Evolution of distal limb perfusion management in adult peripheral venoarterial extracorporeal membrane oxygenation with femoral artery cannulation.

Limb ischaemia is a clinically relevant complication of venoarterial extracorporeal membrane oxygenation (VA ECMO) with femoral artery cannulation. No selective distal perfusion or other advanced techniques were used in the past to maintain adequate distal limb perfusion. A more recent trend is the shift from the reactive or emergency management to the pro-active or prophylactic placement of a distal perfusion cannula to avoid or reduce limb ischaemia-related complications. Multiple alternative cannulation techniques to the distal perfusion cannula have been developed to maintain distal limb perfusion, including end-to-side grafting, external or endovascular femoro-femoral bypass, retrograde limb perfusion (e.g., via the posterior tibial, dorsalis pedis or anterior tibial artery), and, more recently, use of a bidirectional cannula. Venous congestion has also been recognized as a potential contributing factor to limb ischaemia development and specific techniques have been described with facilitated venous drainage or bilateral cannulation being the most recent, to reduce or avoid venous stasis as a contributor to impaired limb perfusion. Advances in monitoring techniques, such as near-infrared spectroscopy and duplex ultrasound analysis, have been applied to improve decision-making regarding both the monitoring and management of limb ischaemia. This narrative review describes the evolution of techniques used for distal limb perfusion during peripheral VA ECMO.

Feasibility and efficacy of indocyanine green in monitoring systemic drug leakage during isolated limb perfusion for recurrent melanoma of extremity.

Melanoma is known for its high metastatic potential and aggressive growth. Recurrence is common post-surgery, sometimes leading to unresectable disease. Locally recurrent unresectable melanoma of extremity has been treated with high-dose anticancer chemotherapy via isolated limb perfusion (ILP) to improve local efficacy of drug and salvage limbs. Standard ILP monitoring uses radiolabeled dyes, requiring specialized personnel and involving radiation exposure. In this case, we used indocyanine green (ICG) to track systemic drug leakage during ILP. A 47-year-old gentleman with recurrent malignant melanoma of the left foot, operated twice earlier and treated with adjuvant pembrolizumab, presented with multiple in-transit metastases in the limb. ILP was planned, with 5 mg ICG administered in the perfusion solution along with high-dose melphalan. Stryker's SPI PHI handheld device was employed to visualize ICG during ILP. Absence of fluorescence beyond the involved extremity, such as fingers, ears, and the abdominal wall, indicated no systemic drug dispersion. For control, technetium radiocolloid dye was co-administered, monitored by a precordial gamma probe, confirming no systemic leakage, and validating effectiveness of ICG in leakage monitoring. ICG proves to be a safe, reliable, cost-effective, radiation-free approach for precise systemic drug leakage monitoring during ILP for recurrent melanoma of extremity.

Tourniquet Use in Extremity-Based Microsurgery.

BACKGROUND: The use of tourniquets and their role in extremity-based microsurgery has not been thoroughly investigated. The purpose of this study was to investigate tourniquet use and its associated outcomes and complications. The authors hypothesize that tourniquets enhance visualization, bloodless approaches to vessel harvest, flap elevation, and anastomosis without added complications. METHODS: A retrospective chart review was completed for patients who had undergone extremity-based microsurgery with the use of a tourniquet between January 2018 and February 2022 at two large academic institutions. Demographic characteristics, initial reasons for surgery, complications, and outcomes were recorded. Patients were separated into groups based on tourniquet use during three operative segments: (1) flap elevation, (2) vessel harvest, and (3) microvascular anastomosis. An internal comparison of complication rate was performed between cases for which a tourniquet was used for one operative segment to all cases in which it was not used for the same operative segment. Univariate and multivariate statistical analyses were performed to identify statistically significant results. RESULTS: A total of 99 patients (106 surgeries) were included in this study across sites. The mean age was 41.2 years and 67.7% of the patients were male. The most common reason for microsurgical reconstruction was trauma (50.5%). The need for an additional unplanned surgery was the most common surgical complication (16%). A total of 70, 61, and 32% of procedures used a tourniquet for flap elevation, vessel harvest, and for anastomosis, respectively. Statistical analyses identified no difference in complication rates for procedures for which a tourniquet was or was not used for interventions. CONCLUSION: Based on these results, the authors state that tourniquets can be utilized for extremity-based microsurgery to enable bloodless dissection without the concern of increased complication rates.

Remote Ischemic Conditioning for Acute Stroke: The RESIST Randomized Clinical Trial.

Importance: Despite some promising preclinical and clinical data, it remains uncertain whether remote ischemic conditioning (RIC) with transient cycles of limb ischemia and reperfusion is an effective treatment for acute stroke. Objective: To evaluate the effect of RIC when initiated in the prehospital setting and continued in the hospital on functional outcome in patients with acute stroke. Design, Setting, and Participants: This was a randomized clinical trial conducted at 4 stroke centers in Denmark that included 1500 patients with prehospital stroke symptoms for less than 4 hours (enrolled March 16, 2018, to November 11, 2022; final follow-up, February 3, 2023). Intervention: The intervention was delivered using an inflatable cuff on 1 upper extremity (RIC cuff pressure, ≤200 mm Hg [n = 749] and sham cuff pressure, 20 mm Hg [n = 751]). Each treatment application consisted of 5 cycles of 5 minutes of cuff inflation followed by 5 minutes of cuff deflation. Treatment was started in the ambulance and repeated at least once in the hospital and then twice daily for 7 days among a subset of participants. Main Outcomes and Measures: The primary end point was improvement in functional outcome measured as a shift across the modified Rankin Scale (mRS) score (range, 0 [no symptoms] to 6 [death]) at 90 days in the target population with a final diagnosis of ischemic or hemorrhagic stroke. Results: Among 1500 patients who were randomized (median age, 71 years; 591 women [41%]), 1433 (96%) completed the trial. Of these, 149 patients (10%) were diagnosed with transient ischemic attack and 382 (27%) with a stroke mimic. In the remaining 902 patients with a target diagnosis of stroke (737 [82%] with ischemic stroke and 165 [18%] with intracerebral hemorrhage), 436 underwent RIC and 466 sham treatment. The median mRS score at 90 days was 2 (IQR, 1-3) in the RIC group and 1 (IQR, 1-3) in the sham group. RIC treatment was not significantly associated with improved functional outcome at 90 days (odds ratio [OR], 0.95; 95% CI, 0.75 to 1.20, P = .67; absolute difference in median mRS score, -1; -1.7 to -0.25). In all randomized patients, there were no significant differences in the number of serious adverse events: 169 patients (23.7%) in the RIC group with 1 or more serious adverse events vs 175 patients (24.3%) in the sham group (OR, 0.97; 95% CI, 0.85 to 1.11; P = .68). Upper extremity pain during treatment and/or skin petechia occurred in 54 (7.2%) in the RIC group and 11 (1.5%) in the sham group. Conclusions and Relevance: RIC initiated in the prehospital setting and continued in the hospital did not significantly improve functional outcome at 90 days in patients with acute stroke. Trial Registration: ClinicalTrials.gov Identifier: NCT03481777.

Rethinking protocolized completion angiography following extremity vascular trauma: A prospective observational multicenter trial.

BACKGROUND: Completion angiography (CA) is commonly used following repair of extremity vascular injury and is recommended by the Eastern Association for the Surgery of Trauma practice management guidelines for extremity trauma. However, it remains unclear which patients benefit from CA because only level 3 evidence exists. METHODS: This prospective observational multicenter (18LI, 2LII) analysis included patients 15 years or older with extremity vascular injuries requiring operative management. Clinical variables and outcomes were analyzed with respect to with our primary study endpoint, which is need for secondary vascular intervention. RESULTS: Of 438 patients, 296 patients required arterial repair, and 90 patients (30.4%) underwent CA following arterial repair. Institutional protocol (70.9%) was cited as the most common reason to perform CA compared with concern for inadequate repair (29.1%). No patients required a redo extremity vascular surgery if a CA was performed per institutional protocol; however, 26.7% required redo vascular surgery if the CA was performed because of a concern for inadequate repair. No differences were observed in hospital mortality, length of stay, extremity ischemia, or need for amputation between those who did and did not undergo CA. CONCLUSION: Completion angiogram following major extremity injury should be considered in a case-by-case basis. Limiting completion angiograms to those patients with concern for an inadequate vascular repair may limit unnecessary surgery and morbidity. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Tourniquets, types and techniques in emergency prehospital care: A narrative review.

Massive uncontrolled hemorrhage is an important cause of preventable death in trauma. Therefore, applying an arterial tourniquet (TQ) is recommended as a pre-hospital measure to control bleeding after severe traumatic bleeding. Limb TQ applies circumferential compression proximally to the injury site to compress the arteries, resulting in blood flow and consequently hemorrhage interruption. The use of commercial tourniquets (C-TQ), which are designed, tested, and registered to control hemorrhages in pre-hospital care, is a consensus. However, they are still uncommon in many prehospital emergency services and the overall level of evidence in most studies is low. This narrative review aimed to characterize the importance of tourniquets use in prehospital emergency care and its application techniques. Furthermore, it proposes to stimulate the development of new devices, more accessible and easier to use, to suggest new directions of studies and medical education demands, with manikin and simulation development.

Degree of Soft Tissue Injury is a Major Determinant of Successful Arterial Repair in the Extremity: A New Classification of Extremity Arterial Injury?

BACKGROUND: This study aimed to investigate outcomes after extremity arterial injury repair and examined the association between outcomes and the degree of soft tissue injury and vascular repair methods. METHODS: A retrospective study was conducted on 106 patients (108 cases) who underwent emergent microsurgical repair of extremity arterial injury due to trauma and non-perfusion of the affected extremity. The cases were divided into three groups by degree of associated soft tissue injuries: (A) adequate soft tissue coverage over the injured major vessels after radical debridement, (B) inadequate soft tissue coverage over the injured major vessels after radical debridement, and (C) radical debridement was not feasible due to unclear extent of injured soft tissue. Differences in vascular repair methods and outcomes among the three groups were analyzed. RESULTS: In Group A (n = 61), microvascular suture and vessel graft achieved 95.1% and 85.0% successful limb reperfusion, respectively. In Group B (n = 31), vessel reconstruction with flap coverage achieved 100% successful reperfusion. Vessel graft achieved 28.6% successful limb reperfusion, while there were no cases of successful reperfusion using microvascular sutures. In Group C (n = 16), no vascular repair method achieved successful reperfusion. There were significant differences among the three groups in successful reperfusion (p < 0.001) and limb salvage (p < 0.001). CONCLUSION: The extent of associated soft tissue injury was associated with different vascular repair methods and outcomes. We propose a new system for classifying these injuries according to the degree of associated soft tissue injury.

Interventional- and amputation-stage muscle proteomes in the chronically threatened ischemic limb.

BACKGROUND: Despite improved surgical approaches for chronic limb-threatening ischemia (CLTI), amputation rates remain high and contributing tissue-level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation. METHODS AND RESULTS: Gastrocnemius muscle was collected from non-ischemic controls (n = 19) and either pre-interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem-mass-tag-assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre-interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre-intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non-ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. CONCLUSIONS: The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre-intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI.

miR-548j-5p regulates angiogenesis in peripheral artery disease.

Peripheral artery disease (PAD) is a vascular disease involving diffuse atherosclerosis, and is associated with increased cardiovascular mortality and morbidity. Critical limb ischemia (CLI) is the most severe complication of PAD. In addition to medical and interventional treatment, therapeutic angiogenesis is a novel therapy for PAD. Circulating microRNAs (miRNAs) are considered key regulators of gene expression, but their role in ischemic-induced angiogenesis is poorly-characterized. There is currently a limited understanding of the specific miRNAs associated with PAD. To determine the regulation of miRNAs, we obtained miRNA profiles using RNA isolated from patients with PAD and a control group. The effects of specific miRNAs on angiogenesis were evaluated by assessing the in vitro angiogenic function of endothelial progenitor cells (EPCs), performing an in vivo angiogenesis assay, and employing a mouse hindlimb ischemic model. Our results demonstrated that circulating miR-548j-5p was significantly reduced in patients with PAD as compared with the controls. miR-548j-5p promoted EPC angiogenesis by enhancing migration and tube formation. The endothelial nitric oxide synthase (NOS) and stromal cell-derived factor (SDF)-1 signaling pathways appeared to be potential targets of miR-548j-5p. Furthermore, the results of a directed in vivo angiogenesis assay of EPCs and a hindlimb ischemia mouse model demonstrated that miR-548j-5p enhanced the capillary density and blood flow recovery in hindlimb ischemia. In conclusion, our data indicated that up-regulation of miR-548j-5p promotes angiogenesis in ischemic tissue and may represent a novel therapeutic approach for PAD.

Timing is everything: Impact of combined long bone fracture and major arterial injury on outcomes.

BACKGROUND: Timing of extremity fracture fixation in patients with an associated major vascular injury remains controversial. Some favor temporary fracture fixation before definitive vascular repair to limit potential graft complications. Others advocate immediate revascularization to minimize ischemic time. The purpose of this study was to evaluate the timing of fracture fixation on outcomes in patients with concomitant long bone fracture and major arterial injury. METHODS: Patients with a combined long bone fracture and major arterial injury in the same extremity requiring operative repair over 11 years were identified and stratified by timing of fracture fixation. Vascular-related morbidity (rhabdomyolysis, acute kidney injury, graft failure, extremity amputation) and mortality were compared between patients who underwent fracture fixation prerevascularization (PRE) or postrevascularization (POST). RESULTS: One hundred four patients were identified: 19 PRE and 85 POST. Both groups were similar with respect to age, sex, Injury Severity Score, admission base excess, 24-hour packed red blood cells, and concomitant venous injury. The PRE group had fewer penetrating injuries (32% vs. 60%, p = 0.024) and a longer time to revascularization (9.5 vs. 5.8 hours, p = 0.0002). Although there was no difference in mortality (0% vs. 2%, p > 0.99), there were more vascular-related complications in the PRE group (58% vs. 32%, p = 0.03): specifically, rhabdomyolysis (42% vs. 19%, p = 0.029), graft failure (26% vs. 8%, p = 0.026), and extremity amputation (37% vs. 13%, p = 0.013). Multivariable logistic regression identified fracture fixation PRE as the only independent predictor of graft failure (odds ratio, 3.98; 95% confidence interval, 1.11-14.33; p = 0.03) and extremity amputation (odds ratio, 3.924; 95% confidence interval, 1.272-12.111; p = 0.017). CONCLUSION: Fracture fixation before revascularization contributes to increased vascular-related morbidity and was consistently identified as the only modifiable risk factor for both graft failure and extremity amputation in patients with a combined long bone fracture and major arterial injury. For these patients, delaying temporary or definitive fracture fixation until POST should be the preferred approach. LEVEL OF EVIDENCE: Prognostic study, Level IV.

Pushing the Limits in Extremity Reconstruction Using Virtual Surgical Planning: A Case Series Study.

SUMMARY: Technology is advancing in benefit to solving complex problems. Preoperative planning is essential in any reconstructive process given the importance of achieving good results. New technologies facilitate the process to anticipate intraoperative findings. Virtual surgical planning has contributed in the evolution of craniomaxillofacial surgery. However, limited reports have been published regarding its usefulness in extremity reconstruction. The aim of this study was to push the limits and evaluate the use of virtual surgical planning with three-dimensional images for reconstruction of complex extremity defects using a free, open-source software. Patient candidates for upper or lower extremity microsurgical reconstruction with multiple defects or defects requiring reconstruction of various tissue components were included. Computed tomography angiography images were analyzed for virtual surgical planning using Horos software (Horos, Annapolis, Md.). Two upper and eight lower extremities were reconstructed with free flaps using virtual surgical planning; six cases had multiple defects, and four cases underwent different tissue components reconstruction. The postoperative period was uneventful, and there was no flap failure. A didactic video of the process and examples of some cases are presented. Virtual surgical planning is a powerful planning method, and the authors propose its use in complex extremity defects reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Characteristics, clinical presentation, and treatment outcomes of venous malformation in the extremities.

OBJECTIVE: The clinical presentation of venous malformations (VMs) is variable and not well documented. The present study was designed to determine the clinical characteristics and outcomes in association with the type and extent of VM in the extremities. METHODS: Patients with a diagnosis of a VM using ultrasound, computed tomography, or magnetic resonance imaging were included in the present study. The VM extent and tissue involvement, signs, and symptoms were retrospectively collected. Those with arteriovenous malformations, Klippel-Trenaunay syndrome, lymphedema, and symptoms from other unrelated diseases were excluded. The VMs were classified as extensive or localized according to whether different tissues or the entire compartment was involved. The clinical outcomes and imaging studies were obtained for both the treated patients and those who had chosen to not undergo any intervention. RESULTS: A total of 72 patients, of whom 26 were men, were included in the present study, with a median age of 30 years. The VM had extended into the subfascial space in 40 patients (55.6%). Patients with VM distributed on their leg had mostly experienced pain, which was more evident during physical activity (n = 40; 80.0%), with swelling worsening with prolonged standing (n = 35; 70.0%). For those with VMs in the upper extremities, the most prominent complaints were venous enlargement (n = 10; 45.5%), pain (n = 9; 40.9%), and swelling (n = 11; 50.0%). The symptoms were related to the extent of the lesion (odds ratio, 7.664; 95% confidence interval, 2.006-29.291; P = .003). Treatment was decided by the extent and depth of the lesions. Excision was performed in 15 patients (20.8%), sclerotherapy in 12 (16.7%), sclerotherapy with phlebectomy or coil embolization in 8 (11.1%), and stripping in 2 (2.8%). An excellent result was achieved with the treatment of localized VMs. For those with extensive VMs, the symptom intensity was reduced or controlled after multiple treatments. CONCLUSIONS: VMs of the extremities affect patients' quality of life significantly owing their appearance and the resulting pain. The VM extent was associated with symptom severity. The clinical outcomes have been excellent for localized VMs; however, extensive VMs will require multiple treatments to reduce the symptom intensity.

Extracorporeal sheath shunt technique in trauma: A different vascular shunt in civilian trauma.

BACKGROUND/OBJECTIVE: Temporary intravascular shunts are widely used in military surgery, representing a bridging until definitive vascular reconstruction. In civilian practice, shunts are mainly used as damage control and as a temporary measure until orthopaedic fixation. The objective of this report is to illustrate a new approach to the temporary restoration of perfusion during open management of extremity arterial injury. METHODS: The authors present a technique that uses sheaths introducers, instead of commercial or purpose-built shunts, which can be used through surgical or percutaneous approaches. Three clinical cases are presented where this technique was performed.Results/Conclusion: In the presented cases, this technique reduced time of shunt construction by avoiding artery surgical approach. This technique can facilitate the creation of an intravascular shunt among other than vascular surgeons.

Acute limb ischemia among patients with COVID-19 infection.

OBJECTIVE/BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with thrombotic complications such as deep vein thrombosis or stroke. Recently, numerous cases of acute limb ischemia (ALI) have been reported although pooled data are lacking. METHODS: We systematically searched PubMed, Embase, Scopus, and the Cochrane Library for studies published online up to January 2021 that reported cases with SARS-CoV-2 infection and ALI. Eligible studies should have reported early outcomes including mortality. Primary endpoints included also pooled amputation, clinical improvement, and reoperation rates. RESULTS: In total, 34 studies (19 case reports and 15 case series/cohort studies) including a total of 540 patients (199 patients were eligible for analysis) were evaluated. All studies were published in 2020. Mean age of patients was 61.6 years (range, 39-84 years; data from 32 studies) and 78.4% of patients were of male gender (data from 32 studies). There was a low incidence of comorbidities: arterial hypertension, 49% (29 studies); diabetes mellitus, 29.6% (29 studies); dyslipidemia, 20.5% (27 studies); chronic obstructive pulmonary disease, 8.5% (26 studies); coronary disease, 8.3% (26 studies); and chronic renal disease, 7.6% (28 studies). Medical treatment was selected as first-line treatment for 41.8% of cases. Pooled mortality rate among 34 studies reached 31.4% (95% confidence interval [CI], 25.4%%-37.7%). Pooled amputation rate among 34 studies reached 23.2% (95% CI, 17.3%-29.7%). Pooled clinical improvement rate among 28 studies reached 66.6% (95% CI, 55.4%%-76.9%). Pooled reoperation rate among 29 studies reached 10.5% (95% CI, 5.7%%-16.7%). Medical treatment was associated with a higher death risk compared with any intervention (odds ratio, 4.04; 95% CI, 1.075-15.197; P = .045) although amputation risk was not different between the two strategies (odds ratio, 0.977; 95% CI, 0.070-13.600; P = .986) (data from 31 studies). CONCLUSIONS: SARS-CoV-2 infection is associated with a high risk for thrombotic complications, including ALI. COVID-associated ALI presents in patients with a low incidence of comorbidities, and it is associated with a high mortality and amputation risk. Conservative treatment seems to have a higher mortality risk compared with any intervention, although amputation risk is similar.

Systematic review of temporary intravascular shunt use in military and civilian extremity trauma.

BACKGROUND: The use of temporary intravascular shunts (TIVS) in the setting of military and civilian trauma has grown in recent years, predominantly because of the mounting evidence of improved limb outcomes. We sought to characterize the use and outcomes of TIVS in trauma through a systematic review of military and civilian literature. METHODS: The MEDLINE, EBSCO, EMBASE, and Cochrane databases were searched for studies on TIVS use in military and civilian trauma settings published between January 2000 and March 2021. Reports lacking systematic data collection along with those with insufficient TIVS descriptive and outcome data were excluded. Data regarding the characteristics and outcomes of TIVS were assessed and collective syntheses of military and civilian data performed. RESULTS: Twenty-one reports were included, 14 from civilian trauma centers or databases and 7 from military field data or databases (total of 1,380 shunts in 1,280 patients). Sixteen were retrospective cohort studies, and four were prospective. Five studies had an unshunted comparison group. Shunts were predominantly used in the lower extremity and most commonly for damage control indications. Dwell times were infrequently reported and were not consistently linked to shunt thrombosis or other complications. Anticoagulation during shunting was sparsely reported and inconsistently applied. Shunted limbs had higher injury severity than unshunted limbs but similar salvage rates. CONCLUSION: Temporary intravascular shunts are effective for expeditious restoration of perfusion in severely injured limbs and likely contribute to limb salvage. There is a paucity of comparative TIVS data in the literature and no consistently applied reporting standards, so controversies regarding TIVS use remain. LEVEL OF EVIDENCE: Systematic Review, level IV.

SDF-1 secreted by mesenchymal stem cells promotes the migration of endothelial progenitor cells via CXCR4/PI3K/AKT pathway.

Cell-based therapeutics bring great hope in areas of unmet medical needs. Mesenchymal stem cells (MSCs) have been suggested to facilitate neovascularization mainly by paracrine action. Endothelial progenitor cells (EPCs) can migrate to ischemic sites and participate in angiogenesis. The combination cell therapy that includes MSCs and EPCs has a favorable effect on ischemic limbs. However, the mechanism of combination cell therapy remains unclear. Herein, we investigate whether stromal cell-derived factor (SDF)-1 secreted by MSCs contributes to EPC migration to ischemic sites via CXCR4/Phosphoinositide 3-Kinases (PI3K)/protein kinase B (termed as AKT) signaling pathway. First, by a "dual-administration" approach, intramuscular MSC injections were supplemented with intravenous Qdot® 525 labeled-EPC injections in the mouse model of hind limb ischemia. Then, the mechanism of MSC effect on EPC migration was detected by the transwell system, tube-like structure formation assays, western blot assays in vitro. Results showed that the combination delivery of MSCs and EPCs enhanced the incorporation of EPCs into the vasculature and increased the capillary density in mouse ischemic hind limb. The numbers of CXCR4-positive EPCs increased after incubation with MSC-conditioned medium (CM). MSCs contributed to EPC migration and tube-like structure formation, both of which were suppressed by AMD3100 and wortmannin. Phospho-AKT induced by MSC-CM was attenuated when EPCs were pretreated with AMD3100 and wortmannin. In conclusion, we confirmed that MSCs contributes to EPC migration, which is mediated via CXCR4/PI3K/AKT signaling pathway.

Guideline-Directed Medical Therapy in Patients with Chronic Kidney Disease Undergoing Peripheral Vascular Intervention.

INTRODUCTION: Guideline-directed medical therapy (GDMT) is imperative to improve cardiovascular and limb outcomes for patients with critical limb ischemia (CLI), especially amongst those at highest risk for poor outcomes, including those with comorbid chronic kidney disease (CKD). Our objective was to examine GDMT prescription rates and their variation across individual sites for patients with CLI undergoing peripheral vascular interventions (PVIs), by their comorbid CKD status. METHODS: Patients with CLI who underwent PVI (October 2016-April 2019) were included from the Vascular Quality Initiative (VQI) database. CKD was defined as GFR <60 mL/min/1.73 m2. GDMT included the composite use of antiplatelet therapy and a statin, as well as an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker if hypertension was present. The use of GDMT before and after the index procedure was summarized in those with and without CKD. Adjusted median odds ratios (MORs) for site variability were calculated. RESULTS: The study included 28,652 patients, with a mean age of 69.4 ± 11.7 years, and 40.8% were females. A total of 47.5% had CKD. Patients with CKD versus those without CKD had lower prescription rates both before (31.7% vs. 38.9%) and after (36.5% vs. 48.8%) PVI (p < 0.0001). Significant site variability was observed in the delivery of GDMT in both the non-CKD and CKD groups before and after PVI (adjusted MORs: 1.31-1.41). DISCUSSION/CONCLUSION: In patients with CLI undergoing PVI, patients with comorbid CKD were less likely to receive GDMT. Significant variability of GDMT was observed across sites. These findings indicate that significant improvements must be made in the medical management of patients with CLI, particularly in patients at high risk for poor clinical outcomes.