angles (dorsiflexion at 90 degrees, relaxed position, and complete plantar flexion). The average flow volumes of the dorsalis pedis artery varied dramatically at the different ankle positions, as follows: dorsiflexion, 19.81 ± 3.88 ml/minute; relaxed position, 11.71 ± 4.72 ml/minute; and plantar flexion, 3.47 ± 1.41 ml/minute. The average flow volume of the posterior tibial artery also varied dramatically at these different ankle positions: dorsiflexion, 9.08 ± 8.25 ml/minute; relaxed position, 14.78 ± 2.45 ml/minute; and plantar flexion, 19.03 ± 5.03 ml/minute. The ankle position dramatically affects the flow velocity in the anterior and posterior tibial vessels, which is an important consideration when performing free tissue transfer reconstruction of the foot. Ankle dorsiflexion would be recommended when using the anterior tibial artery as a recipient vessel, whereas plantar flexion of the ankle would be advised when the posterior tibial artery is used as a recipient vessel., (Copyright © 2021 by the American Society of Plastic Surgeons.)

There is a deficiency in publications on the topic of midfoot cavus. The limited research available does not have a standard definition for the diagnosis of this deformity and lacks a reliable algorithm for its surgical management. The authors performed an extensive review of the literature that found a majority of patients are satisfied with the Cole osteotomy and the dorsiflexory first metatarsal osteotomy for treatment of this condition. High patient satisfaction has been observed with lateralizing calcaneal osteotomies in the setting of midfoot cavus with a secondary rigid rearfoot deformity. Further research on this topic is encouraged., Competing Interests: Disclosure No authors have any commercial or financial conflicts of interest or funding of any kind., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Rationale: Degloving foot injuries are challenging to treat and associated with life-long sequelae for patients. An appropriate debridement of ischemic soft tissues with maximal preservation of glabrous skin is key during the reconstruction of these injuries. Indocyanine green (ICG) fluorescence angiography is an established technique for the intraoperative evaluation of tissue perfusion., Patient Concerns: Two patients sustained complex foot injuries in traffic accidents, including multiple fracture dislocations and extensive degloving of the plantar skin., Diagnosis: Clinical inspection revealed significant degloving of the glabrous skin in both patients., Interventions: After fracture fixation, ICG fluorescence angiography-assisted debridement with immediate latissimus dorsi free flap reconstruction was performed., Outcomes: In both cases, this technique allowed a precise debridement with maximal preservation of the glabrous skin. The healing of the remaining glabrous skin was uneventful and the 6-month follow-up was characterized by stable soft tissues and satisfying ambulation., Lessons: ICG fluorescence angiography is a safe, user-friendly, and quick procedure with minimal risks, expanding the armamentarium of the reconstructive surgeon. It is highly useful for the debridement of extensive plantar degloving injuries and may also help to minimize the number of procedures and the risk of infection., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Arterial vascularization is intimately related to the peroneal tendon ruptures. Our purpose is to describe the vascular anatomy of peroneal tendons and assess differences in the vascularization patterns between peroneus brevis tendon (PBT) and peroneus longus tendon (PLT)., Methods: Anatomical study of 22 cadaveric lower extremities. We exposed tendons' vascularization by injecting latex. To systematize the vascular description, we considered four anatomical regions in the PBT and six in the PLT., Results: Vascularization was supplied by the peroneal, anterior tibial and lateral plantar arteries and from the deep plantar arch through the vincula connecting the tendons. No avascular areas were found in the PLT. 22.7% of specimens had avascular areas in the PBT. Two visual vascularization patterns were found (arcuate and weblike). Increasing age and a web-like vascularization were associated with a lower number of blood vessels at the tendons' post malleolus area., Conclusion: Peroneal tendons are well vascularized throughout their course, running through a common vincula, with vascularization provided by various arteries. Avascular areas were observed in the PBT, but none at the PLT., (Copyright © 2020 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.)

Objective: Two dimensional (2D) perfusion angiography is a method that provides quantitative foot perfusion information from standard digital subtraction angiography acquisitions. The aim of this study was to test the reliability of this method in patients with chronic limb threatening ischaemia (CLTI) by investigating repeatability, and intra-observer and interobserver agreement., Methods: Twenty patients with CLTI and a below the knee endovascular revascularisation were included in a prospective clinical study. Prior to treatment two perfusion angiography runs were acquired with a five minute interval without performing an intervention. In these recordings, regions of interest were selected and time density curves and perfusion parameters were determined. To investigate intra-observer agreement one observer performed five measurements on the same acquisition for each patient. To investigate interobserver agreement three observers performed measurements on the same acquisition for each patient. Results were presented in Bland-Altman plots and as the intraclass correlation coefficient per parameter., Results: Two patients were excluded from repeatability analyses because of major motion artefacts. Repeatability analyses of the 18 remaining patients showed excellent correlation for every parameter (> .96). Intra-observer and interobserver agreement for all 20 patients were excellent for all parameters (1.00)., Conclusion: Repeatability and intra-observer and interobserver agreement of 2D perfusion angiography in patients with CLTI were found to be excellent. It is therefore a reliable tool when used according to the standardised methods described in this study., (Copyright © 2021 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: The purpose of this article was to review our clinical experience with COVID-19 patients observed in the Cardiovascular Division of Pompidou Hospital (University of Paris, France) and the Department of Neurology of the Eastern Piedmont University (Novara, Italy), related to the impact on the cardiovascular, hematological, and neurologic systems and sense organs., Patients and Methods: We sought to characterize cardiovascular, hematological, and neurosensory manifestations in patients with COVID-19 and variants. Special attention was given to initial signs and symptoms to facilitate early diagnosis and therapy. Indications of ECMO (extracorporeal membrane oxygenation) for cardiorespiratory support were evaluated., Results: Preliminary neurosensorial symptoms, such as anosmia and dysgeusia, are useful for diagnosis, patient isolation, and treatment. Early angiohematological acro-ischemic syndrome includes hand and foot cyanosis, Raynaud digital ischemia phenomenon, skin bullae, and dry gangrene. This was associated with neoangiogenesis, vasculitis, and vessel thrombosis related to immune dysregulation, resulting from "cytokine storm syndrome". The most dangerous complication is disseminated intravascular coagulation, with mortality risks for both children and adults., Conclusions: COVID-19 is a prothrombotic disease with unique global lethality. A strong inflammatory response to viral infection severely affects cardiovascular and neurological systems, as well as respiratory, immune, and hematological systems. Rapid identification of acro-ischemic syndrome permits the treatment of disseminated intravascular coagulation complications. Early sensorial symptoms, such as gustatory and olfactory loss, are useful for COVID-19 diagnosis. New variants of SARS-CoV-2 are emerging, principally from United Kingdom, South Africa, and Brazil. These variants seem to spread more easily and quickly, which may lead to more cases of COVID.

Background: For patients with diabetic foot ulcers, offloading is one crucial aspect of treatment and aims to redistribute pressure away from the ulcer site. In addition to offloading strategies, patients are often advised to reduce their activity levels. Consequently, patients may avoid exercise altogether. However, it has been suggested that exercise induces an increase in vasodilation and tissue blood flow, which may potentially facilitate ulcer healing. The aim of this systematic review was to determine whether exercise improves healing of diabetic foot ulcers., Review: We conducted a systematic search of MEDLINE, CINAHL and EMBASE between July 6, 2009 and July 6, 2019 using the key terms and subject headings diabetes, diabetic foot, physical activity, exercise, resistance training and wound healing. Randomised controlled trials were included in this review. Three randomised controlled trials (139 participants) were included in this systematic review. All studies incorporated a form of non-weight bearing exercise as the intervention over a 12-week period. One study conducted the intervention in a supervised setting, while two studies conducted the intervention in an unsupervised setting. Two studies found greater improvement in percentage wound size reduction in the intervention group compared with the control group, with one of these studies achieving statistically significant findings (p < 0.05). The results of the third study demonstrated statistically significant findings for total wound size reduction (p < 0.05), however results were analysed within each treatment group and not between groups., Conclusion: This systematic review found there is insufficient evidence to conclusively support non-weight bearing exercise as an intervention to improve healing of diabetic foot ulcers. Regardless, the results demonstrate some degree of wound size reduction and there were no negative consequences of the intervention for the participants. Given the potential benefits of exercise on patient health and wellbeing, non-weight bearing exercise should be encouraged as part of the management plan for treatment of diabetic foot ulcers. Further research is required to better understand the relationship between exercise and healing of diabetic foot ulcers.

Objective: Clear imaging of below knee and foot arteries is essential to plan distal reconstructions. Contrast enhanced tomographic 3D ultrasound (CEtUS) is novel and entirely safe with no exposure to ionising radiation or nephrotoxic contrast. In the present study, inter- and intra-observer agreement of CEtUS was calculated, and compared with below knee angiography., Methods: In the same week as computed tomography, magnetic resonance or catheter angiography, CEtUS was performed using intravenous 1.2 mL bolus injections of Sonovue with a maximum of 5 mL administered per patient. CEtUS was reported by a vascular scientist blinded to the angiograms reported by a consultant radiologist. Images were compared using a modified Society of Vascular Surgery (SVS) runoff score., Results: Of the 181 patients recruited with peripheral arterial disease, 20 were excluded from analysis as they withdrew consent, could not be cannulated, or their images were non-diagnostic. In the remaining 161 patients, there were 175 comparative patient images split into two groups: 81 had calf imaging and 94 had pedal imaging representing 405 and 198 imaged arteries, respectively. Weighted quadratic kappa/ICC values for intra- and inter-observer agreement were excellent (κ/ICC = 0.83 to 0.95) and had narrow confidence intervals in both groups. When comparing angiography and CEtUS, weighted quadratic κ/ICC agreement was moderate with acceptable confidence intervals in both groups (Calf κ/ICC = 0.54; Pedal κ/ICC = 0.53). Agreement decreased from popliteal to pedal vessels as diameter decreased. Agreement between CEtUS and digital subtraction angiography was best, and computed tomography angiography the weakest., Conclusion: CEtUS is a novel imaging modality with strong observer agreement that achieves clear peripheral and foot images without ionising radiation exposure or nephrotoxic X-ray contrast media. CEtUS enhances visualisation of runoff vessels, which may play a role in planning of limb salvage or targeted assessment., Competing Interests: Conflicts of interest Charles McCollum is a founder of PIUR imaging GmBH., (Copyright © 2020 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Objective: Activation of the venous muscle pumps of the leg by intermittent transdermal neuromuscular stimulation of the common peroneal nerve has been previously shown to augment venous and arterial flow in patients with leg ulcers. This study aims to establish if microcirculation in the wound bed and periwound area are augmented by the activation of a neuromuscular electrostimulation device (NMES) (Geko, Firstkind Ltd., UK)., Method: In this self-controlled, observational study, laser speckle contrast imaging was used to map and quantify microcirculatory flow in the wound bed and periwound area of patients with venous leg ulcers (VLU). Values of flow and pulsatility in these locations were compared with the NMES device, both active and inactive., Results: A total of 16 patients took part in the study. Microvascular flux increased by 27% (p=0.014) in the wound bed, and by 34% (p=0.004) in the periwound area, when the NMES device was activated. Pulsatility increased by 170% (p<0.001) in the wound bed and 173% (p<0.001) in the periwound area when the device was activated., Conclusion: Intermittent electrostimulation of the common peroneal nerve substantially increased both microcirculatory flux and pulsatility in the wound bed and in the periwound area of the VLUs of patients in this study. This provides a plausible mechanistic explanation for its reported efficacy in healing VLUs.

Background: The lower extremities of the body often suffer from impaired microcirculation, particularly in the elderly or people with underlying conditions such as diabetes. Especially for people suffering from peripheral vascular diseases, skin lesions or wearing an external fixator in one side of limbs, direct contact treatments are not suitable for them to improve microcirculation. Heating the contralateral limb has been reported to improve blood flow in the impaired limb. However, its effect on plantar microvascular responses has not been previously investigated. Thus, the aim of this study was to explore how heating by warm bath and infrared radiation affects the circulations in the contralateral foot. Twelve healthy adults participated in this study and were randomly assigned to either placing the left foot in a warm bath or exposing it to infrared radiation for 10 min intervention every other day. The skin temperature (Temp) and skin blood flow (SBF) in the second metatarsal head of the contralateral foot were measured before and after the intervention., Results: The results showed that both Temp (Bath: from 29.05 ± 3.56 °C to 31.03 ± 4.14 °C; Infrared: from 29.98 ± 3.86 °C to 31.07 ± 3.92 °C) and SBF (Bath: from 62.26 ± 48.12 PU to 97.76 ± 63.90 PU; Infrared: from 63.37 ± 39.88 PU to 85.27 ± 47.62 PU) in the contralateral foot were significantly increased after heating in both tests (p < 0.05). However, the contralateral SBF increased for 5 min after heating in warm bath test, but only for 1 min in infrared radiation test., Conclusions: The results of this study show that both heating methods are the effective at increasing contralateral Temp and SBF, but the warm bath has a stronger residual thermal effect.

Aim: To compare temperature changes following a challenge of limb elevation, in 3 forefoot angiosomes between type 2 diabetes mellitus patients with and without peripheral arterial disease (PAD)., Methods: Participans were categorized in a no PAD, mild PAD or severe PAD group. All underwent thermal imaging, then successive thermal images were taken at 1 min intervals after the lower limbs were elevated for 5 min. Thereafter, the lower limbs were lowered to the original position and imaged after 1 min. Mean temperatures of the hallux, medial and lateral forefoot were analysed by the angiosome concept., Results: Forty-two limbs were analysed. Mean resting temperatures of all angiosomes of participants with PAD were higher than those with no peripheral arterial disease. A significant difference in the mean initial temperature between the groups was found in the medial and lateral forefoot angiosomes (p=0.048, p=0.049 respectively), whilst at the hallux these temperatures were not significant (p=0.165). After limb elevation, the only significant difference was seen in the lateral foot area at 1 min (p=0.021)., Conclusions: These results confirm that patients with PAD exhibit significantly higher forefoot temperatures, according to the angiosome concept. The challenge by foot elevation did not affect the thermal pattern significantly., Competing Interests: No conflict of interest has been declared by the authors., (Thieme. All rights reserved.)

Summary: The authors present indocyanine green angiography to assess the effects of hyperbaric oxygen therapy and as a potential biomarker to predict healing of chronic wounds. They hypothesize that favorable initial response to hyperbaric oxygen therapy (improved perfusion) would be an early indicator of eventual response to the treatment (wound healing). Two groups were recruited: patients with chronic wounds and unwounded healthy controls. Inclusion criteria included adults with only one active wound of Wagner grade III diabetic foot ulcer or caused by soft-tissue radionecrosis. Patients with chronic wounds underwent 30 to 40 consecutive hyperbaric oxygen therapy sessions, once per day, 5 days per week; controls underwent two consecutive sessions. Indocyanine green angiography was performed before and after the sessions, and perfusion patterns were analyzed. Healing was determined clinically and defined as full skin epithelialization with no clinical evidence of wound drainage. Fourteen chronic-wound patients and 10 controls were enrolled. Unlike unwounded healthy volunteers, a significant increase in indocyanine green angiography perfusion was found in chronic-wound patients immediately after therapy (p < 0.03). Moreover, the authors found that 100 percent of the wounds that demonstrated improved perfusion from session 1 to session 2 went on to heal within 30 days of hyperbaric oxygen therapy completion, compared with none in the subgroup that did not demonstrate improved perfusion (p < 0.01). This study demonstrates a beneficial impact of hyperbaric oxygen therapy on perfusion in chronic wounds by ameliorating hypoxia and improving angiogenesis, and also proposes a potential role for indocyanine green angiography in early identification of those who would benefit the most from hyperbaric oxygen therapy., Clinical Question/level of Evidence: Therapeutic, IV., (Copyright © 2020 by the American Society of Plastic Surgeons.)

Purpose: Spontaneous postural sway during quiet standing has been considered a simple output error of postural control. However, as postural sway and inherent body orientation evoke compensatory activity of the plantar flexors, they might contribute to blood circulation under gravitational stress via the muscle pump. Hence, the present study employed an external support device to attenuate the plantar flexor activity in supported standing (SS), to experimentally identify its physiological impact on blood circulation., Methods: Eight healthy young subjects performed two 5-min quiet standing trials (i.e., normal standing (NS) and SS), and the beat-to-beat interval (RRI) and blood pressure (BP) were compared between trials. We confirmed that postural sway and corresponding plantar flexor activity, quantified by the anteroposterior displacement of the foot center of pressure and lower back position with respect to the wall, and by the amplitude of electromyography and mechanomyography, respectively, were attenuated in SS, while mean body orientation angle and relative position of the BP sensor were comparable to NS., Results: The 5-min averages of diastolic BP and mean arterial pressure during SS were significantly higher than during NS, while RRI and systolic BP did not change. These could be interpreted as an increase in peripheral vascular resistance; meanwhile, in NS, this effect was replaced by the muscle pump of the plantar flexors., Conclusion: The muscle contractions related to spontaneous postural sway and body orientation produce substantial physiological impact on blood circulation during quiet standing.

A growing number of skin lesions during the COVID-19 pandemic are being recognized. Acral ischemic lesions identical to chilblains are most typical in children and young adults. We report an infant girl, aged 1 month and 29 days, with a peculiar reticulated purpuric eruption on her soles, with positive immunohistochemistry for SARS-CoV-2 in the endothelia of dermal blood vessels. The patient had an excellent outcome without specific therapy., (© 2020 Wiley Periodicals LLC.)

Purpose: To report our clinical experience with IVUS-guided percutaneous deep vein arterialization (pDVA) to treat chronic critical limb ischemia (cCLI) patients with no-endovascular or surgical options approach due to creation of an arteriovenous fistula (AVF)., Materials and Methods: In a 2 years period, 14 no-option cCLI patients were treated with percutaneous deep vein arterialization (pDVA) by creating an AVF with a IVUS-guided system between posterior tibial artery and its satellite deep vein. Technical success was defined as successful AVF creation and venous perfusion of the wound site. Patients' characteristics, procedure details, mortality and wound outcomes were assessed prospectively., Results: Successful pDVA was successfully performed in all patients (mean age 82 years) without any procedural complications. Clinical improvement was achieved in all patients with resolution of rest pain, tissue formation of granulation tissue or both; only 3 major amputations were performed within the study period with a limb salvage rate of 78%. Median wound healing time was 4.8 months., Conclusion: pDVA is a safe and feasible revascularization technique alternative in no-option cCLI patients.

Objective: To clarify the role of clinical anatomy of foot and ankle perforator veins (PV) in surgical treatment of varicose vein disease., Material and Methods: Anatomy of foot and ankle PV was assessed in 50 amputated lower extremities by anatomical dissection., Results: There were 4-6 PVs at the medial surface of the foot. These veins connected medial marginal vein and vv. plantaris medialis (VPM). There were 2-3 PVs at the lateral surface of the foot. These veins connected lateral marginal vein and vv. plantaris lateralis (VPL). All PVs on the lateral surface of the foot constitute the neurovascular bundles. PVs flowing into vv. dorsalis pedis are localized on the medial surface of the medial marginal vein at the level of the ankle base. In most cases, we found an arterial branch nearby at the subfascial level. In anterior part of the plantar surface of the foot, we distinguished 4-5 small PVs (~1 mm) flowing into vv. digitales plantares through the commissural orifices of the aponeurosis. There were 6-9 vessels (~1 mm) along the fascial aponeurotic septa. These vessels connected superficial plantar venous network and plantar veins. Small arterial branch was found almost in all cases near these veins. Noteworthy is the area where the plantar veins lie on the quadratus plantae and are covered by a leaf of deep plantar fascia. This anatomy is similar to topography of posterior tibial veins., Conclusion: Foot perforator veins constitute the neurovascular bundles as a rule. Plantar vein topography and their relationship with PV confirm an existence of muscular-venous pump of the foot.

New Findings: What is the central question of this study? Does recreational cold exposure result in cold sensitivity and is this associated with endothelial dysfunction and impaired sensory thermal thresholds? What is the main finding and its importance? Previous cold exposure was correlated with cold sensitivity of the foot, which might indicate the development of a subclinical non-freezing cold injury. Endothelial function and thermal detection were not impaired in cold-sensitive individuals; therefore, further research is required to understand the pathophysiology of subclinical and clinical forms of non-freezing cold injury., Abstract: In this study, we investigated whether cold-sensitive (CS) individuals, who rewarm more slowly after a mild cold challenge, have impaired endothelial function and sensory thermal thresholds (STTs) and whether this is related to reported cold exposure. Twenty-seven participants with varying previous cold exposure undertook three tests: an STT test, i.e. determination of warm and cold STTs of the fingers and dorsal foot; an endothelial function test, i.e. measurement of cutaneous vascular conductance (CVC) during iontophoresis of ACh on the forearm, finger and foot; and a CS test, involving immersion of a foot for 2 min in water at 15°C followed by 10 min of rewarming in air at 30°C. Toe skin temperature (T sk ) measured during the CS test was used to form a CS group (<32°C before and 5 min after immersion) and an otherwise closely matched control group [T sk >32°C; n = 9 (four women) for both groups]. A moderate relationship was found between cold exposure ranking and T sk rewarming (r = 0.408, P = 0.035, n = 27) but not STT or endothelial function. The T sk and blood flow were lower in CS compared with control subjects before and after foot immersion [T sk , mean (SD): 30.3 (0.9) versus 34.8 (0.8) and 27.9 (0.8) versus 34.3 (0.8)°C, P < 0.001; and CVC: 1.08 (0.79) versus 3.82 (1.21) and 0.79 (0.52) versus 3.45 (1.07) flux mmHg -1 , n = 9, P < 0.001, respectively]. However, no physiologically significant differences were observed between groups for endothelial function or STT. A moderate correlation between previous cold exposure and toe T sk rewarming after foot immersion was observed; however, CS was not associated with impaired endothelial function or reduced thermal detection., (© 2020 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Far-infrared irradiation (FIR) is used in the medical field to improve wound healing, hemodialysis with peripheral artery occlusive disease, and osteoarthritis but seldom used in ameliorating poor lower extremity circulation. The purpose of this study was to evaluate the effect of FIR on changes in foot skin surface temperature (FSST) and autonomic nerve system (ANS) activity to evaluate its effectiveness in improving lower limb circulation., Methods: A randomized controlled study was conducted. Subjects (n = 44), all over the age of 50 years and satisfying the inclusion criteria, were randomly allocated into 2 groups. The intervention group received FIR on a lower limb for 40 minutes and the control group received no intervention. Left big toe (LBT), right big toe (RBT), left foot dorsal (LFD), right foot dorsal (RFD) surface skin temperature, autonomic nervous activity, and blood pressure were assessed., Results: The main results were skin surface temperature at the LBT increased from 30.8 ± 0.4°C to 34.8 ± 0.4°C, at RBT increased from 29.6 ± 0.4°C to 35.3 ± 0.4°C and LFD increased from 31.9 ± 0.3°C to 36.4 ± 0.4°C, RFD increased from 30.7 ± 0.3°C to 37.7 ± 0.2°C. FIR caused a significant increase of the FSST ranging in a 4°C to 7°C increase after 40 minutes irradiation (P < .001). The ANS low-frequency (LF) and high-frequency (HF) activity showed a statistically significant increase in the FIR group (P < .05) but not the LF/HF ratio., Conclusion: FIR significantly increased the FSST from between 4°C and 7°C after 40 minutes irradiation, which might improve lower extremity circulation and regulation of ANS activity.

In the last 15 years an abundance of literature has demonstrated that angiosome-targeted revascularization, either endovascular or open, can lead to better clinical results in patients with chronic limb-threatening ischemia. According to this literature, the angiosome concept should guide our treatment strategy in every chronic limb-threatening ischemia patient. However, in our daily practice, its application is often difficult or impossible. Most foot wounds spread over multiple angiosomes and, moreover, the value of an angiosome-guided revascularization approach can vary according to vascular anatomy, collateral vessel network, type of revascularization, and wound. The aim of this article is to explore values and limits of the angiosome concept, and to propose some "instructions for use" regarding its application in our daily practice.

Objective: To explore the clinical efficacy and advantages of five-in-one comprehensive limb salvage technologies for the treatment of severe diabetic foot ulcer (DFU). Approach: Clinical data for 120 patients with severe DFU treated between January 2012 and December 2017 were analyzed retrospectively. The control group (48 cases) was treated with traditional therapies, including controlling blood sugar, improving microcirculation, preserving nerve function, and dressing changes, whereas the experimental group (72 cases) was treated with traditional therapy combined with additional techniques, such as early and thorough debridement, negative pressure wound therapy, revascularization, and skin graft or flap. Ankle-brachial index (ABI), transcutaneous oxygen pressure (TcPO 2 ), wound healing rate, healing time, ulcer recurrence rate, and amputation rate were recorded. Results: Compared with the control group, the experimental group significantly improved wound healing rate (93.1% vs. 72.9%; p  < 0.01), decreased wound healing time (16.2 ± 5.4 days vs. 32.2 ± 7.8 days; p  < 0.05), reduced major limb amputation rate (1.4% vs. 10.4%, p  < 0.05), and ulcer recurrence rate (5.6% vs. 14.6%; p  < 0.05). There were no significant differences in amputation rate between experimental and control group (29.2% vs. 33.3%, p  = 0.628). After revascularization, the revascularization group showed significantly improved ABI (0.75 ± 0.21 vs. 0.35 ± 0.16, p  < 0.05) and TcPO 2 (36 ± 6 mmHg vs. 15 ± 4 mmHg, p  < 0.05). Innovation: We propose a five-in-one comprehensive treatment method, which provides a multidisciplinary cooperative model for comprehensive medical and surgical treatments for DFU. Conclusion: The five-in-one comprehensive limb salvage treatment technologies played a vital role in enhancing the healing rate of severe DFU, shortening the healing time, and reducing the rate of recurrence and major amputation, thus improving the overall quality of life.

Oscillometry is an alternative to continuous-wave Doppler (cw-Doppler) to determine peripheral artery disease (PAD) severity using the ankle-brachial index (ABI). cw-Doppler ABI differentiates systolic pressure of ATP and ADP where either one of both values in most patients is higher (high) and the other value is lower (low). In contrast, oscillometric ABI measures the strongest signal and hence misses the lower value. Both do not take pedal perfusion into consideration. Simultaneous determination of tissue microperfusion cares for pedal PAD. ABI was determined by cw-Doppler and oscillometry. Tissue optical perfusion pressure (TOPP) was taken from the first toe using photoplethysmography. 323 patients were evaluated retrospectively in 3 independent groups. group 1 (99 patients) compared TOPP and oscillometric ABI with systolic cw-Doppler-pressure and cw-Doppler ABI. In group 2 (103 patients) TOPP was compared with toe pressure (TP). In group 3 (121 symptomatic patients) TOPP and ABI at rest and after stress were compared (ultrasound examination and magnetic resonance angiography (MRA) or computer tomography angiography (CTA) as control). Bland-Altman-plot analysis presented no significant difference between oscillometric ABI and the high cw-Doppler ABI ( group 1 ). TOPP showed a difference of 26mmHg to the low cw-Doppler-pressure and none to the high cw-Doppler-pressure. In group 2 TOPP correlates to TP but presented a difference of 37 mmHg. group 3 showed weak or no correlation between ABI and walking distance. Oscillometric ABI correlates significantly to TOPP. To conclude, data after stress present a better correlation than at rest. We conclude that TOPP provides absolute values of pedal macro-/microcirculation at rest and after stress tests. NEW & NOTEWORTHY This new application of photoplethysmography investigated the microcirculation in peripheral artery disease at the level of the toe pad and determined the tissue optical perfusion pressure as the first pulsatile signal during automatic cuff deflation at the ankle. It is the first time that this method has been integrated for simultaneous routine examination in an automatic oscillometric ankle-brachial index (ABI) system. This quick and simple measurement technique provides clinical information on the microcirculation downstream the routine ABI measurement at rest and in particular after stress test.

Background: The deep plantar (D-PL) artery originates from the dorsalis pedis artery in the proximal first intermetatarsal space, an area where many procedures are performed to address deformity, traumatic injury, and infection. The potential risk of injury to the D-PL artery is concerning. The D-PL artery provides vascular contribution to the base of the first metatarsal and forms the D-PL arterial arch with the lateral plantar artery., Methods: In an effort to improve our understanding of the positional relationship of the D-PL artery to the first metatarsal, dissections were performed on 43 embalmed cadaver feet to measure the location of the D-PL artery with respect to the base of the first metatarsal. Digital images of the dissected specimens were acquired and saved for measurement using in-house software. Means, standard deviations, and 95% confidence intervals (CIs) were calculated for all of the measurement parameters., Results: We found that the origin of the D-PL artery was located at a mean ± SD of 11.5 ± 3.9 mm (95% CI, 4.5-24.7 mm) distal to the first metatarsal base and 18.6% ± 6.5% (95% CI, 8.1%-43.4%) of length in reference to the proximal base. The average interrater reliability across all of the measurements was 0.945., Conclusions: This study helps clarify the anatomical location of the D-PL artery by providing parameters to aid the surgeon when performing procedures in the proximal first intermetatarsal space. Care must be taken when performing procedures in the region to avoid unintended vascular injury to the D-PL artery.

An angiosome refers to a 3D tissue volume that is vascularized by a single artery and is a relatively new concept that is useful in vascular surgery; however, the direct relationship between arterial blood flow and micro-perfusion is still controversial. Here, we propose a diffuse speckle contrast analysis (DSCA), which is an emerging tissue perfusion monitoring modality, to investigate the correlations among low frequency oscillations (LFOs) measured from different areas on the feet of healthy subjects. We obtained reproducible results from the correlation analyses of LFOs, and their physiological implications were discussed. In order to confirm the changes in the frequency oscillations, we analyzed and compared the power spectral density changes due to heart rate variability in the electrocardiographic signal during reactive hyperemia and head-up tilt protocols.

Respecting vascular territories is crucial for flap design and viability. There are 6 angiosomes in the foot and ankle originating from the posterior tibial, anterior tibial, and peroneal arteries. Reliable perforators from the 3 major source vessels of the lower extremity are found in 5-cm intervals within intermuscular septa. Computed tomography angiography, Doppler, and infrared cameras can be used preoperatively to help identify the perforators of the lower extremity., Competing Interests: Disclosure The authors declare that they have no relevant or material financial interests that relate to the research described in this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: In the context of chronic limb-threatening ischemia, the prognostic impact of angiosome-targeted revascularization and of the status of the pedal arch are debated., Methods: This series includes 580 patients who underwent endovascular (n = 407) and surgical revascularization (n = 173) of the infrapopliteal arteries for chronic limb-threatening ischemia associated with foot ulcer or gangrene. The risk of major amputation after infrapopliteal revascularization was assessed by a competing risk approach. A subanalysis was made separately for patients who underwent endovascular or open surgical revascularization., Results: At 2 years, survival was 65.1% and leg salvage was 76.1%. Multivariable competing risk analysis showed that C-reactive protein ≥10 mg/dL, diabetes, rheumatoid arthritis, increased number of affected angiosomes, and the incomplete or total absence of pedal arch compared with complete pedal arch (CPA) were independent predictors of major amputation after infrapopliteal revascularization. Multivariable analysis showed increasing risk estimates of major amputation in patients with incomplete (subdistribution hazard ratio [SHR], 2.131; 95% confidence interval [95% CI], 1.282-3.543) and no visualized pedal arch (SHR, 3.022; 95% CI, 1.553-5.883) compared with CPA. Pedal arch was important even if angiosome-targeted revascularization was achieved: Angiosome-directed revascularization in presence of CPA had a lower risk of major amputation (adjusted SHR, 0.463; 95% CI, 0.240-0.894) compared with angiosome-directed revascularization without CPA. In the subanalysis, among patients who underwent endovascular revascularization, CPA (SHR, 0.509; 95% CI, 0.286-0.905) and angiosome-targeted revascularization (SHR, 0.613; 95% CI, 0.394-0.956) were associated with a lower risk of major amputation., Conclusions: Competing risk analysis showed that a patent pedal arch had significant impact on leg salvage and that the subset of patients undergoing endovascular procedure may most benefit of an angiosome-targeted revascularization., (Copyright © 2020. Published by Elsevier Inc.)

Background: Foot perfusion has been recently implemented as a new tool for optimizing outcomes of peripheral endovascular procedures. A custom-made, two-dimensional perfusion digital subtraction angiography (PDSA) algorithm has been implemented to quantify outcomes of endovascular treatment of critical limb ischemia (CLI), assist intra-procedural decision-making, and enhance clinical outcomes., Methods: The study was approved by the Hospital's Ethics Committee. This prospective, single-center study included seven consecutive patients scheduled to undergo infrapopliteal endovascular treatment of CLI. Perfusion blood volume (PBV), mean transit time (MTT), and perfusion blood flow (PBF) maps were extracted by analyzing time-intensity curves and signal intensity on the perfused vessel mask. Mean values calculated from user-specified regions of interest (ROIs) on perfusion maps were employed to evaluate pre- and post-endovascular treatment condition. Measurements were performed immediately after final PDSA., Results: In total, five patients (aged 54 ± 16 years, mean ± standard deviation) were analyzed, as two patients were excluded due to significant motion artifacts. Post-procedural MTT presented a mean decrease of 19.1% for all patients and increased only in 1 of 5 patients, demonstrating in 4/5 patients an increase in tissue perfusion after revascularization. Overall mean PBF and PBV values were also analogously increased following revascularization (446% and 69.5% mean, respectively) and in the majority of selected ROIs (13/15 and 12/15 ROIs, respectively)., Conclusions: Quantification of infrapopliteal angioplasty outcomes using this newly proposed, custom-made, intra-procedural PDSA algorithm was performed using PBV, MTT, and PBF maps. Further studies are required to determine its role in peripheral endovascular procedures ( ClinicalTrials.gov Identifier: NCT04356092).

Objective: The aim of this study was to quantitatively evaluate the changes of the foot's blood supply after endovascular treatment in patients with peripheral artery disease (PAD) using foot computed tomography (CT) perfusion., Methods: Nineteen patients who underwent endovascular treatment for PAD between January 2018 and November 2018 were included in the study. Perfusion CT scanning was performed before and after intervention with the measurement of ankle-brachial index. Regions of interest were selected from two arteries and four different tissues per foot. Perfusion maps of blood volume, blood flow, permeability surface area product, time to peak (TTP), mean transit time (MTT), mean slope of increase (MSI), Tmax, and impulse response function (IRFt 0 ) were constructed and calculated by the perfusion analysis software. Wilcoxon signed rank test was performed on the eight parameter pairs of the limbs on the treated and untreated sides before and after intervention in the 19 patients., Results: Differences in blood flow, MTT, TTP, Tmax, MSI, and IRFt 0 on the treated side of the tissue perfusion group and statistical difference in blood flow, MTT, and MSI on the treated side of the arterial perfusion group were observed (all P < .05). Ankle-brachial index improved from 0.41 ± 0.11 to 0.76 ± 0.10 (P < .001). For the untreated side, TTP of the tissue perfusion group was significantly shortened (by 7.71 seconds) after surgery (P = .006), whereas there were no differences in the other parameters. In addition, no significant differences in parameters were observed on the untreated side of the arterial perfusion group. The average radiation dose per phase of perfusion scan was 0.00097 mSv. Moreover, the hyperperfusion zone in the plantar dermis and periosteum reappeared after revascularization., Conclusions: Perfusion CT is a feasible and repeatable approach for quantifying blood supply in patients with PAD. The increase of blood flow, MSI, and MTT shortening suggest blood supply improvement after revascularization in both arterial perfusion and tissue perfusion. In addition, TTP may be a sensitive indicator of blood supply changes in tissue perfusion., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Imaging modalities such as CTA and MRA provide significant information about the distribution of macrovascular lesions of the limbs in patients with peripheral arterial disease but not for the local microvascular perfusion of the feet. The purpose of this study is to evaluate foot perfusion in patients with critical limb ischemia (CLI) and estimate percutaneous transluminal angioplasty (PTA) results, using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)., Methods: Ten patients (6 male, median age 68 years) with CLI were examined. All patients underwent DCE-MRI of the lower limb before and within first month after PTA. Perfusion parameters such as blood flow (BF), Ktrans, Kep were analyzed and applied for statistical comparisons. The studies were also examined by a second observer to determine inter-observer reproducibility., Results: Revascularization was technically successful in all patients and mean ankle brachial index (ABI) increased from 0.37 ± 0.18 to 0.76 ± 0.23, p < 0.05. After PTA, mean BF increased from 6.232 ± 2.867-9.867 ± 2.965 mL/min/100 g, K trans increased from 0.060 ± 0.022 to 0.107 ± 0.041 min -1 and K ep increased from 0.103 ± 0.024 to 0.148 ± 0.024 min -1 , p < 0.05. All measurements demonstrated very good inter-observer reliability with an ICC > 0.85 for all perfusion parameters., Conclusions: DCE-MRI is a safe and reproducible modality for the diagnosis of foot hypo-perfusion. It seems also to be a promising tool for evaluation of PTA outcome, as significant restitution of perfusion parameters was observed after successful revascularization., Competing Interests: Declarations of Competing Interest All authors of the submitted article entitled "The role of dynamic contrast-enhanced MRI in evaluation of percutaneous transluminal angioplasty outcome in patients with critical limb ischemia" declare that they have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We retrospectively reviewed the cases in which complications occurred during below-the-knee (BTK) endovascular treatments that were performed at our hospital from 2005 to 2014. Several interesting cases have been described herein. All the patients had diabetes and non-healing wounds on their feet and/or rest pain in their foot or leg, and therefore, endovascular treatment was performed for the BTK arteries of the affected lower extremity. The complications that occurred during the procedure were classified into six categories-vascular spasm, flow limiting dissection, perforation, broken guidewire, distal thromboembolism, and unusual puncture site bleeding. Each complication has its own solutions and management. We discuss these different classes of complications and describe how cases of each type were managed., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2020 The Korean Society of Radiology.)

Background: Charcot neuropathic arthropathy is a debilitating, rapidly destructive degenerative joint disease that occurs in diabetic, neuropathic midfoot. Clinicoradiologic assessment for Charcot neuropathic arthropathy previously relied on Eichenholtz stage. There is limited histopathologic data on this entity. We wanted to independently develop a histopathologic scoring system for Charcot neuropathic arthropathy., Design: Retrieval of surgical pathology midfoot specimens from Charcot patients (2012-2019) were analyzed to evaluate joint soft tissue and bone. Considering progression from large (≥half 40× hpf) to small (

Objective: Deep venous arterialization (DVA) is a technique aimed at providing an option for chronic limb-threatening ischemia patients with no options except amputation. In patients with no outflow distal targets permitting bypass, DVA involves creating a connection between a proximal arterial inflow and a distal venous outflow in conjunction with disruption of the vein valves in the foot. This permits blood flow to reach the foot and potentially to resolve rest pain or to assist in healing of a chronic wound. We aimed to provide an up-to-date review of DVA indications; to describe the open, percutaneous, and hybrid technique; to detail outcomes of each of the available techniques; and to relay the postoperative considerations for the DVA approach., Methods: A literature review of relevant articles containing all permutations of the terms "deep venous arterialization" and "distal venous arterialization" was undertaken with the MEDLINE, Cochrane, and PubMed databases to find cases of open, percutaneous, and hybrid DVA in the peer-reviewed literature. The free text and Medical Subject Headings search terms included were "ischemia," "lower extremity," "venous arterialization," "arteriovenous reversal," and "lower limb salvage." Studies were primarily retrospective case series but did include two studies with matched controls. Recorded primary outcomes were patency, limb salvage, wound healing, amputation, and resolution of rest pain, with secondary outcomes of complication and overall mortality. Studies were excluded if there was insufficient discussion of technical details (graft type, target vein) or lack of reported outcome measure., Results: Studies that met inclusion criteria (12 open, 3 percutaneous, 2 hybrid) were identified, reviewed, and summarized to compare technique, patient selection, and outcomes between open, percutaneous, and hybrid DVA. For open procedures, 1-year primary patency ranged from 44.4% to 87.5%; secondary patency was less reported but ranged from 55.6% at 1 year to 72% at 25-month follow-up. Limb salvage rates ranged from 25% to 100%, wound healing occurred in 28.6% to 100% of cases, and rest pain resolved in 11.9% to 100% across cohorts. For the endovascular approach, primary patency ranged from 28.6% to 40% at 6-month and 10-month follow-up. Limb salvage rates ranged from 60% to 71%, with rates of major amputation ranging from 20% to 28.5%., Conclusions: This review provides an up-to-date review of DVA indications, description of various DVA techniques, patient selection associated with each approach, and outcomes for each technique., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Digital skin ulcers are a severe complication of systemic sclerosis. The first-line treatment is intravenous iloprost, but it induces dose-limiting adverse effects. Local administration of treprostinil through skin iontophoresis may be a safe alternative. We conducted a 2-stage, randomized, placebo-controlled single-ascending-dose study in healthy volunteers and patients with systemic sclerosis-related digital ulcer. We further explored the effect of the procedure on skin blood flux. In a first group of healthy subjects, treprostinil and placebo iontophoresis were performed at 3 locations (ie, 6 skin sites): the sole of the foot, the leg, and the fingers. We used a 1-mg/mL hydrogel of treprostinil. We then randomly treated systemic sclerosis-related digital ulcers in a 3:1 ratio of treprostinil or placebo. We used concentrations from 0.1 to 1 mg/mL. All adverse events were recorded and rated according to the Common Terminology Criteria for Adverse Events (CTCAE), whereas skin microvascular blood flux was recorded with laser speckle contrast imaging. Among the 12 healthy volunteers, we observed 60 local adverse effects: burns, skin pain, erythema, and pruritus, graded 1 or 2 on the 5-point CTCAE scale. Treprostinil iontophoresis significantly increased skin blood flux on the leg (AUC 0-4 h at 88 460% ± 6436% versus 12 730% ± 3397% baseline flux.min respectively; P < .001) and on the sole of the foot (AUC 0-3 h at 20 124% ± 6119% versus 3142% ± 3036% baseline flux.min, respectively; P = .018) with a trend on the finger. Among 5 patients with systemic sclerosis-related digital ulcer, 2 resolutive local adverse effects were reported. Iontophoresis of treprostinil hydrogel was safe in systemic sclerosis patients with digital ulcer., (© 2020, The American College of Clinical Pharmacology.)

Patients with critical limb ischemia have nonhealing wounds and/or ischemic rest pain and are at high risk for amputation and mortality. Accurate evaluation of foot perfusion should help avoid unnecessary amputation, guide revascularization strategies, and offer efficient surveillance for patency. Our aim is to review current modalities of assessing foot perfusion in the context of the practical clinical management of patients with critical limb ischemia.