Luminal Delivery of Pectin-Modified Oxygen Microbubbles Mitigates Rodent Experimental Intestinal Ischemia.

INTRODUCTION: Ischemic gut injury is common in the intensive care unit, impairs gut barrier function, and contributes to multiorgan dysfunction. One novel intervention to mitigate ischemic gut injury is the direct luminal delivery of oxygen microbubbles (OMB). Formulations of OMB can be modified to control the rate of oxygen delivery. This project examined whether luminal delivery of pectin-modified OMB (OMBp5) can reduce ischemic gut injury in a rodent model. METHODS: The OMBp5 formulation was adapted to improve delivery of oxygen along the length of small intestine. Adult Sprague-Dawley rats (n = 24) were randomly allocated to three groups: sham-surgery (SS), intestinal ischemia (II), and intestinal ischemia plus luminal delivery of OMBp5 (II + O). Ischemia-reperfusion injury was induced by superior mesenteric artery occlusion for 45 min followed by reperfusion for 30 min. Outcome data included macroscopic score of mucosal injury, the histological score of gut injury, and plasma biomarkers of intestinal injury. RESULTS: Macroscopic, microscopic data, and intestinal injury biomarker results demonstrated minimal intestinal damage in the SS group and constant damage in the II group. II + O group had a significantly improved macroscopic score throughout the gut mucosa (P = 0.04) than the II. The mean histological score of gut injury for the II + O group was significantly improved on the II group (P ≤ 0.01) in the proximal intestine only, within 30 cm of delivery. No differences were observed in plasma biomarkers of intestinal injury following OMBp5 treatment. CONCLUSIONS: This proof-of-concept study has demonstrated that luminal OMBp5 decreases ischemic injury to the proximal small intestine. There is a need to improve oxygen delivery over the full length of the intestine. These findings support further studies with clinically relevant end points, such as systemic inflammation and vital organ dysfunction.

Translational Relevance of Advanced Age and Atherosclerosis in Preclinical Trials of Biotherapies for Peripheral Artery Disease.

Approximately 6% of adults worldwide suffer from peripheral artery disease (PAD), primarily caused by atherosclerosis of lower limb arteries. Despite optimal medical care and revascularization, many PAD patients remain symptomatic and progress to critical limb ischemia (CLI) and risk major amputation. Delivery of pro-angiogenic factors as proteins or DNA, stem, or progenitor cells confers vascular regeneration and functional recovery in animal models of CLI, but the effects are not well replicated in patients and no pro-angiogenic biopharmacological procedures are approved in the US, EU, or China. The reasons are unclear, but animal models that do not represent clinical PAD/CLI are implicated. Consequently, it is unclear whether the obstacles to clinical success lie in the toxic biochemical milieu of human CLI, or in procedures that were optimized on inappropriate models. The question is significant because the former case requires abandonment of current strategies, while the latter encourages continued optimization. These issues are discussed in the context of relevant preclinical and clinical data, and it is concluded that preclinical mouse models that include age and atherosclerosis as the only comorbidities that are consistently present and active in clinical trial patients are necessary to predict clinical success. Of the reviewed materials, no biopharmacological procedure that failed in clinical trials had been tested in animal models that included advanced age and atherosclerosis relevant to PAD/CLI.

Hyperbaric Oxygen Therapy for Threatened Nipple-Sparing Mastectomy Flaps: An Adjunct for Flap Salvage.

BACKGROUND: Nipple-sparing mastectomy (NSM) is emerging as the standard of care for treatment of breast cancer because of its oncologic safety and superior aesthetic outcomes. However, ischemia or necrosis of the skin flap and/or nipple-areola complex remain frequent complications. Hyperbaric oxygen therapy (HBOT) has emerged as a potential adjunct for flap salvage, although it is not currently a widely accepted practice. Here we review our institution's experience using a protocol of HBOT in patients with signs of flap ischemia or necrosis after NSM. METHODS: Retrospective review identified all patients treated with HBOT at our institution's hyperbaric and wound care center because of signs of ischemia after NSM. Treatment parameters consisted of 90-minute dives at 2.0 atmosphere once or twice daily. Patients unable to tolerate dives were considered a treatment failure, whereas those lost to follow-up were excluded from analysis. Patient demographics, surgical characteristics, and treatment indications were recorded. Primary outcomes assessed were flap salvage (no operative revision), need for revision procedures, and treatment complications. RESULTS: A total of 17 patients and 25 breasts met the inclusion criteria. The mean ± SD time to initiation of HBOT was 9.47 ± 12.7 days. The mean ± SD age was 46.7 ± 10.4 years, and mean ± SD follow-up time was 36.5 ± 25.6 days. Indications for NSM included invasive cancer (41.2%), carcinoma in situ (29.4%), and breast cancer prophylaxis (29.4%). Initial reconstruction included tissue-expander placement (47.1%), autologous reconstruction with deep inferior epigastric flaps (29.4%), and direct-to-implant reconstruction (23.5%). Hyperbaric oxygen therapy indications included ischemia or venous congestion for 15 breasts (60.0%) and partial thickness necrosis for 10 breasts (40.0%). Flap salvage was achieved in 22 of 25 breasts (88.0%). Reoperation was required for 3 breasts (12.0%). Hyperbaric oxygen therapy-related complications were observed in 4 patients (23.5%), which included 3 patients with mild ear pain and 1 patient with severe sinus pressure leading to treatment abortion. CONCLUSIONS: Nipple-sparing mastectomy is an invaluable tool for breast and plastic surgeons to achieve oncologic and cosmetic goals. However, ischemia or necrosis of the nipple-areola complex or mastectomy skin flap remains frequent complications. Hyperbaric oxygen therapy has emerged as a possible intervention for threatened flaps. Our results demonstrate the utility of HBOT in this population to achieve excellent NSM flap salvage rates.

WALANT in hand surgery: Ischemic complications and their medicolegal implications in France: A systematic review of the literature and of French legal databases.

WALANT (Wide Awake Local Anesthesia No Tourniquet) presents a theoretical risk of digital ischemia due to the presence of epinephrine, associated to the local anesthetic. For this reason, in France, the market authorization prohibits the use of epinephrine in digital extremities. The main objective of the present study was to assess the risk of ischemic complications reported in literature, and then to analyze the medicolegal implications in France. A systematic literature review was performed by three independent readers, using the PubMed and Embase databases. Also, declarations of claims and legal proceedings between 2007 and 2020 in France were examined in the official national Légifrance and Doctrine databases. Eight of the 424 articles retrieved were selected. Only 3 cases of digital necrosis following local anesthesia with adrenalized lidocaine were reported. Adrenalized xylocaine may be considered in case of peripheral microcirculation disorder. From a medicolegal point of view, no complaints or medicolegal implications were associated with WALANT in France. It seems that the market authorization for adrenalized local anesthesia could be extended to use in the digital extremities. However, the lack of medical and legal data calls for caution. We therefore recommend the use of an institutional protocol specifying the cases of overdose and the patient's pathway, and training for practitioners wishing to use this technique.

Editor's Choice - External Applicability of the COMPASS and VOYAGER-PAD Trials on Patients with Symptomatic Lower Extremity Artery Disease in France: The COPART Registry.

OBJECTIVE: The aim of this study was to examine the external applicability of the COMPASS and the VOYAGER-PAD trials in patients with lower extremity artery disease (LEAD) in the real world. METHODS: This was a multicentre retrospective analysis of prospectively collected COPART data, a French multicentre registry of patients hospitalised for symptomatic LEAD. The proportion of patients eligible for the combination of rivaroxaban 2.5 mg twice daily plus aspirin based on either COMPASS or VOYAGER-PAD criteria is reported. The one year cumulative incidence of outcomes between eligible and non-eligible patients, as well as eligible patients vs. control arms of the COMPASS (LEAD patient subgroup) and the VOYAGER-PAD trials were compared. Analyses were performed using Cox models. RESULTS: Of 2 259 evaluable patients, only 679 (30.1%) were eligible for a low dose rivaroxaban plus aspirin regimen. Others were not eligible because of the need for anticoagulant (48.5% and 38.9% of patients meeting COMPASS and VOYAGER-PAD exclusion criteria, respectively) or dual antiplatelet therapy use (15.7% and 16.5%, respectively), high bleeding risk (14.4% and 11.6%, respectively), malignancy (26.1% and 21.0%, respectively), history of ischaemic/haemorrhagic stroke (21.1% and 19.8%, respectively), and severe renal failure (13.2% and 10.5%, respectively). COMPASS and VOYAGER-PAD eligible and ineligible patients were at higher risk of ischaemic events than participants in these trials. The one year cumulative incidences were 6.0% (95% CI 4.3 - 8.1) in the COMPASS eligible subset vs. 3.5% (95% CI 2.9 - 4.3) in the COMPASS control arm for major adverse cardiovascular events, and 27.9% (95% CI 19.9 - 38.3) in the VOYAGER-PAD eligible subset vs. 6.0% (95% CI 5.3 - 6.9) in the VOYAGER-PAD control arm for major adverse limb events. CONCLUSION: Many patients hospitalised for symptomatic LEAD in France are not eligible for the low dose rivaroxaban plus aspirin combination. In turn, those eligible may potentially have greater absolute benefit because of higher risk than those enrolled in the trials.

Chronic limb ischaemia: case study and clinical literature review.

This article will discuss chronic limb ischaemia as the result of peripheral artery disease (PAD) using a case study. The patient's concurrent diagnosis of metastases meant clinical decision making was complex and treatment options were limited. PAD is the third most common clinical presentation of atherosclerosis after coronary artery disease and stroke. Although advances in radiological technology and biochemical screening offer the potential for earlier intervention and improved survival rates for patients with PAD, a review of the evidence suggests that commitment to more conservative approaches, such as exercise therapy and health promotion, could have more sustainable, longer-term benefits for patients with chronic limb ischaemia. The therapeutic nature of the nurse-patient relationship makes nurses ideally placed for encouraging lifestyle changes and signposting to support services. Active participation from the patient is imperative for any potential modifications, which should be individualised as part of a holistic care plan, to ensure patient engagement and compliance. Therefore emphasis should remain on the management and prevention of modifiable risk factors, for which the nurse's role is an integral part to ensure success.

Hirudotherapy for neonatal limb ischemia during ECMO support: A word of caution.

INTRODUCTION: Disordered coagulation, clot formation and distal limb ischemia are complications of extracorporeal membrane oxygenation (ECMO) with significant morbidity and mortality. Medicinal leech therapy (hirudotherapy) has been attempted in plastic and orthopedic surgeries to improve venous congestion and salvage ischemic flaps. To our knowledge this has not been reported in pediatric cardiac surgery or during ECMO support. We present a complex neonate whose ECMO course was complicated by distal limb ischemia for whom leech therapy was attempted. PATIENT AND INTERVENTION: A 2-week-old 2.7 kg infant required ECMO support secondary to perioperative multiorgan system dysfunction following repair of critical coarctation and ventricular septal defect. Despite systemic anticoagulation, his clinical course was complicated by arterial thrombus, vasopressor-induced vascular spasm and bilateral distal limb ischemia. Medicinal leech therapy was tried after initially failing conventional measures. RESULT: Following the third leech application, this patient developed significant hemorrhage from the web space adjacent to the left great toe. An estimated 450 ml of blood loss occurred and more than 300 ml of blood product transfusions were required. He ultimately progressed to irreversible systemic end organ dysfunction and comfort care was provided. CONCLUSION: The use of medicinal leech therapy in pediatric cardiac surgery may be considered to minimize the consequences of advanced limb ischemia and venous congestion. However, this should be used with caution while patients are systemically anticoagulated during ECMO support. A directed review is presented here to assist in determining optimal application and potential course of therapy.

Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.

BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.

Hyperbaric Oxygen as Salvage Therapy for Neonates Suffering From Critical Ischemia of the Glans Penis After Circumcision.

Ischemic complications of glans penis following circumcision are rare, and if occurs can culminate in irreversible necrosis with severe long-term consequences. Here we present 2 challenging cases of neonates suffering from acute severe glans penis ischemia after circumcision that were treated by hyperbaric oxygen treatment (HBOT). In addition to case presentations, the literature related to complications of circumcision and the physiological effects of HBOT are being reviewed. Based on the review and the case presented, we conclude that HBOT can be used as salvage treatment for circumcision induced glans ischemia as early as possible before full necrosis develops.

Tetrahydrobiopterin prevents chronic ischemia-related lower urinary tract dysfunction through the maintenance of nitric oxide bioavailability.

This study aimed to investigate the influence of chronic ischemia on nitric oxide biosynthesis in the bladder and the effect of administering tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), on chronic ischemia-related lower urinary tract dysfunction (LUTD). This study divided male Sprague-Dawley rats into Control, chronic bladder ischemia (CBI) and CBI with oral BH4 supplementation (CBI/BH4) groups. In the CBI group, bladder capacity and bladder muscle strip contractility were significantly lower, and arterial wall was significantly thicker than in Controls. Significant improvements were seen in bladder capacity, muscle strip contractility and arterial wall thickening in the CBI/BH4 group as compared with the CBI group. Western blot analysis of bladder showed expressions of eNOS (p = 0.043), HIF-1α (p < 0.01) and dihydrofolate reductase (DHFR) (p < 0.01), which could regenerate BH4, were significantly higher in the CBI group than in Controls. In the CBI/BH4 group, HIF-1α (p = 0.012) and DHFR expressions (p = 0.018) were significantly decreased compared with the CBI group. Our results suggest that chronic ischemia increases eNOS and DHFR in the bladder to prevent atherosclerosis progression. However, DHFR could not synthesize sufficient BH4 relative to the increased eNOS, resulting in LUTD. BH4 supplementation protects lower urinary tract function by promoting eNOS activity.

[Multilevel arterialization of the venous bed in treatment of critical lower limb ischaemia]. / Étazhnaia arterializatsiia venoznogo rusla v lechenii kriticheskoi ishemii nizhnikh konechnostei.

Presented herein is original experience in using a technique of arterialization in patients with critical lower limb ischaemia on the background of diffuse multilevel occlusive lesions of femoral, crural arteries and arteries of the foot in 214 patients. We used a new method of treatment by means of oxygenation of the sural group of muscles and the foot through the small saphenous vein and indirect communicating veins. This method does not require destruction of the valvular apparatus of the communicants themselves, promoting opening of previously not functioning ones, as well as appears to be a powerful stimulus for the development of collateral circulation of the extremity. Alterations introduced into the design characteristics of a valvulotome make it possible to avoid lateral injury of the venous wall in the area of confluence of tributaries, preventing incomplete resection of the valve. The method expands the boundaries of operability of patients with the absence of the receiving arterial bed of the calf and foot. It may be combined with arterial primary and repeat reconstructions in patients with depleted receiving channel of the calf as an effective additional path of outflow. It also makes it possible to lower the level of amputation in the developed necrosis of the distal part of the foot. Based on clinical laboratory and instrumental findings, the patients were diagnosed by the aetiological factor of the occlusive process and its extension, substantiating the indications for operative treatment with the use of one or another venous basin. Comparative assessment of reversion of arterial blood flow through the great saphenous vein, small saphenous vein, and posterior tibial vein, according to the findings of bioelectromagnetic diagnosis of reactivity of tissues demonstrated that the most effective method was that of arterialization thought the small saphenous vein. With the help of the questionnaire of quality of life in patients with performed arterialization of the calf and foot through the small saphenous vein for critical lower limb ischaemia we obtained 5-year remote results. Upon completion of this period, 87.3% of the limbs were saved and composite measures of the patients' quality of life proved to be high, ranging from 53 to 69 points.

Successful use of hyperbaric oxygen therapy for limb salvage of acute limb ischemia as a complication of acute carbon monoxide poisoning.

Acute limb ischemia (ALI) as a complication of acute carbon monoxide (CO) poisoning is rare. Several reports have utilized hyperbaric oxygen therapy (HBO2) as an adjunctive therapy for peripheral arterial diseases. However, no study has yet described the use of HBO2 for ALI precipitated by CO poisoning. Herein we report successful limb salvage achieved with adjunctive HBO2 and conventional therapies in a patient with CO-induced ALI. A 69-year-old man was admitted with acute CO poisoning; ALI of both lower extremities occurred on hospitalization day 3. Pre-existing risk factors for ALI other than CO were not definite. After conventional treatments including catheter-directed thrombolysis and endovascular thrombectomy, the right-side lesion remained and a left-side lesion was newly developed. In addition to prior therapies, 47 sessions of serial HBO2 were administered as adjunctive therapy, resulting in limb salvage. Acute CO poisoning can cause ALI as a rare complication. HBO2 may be utilized as an adjunctive treatment in ALI.

Changes in Skin Perfusion Pressure After Hyperbaric Oxygen Therapy Following Revascularization in Patients With Critical Limb Ischemia: A Preliminary Study.

Hyperbaric oxygen (HBO) therapy promotes wound healing in patients with ischemic disease; however, HBO-induced changes in skin peripheral circulation have not been evaluated in clinical practice. Here, we investigated these changes in patients with critical limb ischemia (CLI), with a focus on the angiosome of crural blood vessels with blood flow improved by endovascular therapy (EVT). Six patients with CLI and ulcers who were treated with HBO after EVT (7 limbs; 1 patient had ulcers in the bilateral limbs) and 3 healthy subjects (6 limbs) were enrolled. HBO therapy was performed at 2 atm under 100% oxygen for 90 min per session. Skin perfusion pressure (SPP) was measured in the dorsum and sole of the foot 1 hour before (pre-SPP) and after (post-SPP) HBO therapy. ΔSPP was calculated as post-SPP minus pre-SPP. SPP measurement regions were divided into those that did (direct region) and did not (indirect region) correspond to the vascular angiosome in which angiography findings of the crus were improved after EVT; i.e., when the anterior tibial artery was effectively treated with EVT, the dorsum was the direct region and the sole was the indirect region, and vice versa when the posterior tibial artery was treated. In the direct, indirect, and healthy subject groups, the ΔSPPs were 20.5±8.7 (p=0.002), -6.4±10.9, and -15.1±18.1 (p=0.014), respectively; that of the direct group was significantly greater than that of the other groups. These results suggest that short-term improvement of the peripheral circulation by HBO therapy was significant in patients with successful revascularization.

Idiopathic mesenteric phlebosclerosis treated with laparoscopic subtotal colectomy: A case report.

Idiopathic mesenteric phlebosclerosis is a rare entity characterized by chronic intestinal ischemia due to calcification and obstruction of the mesenteric veins. Here, we report a patient with idiopathic mesenteric phlebosclerosis treated with laparoscopic subtotal colectomy after evaluation by imaging studies. The patient was a 68-year-old Japanese woman with recurrent abdominal pain who had taken a Chinese herbal medicine for more than 20 years. Abdominal CT showed wall thickening of the right colon with calcification of branches of the superior mesenteric vein. Colonoscopy showed cyanotic mucosa from the cecum to the sigmoid colon. The affected area seen on colonoscopy extended to the distal colon. Despite discontinuation of the herbal medicine, her symptoms did not improve. Laparoscopic subtotal colectomy was performed. This report highlights the importance of appropriately evaluating the extent of the affected preoperatively area based on findings from colonoscopy, CT, and contrast enema.

Utilization of Fluorescence Microangiography in Pediatric Acute Compartment Syndrome: A Case Report.

Acute compartment syndrome is a critical condition, most commonly arising as the result of high-energy trauma, fracture, and crush injury. Early diagnosis and treatment are imperative to avoid permanent functional damage to the affected extremity. Although isolated pedal compartment syndrome is well studied in adults, in the pediatric population, it has been seldom reported. Pediatric patients pose a unique challenge when diagnosing compartment syndrome. Their inability to appropriately verbalize symptoms and participate in physical examinations often causes a delay in diagnosis. We present the case of a 5-year-old female who developed compartment syndrome of her left foot 26 hours after sustaining an isolated crush injury to the distal forefoot. Her treatment included emergent fasciotomy in combination with 20 hyperbaric oxygen therapy treatments. The progression of her acute digital ischemia was monitored by using serial fluorescence microangiography studies performed at 17 hours, 7 days, and 3 weeks postinjury. Throughout these serial studies, improvement in hypofluorescence was noted involving the dorsolateral midfoot, as well as digits 3, 4, and 5, which correlated with physical examination. The patient went on to uneventfully autoamputate the distal aspects of digits 4 and 5 within 4 months of injury. At the 12-month follow-up visit, she denied any pain, sensory deficits, or functional disability and had returned to all preinjury activities. Our case study demonstrates the use of serial microangiography to monitor progression of acute ischemia associated with acute pediatric compartment syndrome and discusses prognostic capabilities.

Sodium Tanshinone IIA sulfonate improves post-ischemic angiogenesis in hyperglycemia.

BACKGROUND: Diabetes is a strong risk factor of peripheral arterial disease (PAD), and also leads to impaired perfusion recovery in the ischemic limb, which eventually results in poor outcomes in PAD patients. Sodium Tanshinone IIA Sulfonate (STS), a monomer from herbs, has been shown to improve the outcomes in a variety of ischemic disease including myocardial infarction. However, the effects of STS treatment in PAD is not known. METHODS AND RESULTS: Unilateral femoral artery was ligated in mice as experimental PAD models, STS treatment improved perfusion recovery, increased capillary densities, decreased reactive oxygen species (ROS) level and microRNA-133a (miR-133a) expression in the ischemic hindlimb in diabetic mice; however, STS did not change perfusion recovery in non-diabetic C57BL/6 mice. Ischemic muscle tissue from diabetic mice was harvested 7 days after femoral ligation for biochemical test, STS resulted in reduced malondialdehyde (MDA), and increased GTP cyclohydrolase 1 (GCH1) and cyclic guanine monophosphate (cGMP) levels. In addition, STS treatment increased miR-133a expression in endothelial cells isolated from ischemic muscle tissue of diabetic mice. In endothelial cells cultured in high glucose medium, STS increased tube formation and nitric oxide (NO) production, and reduced cellular ROS level and miR-133a expression under simulated ischemic condition. In addition, GCH1 inhibitor or miR-133a overexpression using exogenous microRNA mimic blunted STS-induced angiogenic effects and ROS neutralization in cultured endothelial cells under hyperglycemic and hypoxic conditions. CONCLUSION: These findings demonstrate STS improves angiogenesis via inhibiting miR-133a expression and increasing GCH-1 protein levels in experimental PAD with diabetes.