How I do it: Pedal access and pedal loop revascularization for patients with chronic limb-threatening ischemia.

An increasing proportion of patients with chronic limb-threatening ischemia are older and have multiple comorbidities, including diabetes and renal failure. For those who are not candidates for a surgical bypass, this set of patients presents a challenge to vascular surgeons and interventionalists owing to the complex below-the-knee and increasingly below-the-ankle disease pattern that can fail traditional approaches for endovascular intervention. Two techniques, the retrograde pedal access and the pedal-plantar loop technique, can be useful in these settings and in skilled hands can be used safely, with a high technical success rate. In patients with chronic limb-threatening ischemia who are not candidates for a single-segment saphenous vein bypass, the retrograde pedal access technique can be used not only in the setting of failed antegrade treatment, but also primarily when faced with a difficult groin or as an adjunct during a planned antegrade-retrograde intervention. The pedal plantar loop technique allows for retrograde access to tibial vessels without retrograde vessel puncture and additionally offers the ability to treat the pedal-plantar arch, which may have added benefit in wound healing. We describe the tips and tricks for these two techniques used in our limb salvage practice.

Preoperative hyponatremia and survival after left ventricular assist device implantation.

BACKGROUND: Hyponatremia is associated with adverse outcomes in heart failure and after cardiac surgery. We hypothesized that hyponatremia is associated with poorer short-term and longer term survival in patients after continuous-flow left ventricular assist device (CF-LVAD) placement. METHODS: We reviewed a single-center database of patients who received a CF-LVAD during 2012-2017. Sodium (Na) values obtained within 14 days before CF-LVAD insertion were averaged; patients (n = 332) were divided into hyponatremia (mean Na <135 mEq/L; n = 160; 48.2%) and normonatremia groups (mean Na 135-145 mEq/L; n = 172; 51.8%). Patients requiring preoperative dialysis or pump exchange were excluded. We compared outcomes between preoperative hyponatremia and normonatremia groups. RESULTS: The two groups' baseline characteristics were similar, although hyponatremia patients more often had preoperative mechanical circulatory support (44.4% vs. 31.4%, p = 0.002). Although hyponatremic and normonatremic patients did not differ in 30-day mortality (7.5% vs. 6.5%, p = 0.7), preoperative hyponatremia was associated with greater 5-year mortality (61% vs. 44%, p = 0.03). On binary logistic regression analysis, the strongest independent predictors of late mortality were hyponatremia (odds ratio [OR] 1.88, 95% CI [1.07-3.31], p = 0.02), older age (OR 1.03, 95% CI [1.01-1.05], p = 0.01), and elevated mean right atrial pressure/pulmonary capillary wedge pressure ratio (OR 4.69, 95% CI [1.76-12.47], p = 0.002). CONCLUSIONS: Hyponatremia was not associated with greater early mortality but was associated with poorer late survival. The optimal timing of LVAD implantation in relation to hyponatremia, and whether correcting hyponatremia perioperatively improves long-term survival, should be investigated.

Hyaluronan, a double-edged sword in kidney diseases.

Over the years, hyaluronic acid (HA) has emerged as an important molecule in nephrological and urological studies involving extracellular matrix (ECM) organization, inflammation, tissue regeneration, and viral sensing. During this time, many have noted the perplexing double-edged nature of the molecule, at times promoting pro-fibrotic events and at other times promoting anti-fibrotic events. Different molecular weights of HA can be attributed to these disparities, though most studies have yet to focus on this subtlety. With regard to the kidney, HA is induced in the initial response phase of injury and is subsequently decreased during disease progression of AKI, CKD, and diabetic nephropathy. These and other kidney diseases force patients, particularly pediatric patients, to face dialysis, surgical procedures, and ultimately, transplant. To summarize the current literature for researchers and pediatric nephrologists, this review aims to expound HA and elucidate its paradoxical effects in multiple kidney diseases using studies that emphasize HA molecular weight when available.

Predictors of renal replacement therapy in patients with continuous flow left ventricular assist devices.

Renal replacement therapy (RRT) after continuous flow left ventricular assist device (CF-LVAD) implantation significantly affects patients' quality of life and survival. To identify preoperative prognostic markers in patients requiring RRT after CF-LVAD implantation, we retrospectively reviewed data from patients who underwent implantation of a CF-LVAD at our institution during 2012-2017. Patients who required preoperative RRT were excluded. Preoperative and operative characteristics, as well as survival and adverse events, were compared between 74 (22.2%) patients requiring any duration of postoperative RRT and 259 (77.8%) not requiring RRT. Patients requiring RRT experienced more postoperative complications than patients who did not, including respiratory failure necessitating tracheostomy (35.7% vs 2.5%, p < 0.001), reoperation for bleeding (34.3% vs 11.7%, p < 0.001), and right heart failure necessitating perioperative mechanical circulatory support (32.4% vs 6.9%, p < 0.001). Patients requiring postoperative RRT also had poorer survival at 30 days (74.7% vs 98.8%), 6 months (48.2% vs 95.1%), and 12 months (45.3% vs 90.2%) (p < 0.001). Significant predictors of RRT after CF-LVAD implantation included urine proteinuria (odds ratio [OR] 3.6, 95% confidence interval [CI] [1.7-7.6], p = 0.001), estimated glomerular filtration rate < 45 mL/min/1.73 m2 (OR 3.4, 95% CI [1.5-17.8], p = 0.004), and mean right atrial pressure to pulmonary capillary wedge pressure ratio ≥ 0.54 (OR 2.6, 95% CI [1.3-5.], p = 0.01). Of the 74 RRT patients, 11 (14.9%) recovered renal function before discharge, 36 (48.6%) still required RRT after discharge, and 27 (36.5%) died before discharge. We conclude that preoperative renal and right ventricular dysfunction significantly predict postoperative renal failure and mortality after CF-LVAD implantation.

Skin-specific knockdown of hyaluronan in mice by an optimized topical 4-methylumbelliferone formulation.

Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and accumulation of HA is implicated in the pathogenesis of diseases such as keloid scarring, lymphedema and metastatic melanoma. To understand how HA synthesis contributes to skin physiology, and pathologic and fibrotic disorders, we propose the development of skin-specific HA inhibition model, which tests an optimal delivery system of topical 4-methylumbelliferone (4-MU). A design-of-experiments (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation comprising propylene glycol, ethanol, and water, topically applied to dorsal skin in male and female C57BL/6J wildtype mice to determine the effect on HAS gene expression and HA inhibition. Serum and skin samples were analyzed for HA content along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and KIAA1199. Using results from DOE and response surface methodology with genetic algorithm optimization, we developed an optimal topical 4-MU formulation to result in ∼70% reduction of HA in dorsal skin, with validation demonstrating ∼50% reduction in HA in dorsal skin. 4-MU topical application resulted in significant decrease in skin HAS2 expression in female mice only. Histology showed thicker dermis in male mice, whereas female mice had thinner dermal layer with more adiposity; and staining for HA-binding protein showed that topical 4-MU resulted in breakdown in HA. Our data suggest a topical 4-MU formulation-based dermal HA inhibition model that would enable elucidating the skin-specific effects of HA in normal and pathologic states.

Impact of the coronavirus disease 2019 pandemic on surgical research and lessons for the future.

BACKGROUND: The current coronavirus disease 2019 pandemic has had an unprecedented impact on all physicians and has resulted in dramatic changes to clinical and research operations. No study has yet looked at the impact of coronavirus disease 2019 on the surgical research community. In this study, we sought to understand the impact of the pandemic and its associated restrictions on academic surgeons. METHODS: We surveyed members of the Association for Academic Surgery and the Society of University Surgeons. Survey questions included demographics, current challenges to basic and clinical research activities, attitudes toward remote work and productivity maintenance, and the solutions implemented to maintain productivity. RESULTS: Of 301 respondents, 70% cited a negative impact on research productivity due to mandatory building shutdowns, minimized personnel as a result of social distancing, and suspensions of animal work and clinical trials, with senior faculty and division chiefs and chairs more likely to report a negative impact (P = .001). Only 11% of respondents are documenting their financial losses, and only 19% indicated they received appropriate guidance regarding why and how to monitor the financial impact of the pandemic. Researchers have attempted to maintain research productivity through a focus on remote work, including manuscript writing, grant writing, and data analysis. Some participants have found silver linings, including more time to dedicate to research and family as a result of fewer clinical duties. CONCLUSION: Productivity strategies developed during the pandemic, including writing, remote work and meetings, and structured scheduling, are lessons that will allow the surgical research community to be resilient in the face of future disruptions.

Global cardiovascular care: an overview of high-level political commitment.

BACKGROUND: Six billion people worldwide lack access to safe, timely, and affordable cardiac surgical and interventional care when needed. Cardiovascular diseases are the leading cause of mortality and morbidity around the world, and include a significant surgical backlog of rheumatic and congenital heart diseases. Here, we review the political commitment by the WHO, the UN, and the World Bank to build and strengthen healthcare services for cardiovascular diseases, with a particular focus on cardiac surgical and interventional cardiology services around the world. METHODS: A literature search was performed in the WHO, UN, and World Bank Governing Body databases to identify policy documents mentioning curative cardiovascular disease care. The Governing Body documentation, the Institutional Repository for Information Sharing database of the WHO, and the Official Document System of the UN were used. Documents only discussing prevention of cardiovascular diseases were excluded. RESULTS: Fifty-nine unique documents were identified, including 56 from the WHO, 3 from the World Bank, and none from the UN; 12 (20.4%) documents mentioned cardiac surgery, and 6 (10.2%) contained some actionable language to incorporate cardiac surgical services, but none was explicitly dedicated to cardiac surgical services. CONCLUSION: Although growing, high-level political commitment for curative cardiovascular health services remains minimal. Increased awareness is needed to develop comprehensive cardiovascular care that is necessary to mitigate the increasing burden of premature morbidity and mortality from cardiac disease, and to work towards the Sustainable Development Goals and Universal Health Coverage.

Factor Xa inhibitors in patients with continuous-flow left ventricular assist devices.

OBJECTIVE: Warfarin is standard anticoagulation therapy for patients with a continuous-flow left ventricular assist device (CF-LVAD). However, warfarin requires regular monitoring and dosage adjustments and fails for many patients, causing thromboembolic and bleeding events. Factor Xa inhibitors have been shown to be noninferior to warfarin in preventing strokes and are associated with less intracranial hemorrhage in patients with atrial fibrillation. We evaluated treatment safety and effectiveness in CF-LVAD patients who switched from warfarin to a factor Xa inhibitor (apixaban or rivaroxaban) after warfarin failure. METHODS: This was a retrospective, single-center study of patients treated between 2008 and 2018. We assessed the occurrence of stroke, non-central nervous system (CNS) embolism, pump thrombosis, and major gastrointestinal bleeding and intracranial hemorrhage during therapy. RESULTS: We identified seven patients: five were male, the average body mass index was 30 kg/m2, and average age was 56 years. Preimplantation comorbidities included hypertension (all patients) and diabetes mellitus, ischemic cardiomyopathy, atrial fibrillation, and previous myocardial infarction (four patients each). Overall, patients received warfarin for 3968 days and apixaban/rivaroxaban for 1459 days. The warfarin group was within the therapeutic INR range (2.0-3.0) 30% of the time. Complication rates did not differ between warfarin and apixaban/rivaroxaban: strokes, 0.20 vs none, non-CNS embolism, 0.54 vs none; pump thrombosis, 0.27 vs none; major gastrointestinal bleeding, 0.20 vs 0.50; intracranial hemorrhage, 0.13 vs none. CONCLUSIONS: Factor Xa inhibitors may be viable treatment options for CF-LVAD patients for whom warfarin therapy has failed. Large prospective studies are necessary to confirm these results.

Delayed Hypoxemia Following Traumatic Brain Injury Exacerbates White Matter Injury.

Hypoxemia immediately following traumatic brain injury (TBI) has been observed to exacerbate injury. However, it remains unclear whether delayed hypoxemia beyond the immediate postinjury period influences white matter injury. In a retrospective clinical cohort of children aged 4-16 years admitted with severe TBI, 28/74 (35%) patients were found to experience delayed normocarbic hypoxemia within 7 days of admission. Based on these clinical findings, we developed a clinically relevant mouse model of TBI with delayed hypoxemia by exposing 5-week old (adolescent) mice to hypoxic conditions for 30 minutes starting 24 hours after moderate controlled cortical impact (CCI). Injured mice with hypoxemia had increased axonal injury using both ß-amyloid precursor protein and NF200 immunostaining in peri-contusional white matter compared with CCI alone. Furthermore, we detected increased peri-contusional white matter tissue hypoxia with pimonidazole and augmented astrogliosis with anti-glial fibrillary acidic protein staining in CCI + delayed hypoxemia compared with CCI alone or sham surgery + delayed hypoxemia. Microglial activation as evidenced by Iba1 staining was not significantly altered by delayed hypoxemia. These clinical and experimental data indicate the prevention or amelioration of delayed hypoxemia effects following TBI may provide a unique opportunity for the development of therapeutic interventions to reduce axonal injury and improve clinical outcomes.