An Analysis of Cost-Effectiveness and Clinical Outcomes of a Comprehensive Aortic Service in a Tertiary Center over One Year.

BACKGROUND: Endovascular aortic repair (EVAR) is an established and attractive alternative to open surgical repair (OSR) of abdominal aortic aneurysms (AAA) due to its superior short-term safety profile. However, opinions are divided regarding its long-term cost-effectiveness. We compared the total yearly cost of running endovascular and OSR services in a single tertiary center to determine whether fenestrated EVAR (FEVAR) represents a clinically efficacious, affordable treatment option. METHODS: A single-center retrospective review was performed on 109 patients undergoing a procedure related to index or previous abdominal aortic repair, with 1 year follow-up. Data was collected from the National Vascular Registry and hospital records. The primary outcome was cost per quality-adjusted life year. Secondary outcomes included 30-day mortality and morbidity, reintervention rates, length of hospital stay, aneurysm, and all-cause mortality at 1 year for elective index procedures. RESULTS: The average cost per patient of all FEVAR was £16,041.53 (±8,857.54), £13,893.51 (±£21,425.25) for standard EVAR, and £15,357.22 (±£15,904.49) for OSR (FEVAR versus EVAR P = 0.55, FEVAR versus OSR P = 0.83, OSR versus EVAR P = 0.76). Of the secondary outcomes, significant findings included increased length of stay and respiratory morbidity for patients undergoing open versus endovascular repair. There was no significant difference in 30-day or 1-year mortality between groups. CONCLUSIONS: FEVAR, EVAR, and OSR all represent cost-effective options for aortic repair with similar outcomes. Our data highlights the potential for FEVAR to present a viable alternative to open repair, particularly in higher-risk groups, when performed in specialist centers.

Does Modified Rankin Score (mRS) Matter? The Impact of Stroke Severity on Carotid Artery Endarterectomy (CEA) Outcomes.

BACKGROUND: Carotid artery endarterectomy (CEA) is recommended to reduce stroke risk in patients following nondisabling ischemic stroke (modified Rankin Score mRS<3). We reviewed CEA outcomes in patients after more devastating strokes (mRS≥3). METHODS: An observational cohort study was performed, and data were collected from 1013 CEA cases over 15 years. Patient demographics, comorbidities and postoperative outcomes were compared between preoperative mRS<3 (Group 1) and mRS≥3 (Group 2). Statistical significance was determined by P < 0.05. RESULTS: Ninety-one (9%) patients were mRS ≥3. There was no significant difference between age, gender, and operated side. Group 2 had significantly higher rates of diabetes and frailty. There was no significant difference in anesthetic type. Group 2 spent longer in High Dependency. Return to theater and postoperative complications were similar. Incidence of perioperative stroke, mortality, and readmission rates were not significant at 30 days postoperation between the 2 groups. CONCLUSIONS: Patients with a higher mRS have more preoperative comorbidities but short-term perioperative complication rate is not significantly different. Patient selection should be undertaken with care.

A Retrospective Cohort Study of Cerebrovascular Fibromuscular Dysplasia.

BACKGROUND: Fibromuscular dysplasia (FMD) is a rare vasculopathy for which limited data are available particularly from Europe. Our aim was to study the clinical characteristics of a regional cohort of carotid fibromuscular dysplasia patients to assess their clinical outcomes and the rate of vascular complications. METHODS: A retrospective cohort study of all cases of carotid/cerebrovascular FMD presenting to our regional vascular service (catchment population approximately 2 million), between 1998 and 2020. Imaging reports and patient case notes were screened using the keywords "FMD", "Fibromuscular Dysplasia", and "carotid". From case-note and imaging review, all relevant clinical data were extracted and the anatomical extent of vascular disease recorded. RESULTS: Eighty six patients with a diagnosis of cerebrovascular fibromuscular dysplasia were identified on imaging (31 computed tomography angiography, 46 magnetic resonance angiography, and 9 digital subtraction angiography) by a neurovascular radiologist. The mean age was 64 years, 78 (90%) patients were female, and 45/59 (75%) were Caucasian. Presenting clinical syndromes were Stroke/transient ischemic attack in 54 (63%) patients, symptomatic intracranial aneurysm in 6 (10%), and other neurological symptoms (headache/migraine, tinnitus) in 14 (16%), with 11 (13%) presenting incidentally. Six patients (7%) had a positive family history of FMD (2 patients) or other cerebrovascular event (4 patients: carotid dissection, intracerebral bleed, or stroke). Eight patients (9%) had a known or suspected hereditary connective tissue disorder (2 Ehlers-Danlos syndrome). Involved vessels were as follows: Carotid (mainly extracranial) in 79 (92%), vertebral 19 (22%), and a combination of these in 15 (17%) patients. Fifty eight (67%) patients had bilateral disease. Cerebrovascular complications were observed in 35 (41%) patients as follows: carotid dissection 11 (23%), carotid stenosis or occlusion 8 (9%), carotid aneurysm 8 (9%), cerebral aneurysm 9 (11%), vertebral aneurysm/dissection 2 (2%), and carotid-cavernous fistula 2 (2%). Of the 22 patients who had extracranial imaging, 14 (60%) had FMD affecting other beds-renal artery in 8 (36%) patients, other visceral arteries in 4 (18%), and aorta in 2 (9%). In addition, 4 (18%) patients had aneurysm or dissection affecting renal, splenic, and lower limb arteries. Overall, 67 (80%) patients had FMD affecting more than 1 vessel and 50 (58%) had multisite FMD (>/ = 2 vascular beds involved). Fifty nine (68%) patients were managed conservatively on close surveillance. Nineteen (21%) patients required carotid/cerebrovascular intervention and 9 (10%) required vascular intervention at other sites. Recurrent cerebrovascular events (stroke/transient ischemic attack, symptomatic Berry aneurysm) were seen in 20 (23%) patients. Overall mortality was 7% over a median follow-up period of 47 months. CONCLUSIONS: Carotid FMD patients have a high rate of multisite involvement, extracerebral vascular complications, and evidence of hereditary vasculopathy, requiring careful screening and surveillance.

A Stepwise Haemostasis Intraoperative Protocol Driven Reduction of Haematoma Rate Following Symptomatic Carotidendarterectomy.

INTRODUCTION: Carotid endarterectomy (CEA) for symptomatic stenosis reduces further stroke risk. Post-CEA haematoma increases the risk of complications including stroke. There are few studies considering protocols aimed at reducing post-CEA haematoma rates. Presented are the outcomes of a protocol developed to reduce this surgical complication. METHOD: The protocol was implemented in 112 consecutive CEA. It involves stepwise additional measures to ensure haemostasis before wound closure. Attention to bleeding points is followed by light compression for 10 min. Protamine is then given if haemostasis has not been achieved. If after 20 min the problem persists Tranexamic acid is given. Following a further 20 min if haemostasis is not yet achieved a platelet transfusion is undertaken. Haematoma rates, return to theatre for post-operative haematoma and other complications were compared with 100 consecutive pre-protocol introduction CEA cases. RESULTS: Of 112 CEA patients, 19 received protamine, 8 protamine and tranexamic acid. One case required platelet transfusion. Neck haematoma rate fell from 10 to 3 cases (P = .02, OR: 0.25 [95% CI .07-.94]), of which returned to theatre for haematoma evacuation fell from 6 to 1 case (P = .03, OR: 0.14 [95% CI .02-1.19]). 30 day stroke and death rate reduced from 5% to 1.8% (P = .11, OR: 0.35 [95% CI .07-1.82]). CONCLUSION: The stepwise haemostasis intraoperative protocol can reduce post-CEA haematoma rates.

Infective Native Extracranial Carotid Artery Aneurysms: A Systematic Review.

BACKGROUND: Infective native extracranial carotid artery aneurysms are rare, and their management is variable due to a lack of evidence assessing outcomes. METHODS: We performed a systematic literature review following PRISMA guidelines to identify all reported cases of infective native extracranial carotid artery aneurysms between January 1970 and March 2021. RESULTS: This study identified 193 infective native aneurysms of the extracranial carotid artery from 154 sources. Patients were predominantly male (71.4%), and age ranged from 6 months to 89 years old. The most common presenting features were a neck mass and fever, but also included hemorrhage, respiratory distress, and neurological symptoms. Most aneurysms were located in the internal carotid artery (47.4%). Staphylococcus (23.3%) was the most commonly identified causative pathogen, followed by Mycobacterium tuberculosis (20.9%). Most appeared to become infected by direct local spread. Treatment strategies involved open surgical methods in 101 cases and an endovascular approach in 41 cases. In 4 cases, a hybrid method involving concurrent endovascular and open surgical management was undertaken. In 5 cases, there was antibiotic treatment alone. In the open surgery-treated group, the complication rate was 20.8% compared to 13.2% in the endovascular group. Mortality rate was 5.6%. CONCLUSIONS: Our review identified 193 cases of infective native extracranial carotid artery aneurysms. Direct local spread of a staphylococcus infection was the commonest cause. Endovascular management was associated with fewer early complications than open surgical management.

Toll-like receptors 2 and 6 mediate apoptosis and inflammation in ischemic skeletal myotubes.

Critical limb ischemia (CLI) is associated with skeletal muscle damage. However, the pathophysiology of the muscle damage is poorly understood. Toll-like receptors (TLR) have been attributed to play a role in ischemia-induced tissue damage but their role in skeletal muscle damage in CLI is unknown. TLR2 and TLR6 expression was found to be upregulated in skeletal muscle of patients with CLI. In vitro, ischemia led to upregulation of TLR2 and TLR6 by myotubes, and activation of the downstream TLR signaling pathway. Ischemia-induced activation of the TLR signaling pathway led to secretion of the pro-inflammatory cytokine interleukin-6 and muscle apoptosis, which were abrogated by neutralising TLR2 and TLR6 antibodies. Our study demonstrates that TLR2 and TLR6 are upregulated in ischemic muscle and play a role in ischemia-induced muscle damage. Thus, manipulating the TLR pathway locally may be of potential therapeutic benefit.

Role of surgical thoracic sympathetic interruption in treatment of facial blushing: a systematic review.

OBJECTIVES: This paper aims to review the evidence to support the effectiveness of sympathectomy as a treatment for facial blushing in terms of relief of facial blushing, patient satisfaction, recurrence of blushing, patients regretting treatment and its associated complications. METHODS: A systematic search strategy was performed in Ovid-Medline, Embase, Cochrane library and NICE. Studies reporting outcomes of sympathetic interruption in the treatment of facial blushing were retrieved. RESULTS: Nine studies met the inclusion criteria with 1369 patients included in the final analysis. The age range of patients was 8 to 74 years (from 7 studies) with 56% females. Mean follow up was 21 months in 8 studies (range 6 to 30 months). The pooled proportion of patients who had good relief of facial blushing was 78.30% (95% C.I. 58.20% - 98.39%). Complete satisfaction was reported in 84.02% (95% C.I. 71.71% - 96.33%). Compensatory sweating and gustatory sweating were the commonest complications occurring in 74.18% (95% C.I. 58.10% - 90.26%) and 24.42% (95% C.I. 12.22% - 36.61%) respectively. The estimated proportion of patients regretting surgery was 6.79% (C.I 2.08% 11.50%). CONCLUSION: Sympathetic interruption at T2 or T2-3 ganglia appears to be an effective treatment for facial blushing. However, lack of randomized trials comparing sympathetic interruption with non-surgical methods of treatment and heterogeneity of included studies with respect to assessment of outcome measures preclude strong evidence and definitive recommendations.

Treatment of Primary Craniofacial Hyperhidrosis: A Systematic Review.

BACKGROUND: Primary craniofacial hyperhidrosis (CH) can have a profoundly negative impact on quality of life. No comprehensive review of its management exists. OBJECTIVE: The objective of this review is to present the best clinical evidence to guide CH management. METHODS: A systematic review was performed using PRISMA guidelines. MEDLINE and EMBASE were searched from 1966 to 2014 for articles using the MeSH terms "Hyperhidrosis", "Head", "Neck" and synonymous text words. Inclusion criteria were experimental and observational studies addressing CH treatment. Two reviewers independently assessed study quality and analysed data. RESULTS: Of 833 references yielded, 27 met inclusion criteria and were analysed. Twenty-two studies evaluated T2 sympathetic ablation (Level III evidence). Outcome measures were subjective and mean follow-up was 29 months. Reported efficacy was high (70-100%), recurrence rates were generally low (0-8%) and complications largely transient (e.g. pneumothorax 0-1%). However, 8-95.4% experienced troubling compensatory sweating. One randomised controlled trial and one observational study evaluated botulinum toxin A (Level Ib and III, respectively). Both employed objective outcome measures and demonstrated similar findings. Efficacy was 100%, lasted a median of 5-6 months and frontalis muscle inhibition was the main adverse effect (50-100%). Three studies evaluated anticholinergic therapy: topical glycopyrrolate demonstrated high efficacy (96%) with minimal adverse effects (Level Ib) and oral oxybutynin demonstrated relatively high efficacy (80-100%) but with noticeable adverse effects (76.6-83.6%) (Level III). CONCLUSION: There are few quality studies evaluating CH treatment. Based on available evidence, we recommend topical glycopyrrolate, oral oxybutynin and intradermal botulinum toxin A as first-line therapies due to their efficacy and safety. T2 sympathectomy should be considered for patients refractory to first-line therapy.

Stem cells of the lower limb: their role and potential in management of critical limb ischemia.

Peripheral arterial occlusive disease (PAOD) contributes to decreased exercise tolerance, poor balance, impaired proprioception, muscle atrophy and weakness, with advanced cases resulting in critical limb ischemia (CLI) where the viability of the limb is threatened. Patients with a diagnosis of CLI have a poor life expectancy due to concomitant cardio and cerebrovascular diseases. The current treatment options to avoid major amputation by re-establishing a blood supply to the limb generally have poor outcomes. Human skeletal muscle contains both multipotent stem cells and progenitor cells and thus has a capacity for regeneration. Phase I and II studies involving transplantation of bone marrow-derived progenitor cells into CLI limbs show positive effects on wound healing and angiogenesis; the increase in quiescent satellite cell numbers observed in CLI muscle may also provide a sufficient in vivo source of resident stem cells. These indigenous cells have been shown to be capable of forming multiple mesodermal cell lineages aiding the repair and regeneration of chronically ischemic muscle. They may also serve as a repository for autologous transplantation. The behavior and responses of the stem cell population in CLI is poorly understood and this review tries to elucidate the potential of these cells and their future role in the management of CLI.

Nitric oxide manipulation: a therapeutic target for peripheral arterial disease?

Peripheral Arterial Disease (PAD) is a cause of significant morbidity and mortality in the Western world. Risk factor modification and endovascular and surgical revascularisation are the main treatment options at present. However, a significant number of patients still require major amputation. There is evidence that nitric oxide (NO) and its endogenous inhibitor asymmetric dimethylarginine (ADMA) play significant roles in the pathophysiology of PAD. This paper reviews experimental work implicating the ADMA-DDAH-NO pathway in PAD, focussing on both the vascular dysfunction and effects within the ischaemic muscle, and examines the potential of manipulating this pathway as a novel adjunct therapy in PAD.

Toll-like receptors in ischaemia and its potential role in the pathophysiology of muscle damage in critical limb ischaemia.

Toll-like receptors (TLRs) are key receptors of the innate immune system which are expressed on immune and nonimmune cells. They are activated by both pathogen-associated molecular patterns and endogenous ligands. Activation of TLRs culminates in the release of proinflammatory cytokines, chemokines, and apoptosis. Ischaemia and ischaemia/reperfusion (I/R) injury are associated with significant inflammation and tissue damage. There is emerging evidence to suggest that TLRs are involved in mediating ischaemia-induced damage in several organs. Critical limb ischaemia (CLI) is the most severe form of peripheral arterial disease (PAD) and is associated with skeletal muscle damage and tissue loss; however its pathophysiology is poorly understood. This paper will underline the evidence implicating TLRs in the pathophysiology of cerebral, renal, hepatic, myocardial, and skeletal muscle ischaemia and I/R injury and discuss preliminary data that alludes to the potential role of TLRs in the pathophysiology of skeletal muscle damage in CLI.

Potential of Novel EPO Derivatives in Limb Ischemia.

Erythropoietin (EPO) has tissue-protective properties, but it increases the risk of thromboembolism by raising the haemoglobin concentration. New generation of EPO derivatives is tissue protective without the haematopoietic side effects. Preclinical studies have demonstrated their effectiveness and safety. This paper summarizes the development in EPO derivatives with emphasis on their potential use in critical limb ischaemia.

Development of an in vitro model of myotube ischemia.

Critical limb ischemia causes severe damage to the skeletal muscle. This study develops a reproducible model of myotube ischemia by simulating, in vitro, the critical parameters that occur in skeletal muscle ischemia. Monolayers of C2C12 myoblasts were differentiated into mature myotubes and exposed to nutrition depletion, hypoxia and hypercapnia for variable time periods. A range of culture media and gas mixture combinations were used to obtain an optimum ischemic environment. Nuclear staining, cleaved caspase-3 and lactate dehydrogenase (LDH) release assay were used to assess apoptosis and myotube survival. HIF-1α concentration of cell lysates, pH of conditioned media as well as partial pressures of oxygen (PO2) and carbon dioxide (PCO2) in the media were used to confirm ischemic simulation. Culturing myotubes in depleted media, in a gas mixture containing 20% CO+80% N2 for 6-12 h increased the PCO2 and decreased the pH and PO2 of culture media. This attempts to mimic the in vivo ischemic state of skeletal muscle. These conditions were used to study the potential tissue-protective effects of erythropoietin (EPO) in C2C12 myotubes exposed to ischemia. EPO (60 ng/ml) suppressed LDH release, decreased cleaved caspase-3 and reduced the number of apoptotic nuclei, suggesting significantly decreased ischemia-induced apoptosis in myotubes (P<0.01) and a potential role in tissue protection. Additional therapeutic agents designed for tissue protection can also be evaluated using this model.

Isolated endarterectomy of femoral bifurcation in critical limb ischemia: is restoration of inline flow essential?

This retrospective study reviews clinical outcomes of isolated common femoral endarterectomy (CFE) for critical limb ischemia (CLI), in particular whether poor runoff and inability to restore inline flow has negative impact. In 30 patients, runoff was assessed on preoperative angiograms and categorized into groups based on Society of Vascular Surgery criteria. Data were evaluated using Cox Regression survival analysis. Freedom from secondary revascularization was not affected by runoff score (hazard ratio for compromised and poor groups being 1.8 (95% CI 0.16 to 20.8) and 1.47 (95% CI 0.09 to 24.3), respectively; P = .894). Distal inline flow was not achieved in 25 (83%) patients, but this was not associated with significantly worse outcome (P = .295, log-rank test). In conclusion, CFE can be performed in CLI with high technical success and there is no significant effect of runoff score on recurrence of symptoms. Limb salvage can be achieved even if options to restore inline flow are limited.

Review of the role of erythropoietin in critical leg ischemia.

There is a need to develop alternative treatment strategies for the 30% of patients with critical leg ischemia (CLI) for whom conventional modes of revascularization fail. The efficacy erythropoietin (EPO) in this regard has been verified in preclinical models. Erythropoietin receptors are expressed in the human skeletal muscle and possibly, upregulated in CLI. Furthermore, EPO induces angiogenesis and prevents apoptosis in the ischemic skeletal muscle. The use of EPO in conjunction with autologous bone marrow cells or gene-induced angiogenesis with vascular endothelial growth factor may be more effective in inducing angiogenesis and protecting the critically ischemic leg than EPO alone. The recently synthesized nonhemopoietic derivatives of EPO (eg, asialo erythropoietin and carbamylated erythropoietin) allow higher doses to be administered to achieve tissue protective effects, without an unwanted increase in hematocrit. This may allow translation of preclinical studies into clinical trials.

Angiogenic effects of stromal cell-derived factor-1 (SDF-1/CXCL12) variants in vitro and the in vivo expressions of CXCL12 variants and CXCR4 in human critical leg ischemia.

PURPOSE: Critical leg ischemia (CLI) is associated with a high morbidity and mortality. Therapeutic angiogenesis is still being investigated as a possible alternative treatment option for CLI. CXCL12, a chemokine, is known to have two spliced variants, CXCL12alpha and CXCL12beta, but the significance remains unknown. The study investigated the angiogenic effects of CXCL12, protein expressions of CXCL12, and the receptor CXCR4 in human CLI. METHODS: In vitro, human microvascular endothelial cells (HMEC-1) were used. Cell proliferation was assessed using methylene blue assay and cell count method. Apoptosis was determined by counting the pyknotic nuclei after 4'-6-diamidino-2-phenylindole staining and confirmed by caspase-3 assay. We employed matrigel as capillary tube formation assay. The activity of signaling pathways was measured using Western blotting. In vivo, gastrocnemius biopsies were obtained from the lower limbs of patients with CLI and controls (n = 12 each). Immunohistochemistry, double immunofluorescence labeling, and Western blotting were then performed. RESULTS: CXCL12 attenuated HMEC-1 apoptosis (P < .01), stimulated cell proliferation (P < .05) and capillary tube formation (P < .01). Compared with CXCL12alpha, CXCL12beta has a greater effect on apoptosis and cell proliferation (P < .01). Treatment with both variants resulted in time-dependent activation of PI3K/Akt and p44/42 but not p38 MAP kinase. In CLI, CXCL12alpha was expressed by skeletal muscle fibers with minimal expression of CXCL12beta. CXCR4 was extensively expressed and colocalized to microvessels. A significant 2.6-fold increase in CXCL12alpha and CXCR4 expressions (P < .01) were noted in CLI but not for CXCL12beta (P > .05). CONCLUSIONS: The study showed that CXCL12beta had more potent angiogenic properties but was not elevated in human CLI biopsies. This provided an interesting finding on the role of CXCL12 variants in pathophysiologic angiogenic response in CLI.

Endovascular aortic aneurysm repair (EVAR) has significantly lower perioperative mortality in comparison to open repair: a systematic review.

OBJECTIVE: The objective of this meta-analysis was to evaluate the effectiveness of endovascular abdominal aortic aneurysm repair (EVAR) in reducing inhospital mortality against open graft replacement for aortic aneurysm. METHODS: Generic terms including EVAR, endovascular aneurysm repair and aortic endografting were used to search a variety of electronic databases. Based on selection criteria, decisions regarding inclusion and exclusion of primary studies were made. RESULTS: A total of three randomized controlled trials on 1,468 patients were included. In the EVAR group, 12 of 759 (1.5%) patients died, compared to 33 of 709 (4.6%) patients who died in the open surgery group. In both the fixed and random effect models, EVAR was associated with statistically significantly lower perioperative mortality when compared to open surgical repair of aortic aneurysm. The risk ratio of 0.33 indicates that mortality is 3.3 times more likely in the open surgery group compared to the EVAR group. CONCLUSION: EVAR carries a threefold lower risk of perioperative death in comparison to open repair of abdominal aortic aneurysm. This early advantage must be offset against the increased need for later re-intervention and probable equivalence of long-term outcome. In older and high operative risk patients, EVAR should be the treatment of choice.