Characterization and management of type II and complex endoleaks after fenestrated/branched endovascular aneurysm repair.

INTRODUCTION: Endoleaks are more common after fenestrated/branched endovascular aneurysm repair (F/B-EVAR) than infrarenal EVAR secondary to the length of aortic coverage and number of component junctions. Although reports have focused on type I and III endoleaks, less is known regarding type II endoleaks after F/B-EVAR. We hypothesized that type II endoleaks would be common and often complex (associated with additional endoleak types), given the potential for multiple inflow and outflow sources. We sought to describe the incidence and complexity of type II endoleaks after F/B-EVAR. METHODS: F/B-EVAR data prospectively collected at a single institution in an investigational device exemption clinical trial (G130210) were retrospectively analyzed (2014-2021). Endoleaks were characterized by type, time to detection, and management. Primary endoleaks were defined as those present on completion imaging or at first postoperative imaging, and secondary were those on subsequent imaging. Recurrent endoleaks were those that developed after a successfully resolved endoleak. Reinterventions were considered for type I or III endoleaks or any endoleak associated with sac growth >5 mm. Technical success defined as the absence of flow in the aneurysm sac at procedure conclusion and methods of intervention were captured. RESULTS: Among 335 consecutive F/B-EVARs (mean ± standard deviation follow-up: 2.5 ± 1.5 years), 125 patients (37%) experienced 166 endoleaks (81 primary, 72 secondary, and 13 recurrent). Of these 125 patients, 50 (40% of patients) underwent 71 interventions for 60 endoleaks. Type II endoleaks were the most frequent (n = 100, 60%), with 20 identified during the index procedure, 12 (60%) of which resolved before 30-day follow-up. Of the 100 type II endoleaks, 20 (20%; 12 primary, 5 secondary, and 3 recurrent) were associated with sac growth; 15 (75%) of those with associated sac growth underwent intervention. At intervention, 6 (40%) were reclassified as complex, with a concomitant type I or type III endoleak. Initial technical success for endoleak treatment was 96% (68 of 71). There were 13 recurrences, all of which were associated with complex endoleaks. CONCLUSIONS: Nearly half of the patients who underwent F/B-EVAR experienced an endoleak. The majority were classified as type II, with nearly a fifth associated with sac expansion. Interventions for a type II endoleak frequently led to reclassification as complex, with a concomitant type I or III endoleak not appreciated on computed tomography angiography and/or duplex. Further study is needed to determine if the primary treatment goal for complex aneurysm repair is sac stability or sac regression, as this would inform both the importance of properly classifying endoleaks noninvasively and the intervention threshold for managing type II endoleaks.

Initial single-center experience using Fiber Optic RealShape guidance in complex endovascular aortic repair.

OBJECTIVE: In the present study, we have described the technical success using Fiber Optic RealShape (FORS) endovascular guidance and its effects on the overall procedural time and radiation usage during complex endovascular aortic repair (EVAR). METHODS: Fenestrated and branched EVARs performed at a single center from 2017 to 2022 were prospectively studied. FORS-guided procedures were matched retrospectively 1:3 to non-FORS-guided procedures by the incorporated target arteries and body mass index. Technical success was defined as successful target vessel cannulation using FORS for the entirety of navigation (wire insertion to exchange for a stiff wire). The predictors of technical success were evaluated via logistic regression. The procedural times and radiation doses were compared between the matched cohorts using the Wilcoxon rank sum test. RESULTS: A total of 21 FORS-guided procedures were matched to 61 non-FORS-guided procedures. A total of 95 FORS cannulations were attempted (87 for the visceral target artery and 8 for the bifurcate gate). Technical success was achieved in 81 cannulations (85%); 15 (16%) were completed without the use of live fluoroscopy. The univariate predictors of FORS technical success included <50% target artery stenosis, <50% target artery calcification, and the target vessel attempted (P < .05 for each). FORS failures were attributed to device material properties in six cases, device failure in two cases, and the wire/catheter combination in six. The use of FORS guidance was associated with shorter median procedural and fluoroscopy times and a lower dose area product and air kerma (P ≤ .0001 for each). CONCLUSIONS: The results from our initial experience with FORS during complex EVAR, including our learning curve, has shown promise, with acceptable technical success and reductions in procedural times and radiation usage.

Acute management of atrial fibrillation in congestive heart failure with reduced ejection fraction in the emergency department.

INTRODUCTION: Acute heart rate control for atrial fibrillation (AF) with rapid ventricular response (RVR) in the emergency department (ED) is often achieved utilizing intravenous (IV) non-dihydropyridine calcium channel blockers (CCB) or beta blockers (BB). For patients with concomitant heart failure with a reduced ejection fraction (HFrEF), the American Heart Association and other clinical groups note that CCB should be avoided due to their potential negative inotropic effects. However, minimal evidence exists to guide this current recommendation. The primary objective of this study was to compare the incidence of adverse effects in the HFrEF patient population whose AF with RVR was treated with IV diltiazem or metoprolol in the ED. METHODS: This single center, retrospective review included patients ≥18 years old with HFrEF who presented in AF with RVR and received IV diltiazem or metoprolol in the ED. The primary outcome was adverse effects of therapy defined as: 1) hypotension (systolic blood pressure < 90 mmHg requiring fluid bolus or vasopressors) or bradycardia (heart rate < 60 beats/min) within 60 min of medication administration 2) worsening heart failure symptoms defined as increased oxygen requirements within four hours or inotropic support within 48 h. Secondary outcomes included the incidence of rate control failure, patient disposition, ED length of stay, hospital length of stay, and in-hospital mortality. RESULTS: One hundred and twenty-five patients met inclusion criteria, with 57 receiving diltiazem and 68 receiving metoprolol. Overall adverse effects for diltiazem and metoprolol were similar (32% vs. 21%, P = 0.217). However, there was a significantly higher incidence of worsening heart failure symptoms within the diltiazem group (33% vs 15%, P = 0.019). Rate control failure at 60 min did not differ significantly between diltiazem and metoprolol (51% vs 62%, P = 0.277). CONCLUSIONS: In HFrEF patients with AF, there was no difference in total adverse events in patients treated with IV diltiazem compared to metoprolol. However, the diltiazem group had a higher incidence of worsening CHF symptoms defined as increased oxygen requirement within four hours or initiation of inotropic support within 48 h.

Utilization and extravasation of peripheral norepinephrine in the emergency department.

OBJECTIVE: Vasopressors are typically administered through central venous catheters (CVC) due to a historical risk of extravasation with peripheral administration. However, CVC insertion is a time-consuming process that may delay vasopressor administration and is associated with complications. The Virginia Commonwealth University Health System (VCUHS) Emergency Department (ED) implemented a protocol that recommends peripheral norepinephrine (pNE) be administered through an 18 gauge or larger at or above the antecubital fossa or the external jugular vein with a maximum dose of 20 µg/min. This study characterizes the use and incidence of extravasation in all adult patients who received pNE initiated in the VCUHS ED. METHODS: This was an observational, retrospective cohort study in adult patients from March 2016 to March 2019. Of the 331 patients that were screened, 177 met inclusion criteria. Data were analyzed using descriptive statistics. RESULTS: Patients had a median age of 60 years and 59% were male. The median APACHE II score was 25 with an overall hospital mortality of 27%. A majority of patients received pNE for distributive shock (63%). Approximately 69% received pNE through an antecubital infusion site. The median total pNE duration was 62 min (IQR 32, 142). Eighty-four percent of patients received a central line. Only 2.3% of patients had confirmed extravasation in addition to another 2.3% where extravasation could not be excluded, for a total rate of 4.5%. None had subsequent extremity injury. CONCLUSIONS: Administration of pNE according to the VCUHS ED protocol resulted in a low extravasation rate.

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease.

Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease.

Allergic Reaction to Ketamine as Monotherapy for Procedural Sedation.

BACKGROUND: Ketamine is a cyclohexamine derivative that acts as a noncompetitive N-methyl D-aspartate receptor antagonist. Its use for procedural sedation is recommended by national clinical policy. However, its immunogenic potential is not well documented. CASE REPORT: We report a case of allergic reaction associated with the administration of intravenous ketamine for procedural sedation in a 16-year-old male. Minutes after administration, the patient developed a morbilliform, erythematous rash that extended to the upper and lower torso and resolved with intravenous diphenhydramine. It is most likely that this allergic reaction was caused by a ketamine-induced histamine release that has been described in vitro. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This is the first case report in which ketamine was used as monotherapy in the emergency department for the facilitation of procedural sedation that resulted in an allergic reaction. Supportive measures, including advanced airway procedures and hemodynamic support, may be necessary in more severe anaphylactic cases. Providers should be aware of this potential adverse effect when using ketamine for procedural sedation.

Lack of adverse effects from flumazenil administration: an ED observational study.

BACKGROUND: Flumazenil is an effective benzodiazepine (BZD) antagonist. Empiric use of flumazenil in the emergency department (ED) is not widely recommended due to concerns of seizures, which are commonly associated with coingestants and BZD withdrawal. OBJECTIVE: The objective of the study is to assess adverse events and clinical outcomes of flumazenil administration in known and suspected BZD overdose in an ED at a tertiary academic medical center. METHODS: This is a retrospective observational study of adult patients administered flumazenil for known or suspected BZD overdose in the ED over 7 years. Outcomes included mental status improvement, the incidence of seizures, and intubation of the trachea after flumazenil administration. RESULTS: Twenty-three patients were included in the analysis, of which 15 (65%) of patients experienced some type of clinically significant mental status improvement. No seizures were identified despite 7 (35%) reported proconvulsant coingestants. One patient required intubation of the trachea but was subsequently extubated in the ED. CONCLUSIONS: A majority of patients had improved mental status after the administration of flumazenil. No patient experienced seizures. Additional studies that clarify the role of flumazenil for ED patients with suspected BZD toxicity are warranted.

Gem1 and ERMES do not directly affect phosphatidylserine transport from ER to mitochondria or mitochondrial inheritance.

In yeast, a protein complex termed the ER-Mitochondria Encounter Structure (ERMES) tethers mitochondria to the endoplasmic reticulum. ERMES proteins are implicated in a variety of cellular functions including phospholipid synthesis, mitochondrial protein import, mitochondrial attachment to actin, polarized mitochondrial movement into daughter cells during division, and maintenance of mitochondrial DNA (mtDNA). The mitochondrial-anchored Gem1 GTPase has been proposed to regulate ERMES functions. Here, we show that ERMES and Gem1 have no direct role in the transport of phosphatidylserine (PS) from the ER to mitochondria during the synthesis of phosphatidylethanolamine (PE), as PS to PE conversion is not affected in ERMES or gem1 mutants. In addition, we report that mitochondrial inheritance defects in ERMES mutants are a secondary consequence of mitochondrial morphology defects, arguing against a primary role for ERMES in mitochondrial association with actin and mitochondrial movement. Finally, we show that ERMES complexes are long-lived, and do not depend on the presence of Gem1. Our findings suggest that the ERMES complex may have primarily a structural role in maintaining mitochondrial morphology.

Adipose tissue as a linchpin of organismal ageing.

Ageing is a conserved biological process, modulated by intrinsic and extrinsic factors, that leads to changes in life expectancy. In humans, ageing is characterized by greatly increased prevalence of cardiometabolic disease, type 2 diabetes and disorders associated with impaired immune surveillance. Adipose tissue displays species-conserved, temporal changes with ageing, including redistribution from peripheral to central depots, loss of thermogenic capacity and expansion within the bone marrow. Adipose tissue is localized to discrete depots, and also diffusely distributed within multiple organs and tissues in direct proximity to specialized cells. Thus, through their potent endocrine properties, adipocytes are capable of modulating tissue and organ function throughout the body. In addition to adipocytes, multipotent progenitor/stem cells in adipose tissue play a crucial role in maintenance and repair of tissues throughout the lifetime. Adipose tissue may therefore be a central driver for organismal ageing and age-associated diseases. Here we review the features of adipose tissue during ageing, and discuss potential mechanisms by which these changes affect whole-body metabolism, immunity and longevity. We also explore the potential of adipose tissue-targeted therapies to ameliorate age-associated disease burdens.

Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds.

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design.

Submitting a successful National Institutes of Health career development award for the vascular surgeon scientist.

Obtaining a career development award from the National Institutes of Health (K award) is often an important step in establishing a career as a vascular surgeon scientist. The application and review process is competitive, involves many steps, and may be confusing to the prospective applicant. Further, there are requirements involving mentors and the applicant's institution. This article, authored completely by vascular surgeons with active K awards, is intended for potential applicants and personnel at their institution and reviews relevant information including strategies for a successful application.

Sustained hypotension following intravenous metoclopramide.

OBJECTIVE: To report a case of sustained hypotension associated with the use of intravenous metoclopramide. CASE SUMMARY: A 50-year-old woman developed a hypotensive episode lasting approximately 90 minutes after the administration intravenous metoclopramide for the treatment of a migraine. The patient presented to the emergency department after she woke up with a severe headache that was much worse than her normal migraine headaches. Her past medical history included migraines, diabetes type 2, hypertension, and hyperlipidemia. Fifteen minutes after the administration of intravenous metoclopramide 10 mg, the patient's systolic blood pressure decreased from 138 to 84 mmHg (a mean arterial pressure decrease of 40.7 mmHg). The patient was given 1 L of intravenous NaCl 0.9% that had minimal effect on blood pressure. The patient did not reapproach her baseline systolic blood pressure until 90 minutes after the metoclopramide administration when it was measured at 138 mmHg. Subsequent contrast tomography of the head was negative and the patient's headache was successfully treated with butalbital/acetaminophen/caffeine. The patient was discharged home the same day. DISCUSSION: There are few published case reports of metoclopramide-induced hypotension in the current literature. Of those published, all showed transient hypotension with metoclopramide, lasting seconds to minutes. An objective causality assessment for drug-associated adverse drug reaction showed metoclopramide as a probable cause of the patient's hypotension (Naranjo score of 5). In this case, several indicators of metoclopramide induced hypotension were evident, including the timing of the hypotension after drug administration and the lack of any other possible causes of hypotension. This is the first published case report of sustained hypotension due to intravenous metoclopramide. CONCLUSION: Intravenous metoclopramide may cause sustained episodes of hypotension.

Comprehensive Care of Lower-Extremity Wounds.

There are 5 common types of chronic nonhealing lower-extremity wounds: arterial, venous, diabetic foot ulcer, pressure, and mixed or atypical. Each chronic wound type has distinct features, and understanding the underlying cause will dictate the wound treatment plan. Here, the authors review the distinguishing wound properties for these 5 common chronic nonhealing lower-extremity wounds and outline a comprehensive treatment plan that addresses wound perfusion, debridement, infection control, moisture balance, and use of complementary advanced wound care products.

Physical activity regulates the immune response to breast cancer by a hematopoietic stem cell-autonomous mechanism.

Physical activity is a modifiable lifestyle factor that is associated with a decreased risk for the development of breast cancer. While the exact mechanisms for the reduction in cancer risk due to physical activity are largely unknown, it is postulated that the biological reduction in cancer risk is driven by improvements in inflammation and immune function with exercise. Hematopoietic stem cells (HSCs) are the progenitor for all of the cells of the immune system and are involved in cancer immunosurveillance through differentiation into cytotoxic cell population. In this study, we investigate the role of physical activity (PA) in a spontaneously occurring model of breast cancer over time, with a focus on tumor incidence, circulating and tumor-infiltrating immune cells as well gene expression profiles of tumors and hematopoietic stem cells. Furthermore, we show that, in addition to a direct effect of PA on the immune cells of tumor-bearing mice, PA reduces the oxidative stress in HSCs of wildtype and tumor-bearing mice, and by doing so, alters the differentiation of the HSCs towards T cells in order to enhance cancer immunosurveillance.

Wnt signaling preserves progenitor cell multipotency during adipose tissue development.

Mesenchymal stem/progenitor cells are essential for tissue development and repair throughout life, but how they are maintained under chronic differentiation pressure is not known. Using single-cell transcriptomics of human progenitor cells we find that adipose differentiation stimuli elicit two cellular trajectories: one toward mature adipocytes and another toward a pool of non-differentiated cells that maintain progenitor characteristics. These cells are induced by transient Wnt pathway activation and express numerous extracellular matrix genes and are therefore named structural Wnt-regulated adipose tissue cells. We find that the genetic signature of structural Wnt-regulated adipose tissue cells is present in adult human adipose tissue and adipose tissue developed from human progenitor cells in mice. Our results suggest a mechanism whereby adipose differentiation occurs concurrently with the maintenance of a mesenchymal progenitor cell pool, ensuring tissue development, repair and appropriate metabolic control over the lifetime.

A distinct class of hematopoietic stem cells develop from the human yellow bone marrow.

Aging and metabolic diseases are accompanied by systemic inflammation, but the mechanisms that induce this state are not known. We developed a human bone-marrow organoid system to explore mechanisms underlying metabolic-disease associated systemic inflammation. We find that a distinct type of hematopoietic stem cell (HSC) develops in the adipose-rich, yellow bone marrow, which is known to gradually replace the hematopoietic red marrow as we age and during metabolic disease. Unlike HSCs derived from the red bone marrow, HSCs derived from the yellow bone marrow have higher proliferation rates, increase myeloid differentiation, skew towards pro-inflammatory M1 macrophage differentiation, and express a distinct transcriptomic profile associated with responsiveness to wounding. Yellow marrow-derived HSCs express higher levels of the leptin receptor, which we find to be further increased in patients with type 2 diabetes. Our work demonstrates that the human long bone yellow marrow is a niche for a distinct class of HSCs which could underlie hematopoietic dysfunction during aging and metabolic disease processes suggesting a shared inflammaging mechanism.

Pet Medications: A Tail of Caution.

PURPOSE: A case report of pet medications appearing along with the patient's medications (pet owner) in the external medication history list of the electronic medical record (EMR). CASE PRESENTATION: A 67-year-old female presented to the emergency department for altered mental status. A medication history was performed by the pharmacist in an attempt to identify possible etiologies of the patient's clinical status. An external prescription refill report from the EMR included 2 medications that could not be confirmed by the family as the patient's: phenobarbital 50 mg twice daily and zonisamide 200 mg every 12 hours. The patient's pharmacy identified that the prescriptions were pet medications registered under the patient's name and date of birth for the state's prescription monitoring program. CONCLUSION: A lack of standardization between pet identifiers in community pharmacy databases and state Board of Pharmacy regulations for prescription monitoring programs, has led to the association of pet medications with their human owners in the EMR. Patient medication histories should always be verified and validated utilizing patient/patient family interviews and prescription refill histories. Utilization of pharmacists to identify and scrutinize inconsistencies can reduce medication errors that could occur during medication history or reconciliation.

Does oxidative stress modulate left ventricular diastolic function in asymptomatic subjects with hereditary hemochromatosis?

BACKGROUND: Little is known about the early mechanisms mediating left ventricular (LV) diastolic dysfunction in patients with hereditary hemochromatosis (HH). However, the increased oxidative stress related to iron overload may be involved in this process, and strain rate (SR), a sensitive echocardiography-derived measure of diastolic function, may detect such changes. AIM: we evaluated the relationship between left ventricular diastolic function measured with tissue Doppler SR and oxidative stress in asymptomatic HH subjects and control normal subjects. MATERIALS AND METHODS: Ninety-four consecutive visits of 43 HH subjects, age 30-74 (50 +/- 10, mean +/- SD), and 37 consecutive visits of 21 normal volunteers, age 30-63 (48 +/- 8), were evaluated over a 3-year period. SR was obtained from the basal septum in apical four-chamber views. All patients had confirmed C282Y homozygosity, a documented history of iron overload, and were New York Heart Association functional class I. Normal volunteers lacked HFE gene mutations causing HH. RESULTS: In the HH subjects, the SR demonstrated moderate but significant correlations with biomarkers of oxidative stress; however, no correlations were noted in normal subjects. The biomarkers of iron overload per se did not show significant correlations with the SR. CONCLUSION: Although our study was limited by the relatively small subject number, these results suggest that a possible role of oxidative stress to affect LV diastolic function in asymptomatic HH subjects and SR imaging may be a sensitive measure to detect that effect.

Use of fenestrated-branched endovascular aneurysm repair to treat Carrel patch aneurysmal degeneration after open thoracoabdominal aortic aneurysm repair.

Two patients with a history of open type II thoracoabdominal aortic aneurysm repair presented with saccular aneurysmal degeneration of the Carrel patch. The degenerated segments measured 6.2 cm and 7.4 cm, respectively, and involved the celiac artery, superior mesenteric artery, and right renal artery. Both patients successfully underwent a custom fenestrated-branched endovascular aneurysm repair with downgoing branches to the celiac artery, superior mesenteric artery, and right renal artery and a stented fenestration to the left renal artery. Completion angiography demonstrated no endoleak and patent visceral-renal segments. Both patients were discharged home on postoperative day 2.