Raghu L. Motaganahalli

Treatment and outcomes of aortic endograft infection

OBJECTIVE This study examined the medical and surgical management and outcomes of patients with aortic endograft infection after abdominal endovascular aortic repair (EVAR) or thoracic endovascular aortic repair (TEVAR). METHODS Patients diagnosed with infected aortic endografts after EVAR/TEVAR between January 1, 2004, and January 1, 2014, were reviewed using a standardized, multi-institutional database. Demographic, comorbidity, medical management, surgical, and outcomes data were included. RESULTS An aortic endograft infection was diagnosed in 206 patients (EVAR, n = 180; TEVAR, n = 26) at a mean 22 months after implant. Clinical findings at presentation included pain (66%), fever/chills (66%), and aortic fistula (27%). Ultimately, 197 patients underwent surgical management after a mean of 153 days. In situ aortic replacement was performed in 186 patients (90%) using cryopreserved allograft in 54, neoaortoiliac system in 21, prosthetic in 111 (83% soaked in antibiotic), and 11 patients underwent axillary-(bi)femoral bypass. Graft cultures were primarily polymicrobial (35%) and gram-positive (22%). Mean hospital length of stay was 23 days, with perioperative 30-day morbidity of 35% and mortality of 11%. Of the nine patients managed only medically, four of five TEVAR patients died after mean of 56 days and two of four EVAR patients died; both deaths were graft-related (mean follow-up, 4 months). Nineteen replacement grafts were explanted after a mean of 540 days and were most commonly associated with prosthetic graft material not soaked in antibiotic and extra-anatomic bypass. Mean follow-up was 21 months, with life-table survival of 70%, 65%, 61%, 56%, and 51% at 1, 2, 3, 4, and 5 years, respectively. CONCLUSIONS Aortic endograft infection can be eradicated by excision and in situ or extra-anatomic replacement but is often associated with early postoperative morbidity and mortality and occasionally with a need for late removal for reinfection. Prosthetic graft replacement after explanation is associated with higher reinfection and graft-related complications and decreased survival compared with autogenous reconstruction.

Estimating the risk of solid organ malignancy in patients undergoing routine computed tomography scans after endovascular aneurysm repair

OBJECTIVE Computed tomography (CT) scans are routinely used for graft surveillance in patients who have had endovascular repair (EVAR) of an abdominal aortic aneurysm. There is a growing concern for cancers associated with inadvertent use of CT scans. We report the estimated risk of radiation associated solid organ malignancy caused by routine surveillance CT after EVAR using the Biological Effects of Ionizing Radiation (BEIR VII) model created by U.S. National Institute of Science and National Research Council. METHODS Our study estimated the excess relative risk (ERR) of a patient acquiring a solid organ malignancy secondary to radiation exposure from postoperative EVAR surveillance CT imaging. The radiation dose was calculated in sieverts (Sv). The ERR of solid organ malignancy, as given by the BEIR VII model, is = β(s) D exp {γe*} (a/60)(η), where β(s), γ, and η are data-derived parameters, e is age at exposure, and e* = (e-30)/10 for e < 30 and zero for e ≥ 30, a is attained age, and D is dose in sieverts. Dose-weighted ERRs were calculated to allow a comparison of malignancy risk when using a CT at all time points (model 1: 0, 1, 6, 12, and 18 months, 2, 3, and 4 years, and yearly thereafter) vs replacing the CT scan with two other models (model 2: CT once in 3 years) and (model 3: CT once in 5 years). The risk was stratified by age groups, sex, and use of two different radiation doses (15 or 31 mSv) per CT scan. Statistical analysis used the paired t test. RESULTS There were significant differences between the ERR of solid organ malignancy in those patients who would undergo surveillance CTs at all time points vs those whose surveillance consisted of alternative modalities at some time points (P < .0001). The cumulative ERR of cancer from radiation was higher in those exposed to contrast-enhanced CT scans, younger people, with highest in the group aged 50 to 55 years (ERR, 0.43), and lowest in patients aged ≥ 80 years (ERR, 0.10). CONCLUSIONS Patients undergoing routine CT scans for postoperative surveillance after EVAR are at risk for acquiring new solid organ malignancy due to radiation exposure. The risk is higher in young patients, women, and those exposed to multiple contrast-enhanced CT scans. Our analysis questions the need for routine surveillance CT scans after EVAR in the absence of endoleaks or a change in aneurysm morphology, based on an increased malignancy risk.

Evidence for nonoperative management of acute limb ischemia in infants

Acute limb ischemia (ALI) in infants is a catastrophic event. We performed a query of our database to determine those with ALI. Twelve patients were identified. The most frequent presentation was cyanotic limbs. Eleven patients were treated nonoperatively with anticoagulation. One patient was treated surgically with Fogarty balloon thrombectomy. There were three deaths all due to associated comorbidities. All had viable limbs on follow-up examination. There were three complications in the patients managed conservatively. Our recommendation for infants presenting with ALI is conservative observation with anticoagulation and intervention only for cases with tissue loss.

Thermotherapy reduces blood pressure and circulating endothelin-1 concentration and enhances leg blood flow in patients with symptomatic peripheral artery disease.

Leg thermotherapy (TT) application reduces blood pressure (BP) and increases both limb blood flow and circulating levels of anti-inflammatory mediators in healthy, young humans and animals. The purpose of the present study was to determine the impact of TT application using a water-circulating garment on leg and systemic hemodynamics and on the concentrations of circulating cytokines and vasoactive mediators in patients with symptomatic peripheral artery disease (PAD). Sixteen patients with PAD and intermittent claudication (age: 63 ± 9 yr) completed three experimental sessions in a randomized order: TT, control intervention, and one exercise testing session. The garment was perfused with 48°C water for 90 min in the TT session and with 33°C water in the control intervention. A subset of 10 patients also underwent a protocol for the measurement of blood flow in the popliteal artery during 90 min of TT using phase-contrast MRI. Compared with the control intervention, TT promoted a significant reduction in systolic (∼11 mmHg) and diastolic (∼6 mmHg) BP (P < 0.05) that persisted for nearly 2 h after the end of the treatment. The serum concentration of endothelin-1 (ET-1) was significantly lower 30 min after exposure to TT (Control: 2.3 ± 0.1 vs. TT: 1.9 ± 0.09 pg/ml, P = 0.026). In addition, TT induced a marked increase in peak blood flow velocity (∼68%), average velocity (∼76%), and average blood flow (∼102%) in the popliteal artery (P < 0.01). These findings indicate that TT is a practical and effective strategy to reduce BP and circulating ET-1 concentration and enhance leg blood flow in patients with PAD.

Management of vascular trauma from dog bites

BACKGROUND Vascular trauma from large-dog bites present with a combination of crush and lacerating injuries to the vessel, as well as significant adjacent soft tissue injury and a high potential for wound complications. This retrospective case series evaluates our 15 years of experience in managing this uncommonly seen injury into suggested treatment recommendations. METHODS From our database, 371 adult patients presented with dog bites between July 1997 and June 2012. Twenty (5.4%) of those patients had vascular injuries requiring surgical intervention. Patient demographics, anatomic location of injury, clinical presentation, imaging modality, method of repair, and complication rates were reviewed to assess efficacy in preserving limb function. Pediatric patients were managed at the regional childrens hospital and, therefore, not included in this study. RESULTS Among the 20 surgically treated vascular injuries, there were 13 arterial-only injuries, two venous-only injuries, and five combination arterial and venous injuries. Seventeen patients (85%) had upper extremity injuries; three patients had lower extremity injuries (15%). The axillobrachial artery was the most commonly injured single vessel (n = 9/20; 45%), followed by the radial artery (n = 4/20; 20%). Surgical repair of vascular injuries consisted of resection and primary anastomosis (four), interposition bypass of artery with autogenous vein (13), and ligation (two), with (one) being a combination of bypass and ligation. All patients had debridement of devitalized tissue combined with pulse lavage irrigation and perioperative antibiotics. Associated injuries requiring repair included muscle and skin (n = 10/20; 50%), bone (n = 1/20; 5%), nerve (n = 1/20; 5%), and combinations of the three (n = 5/20; 25%). Postoperative antibiotic therapy was administered for 14.7 ± 8.2 days in all 20 patients. Four patients (20%) developed postoperative wound infections, although this did not compromise their vascular repair. Of the patients compliant with postoperative surveillance, all limbs (100%) were viable at discharge and at 1-year follow-up. CONCLUSIONS Dog bite vascular injuries are an uncommon occurrence, where extremity pulse abnormalities are the most common presentation. These injuries are also associated with significant adjacent soft tissue trauma, which warrants aggressive debridement and perioperative antibiotic therapy. Despite vigilant management, nearly one-fifth of our patients sustained wound infections. All infections were successfully managed with broad-spectrum antibiotics, and all limbs were preserved 1-year postoperatively.

A multi-institutional experience in adventitial cystic disease.

Background: Adventitial cystic disease (ACD) is an unusual arteriopathy; case reports and small series constitute the available literature regarding treatment. We sought to examine the presentation, contemporary management, and long‐term outcomes using a multi‐institutional database. Methods: Using a standardized database, 14 institutions retrospectively collected demographics, comorbidities, presentation/symptoms, imaging, treatment, and follow‐up data on consecutive patients treated for ACD during a 10‐year period, using Society for Vascular Surgery reporting standards for limb ischemia. Univariate and multivariate analyses were performed comparing treatment methods and factors associated with recurrent intervention. Life‐table analysis was performed to estimate the freedom from reintervention in comparing the various treatment modalities. Results: Forty‐seven patients (32 men, 15 women; mean age, 43 years) were identified with ACD involving the popliteal artery (n = 41), radial artery (n = 3), superficial/common femoral artery (n = 2), and common femoral vein (n = 1). Lower extremity claudication was seen in 93% of ACD of the leg arteries, whereas patients with upper extremity ACD had hand or arm pain. Preoperative diagnosis was made in 88% of patients, primarily using cross‐sectional imaging of the lower extremity; mean lower extremity ankle‐brachial index was 0.71 in the affected limb. Forty‐one patients with lower extremity ACD underwent operative repair (resection with interposition graft, 21 patients; cyst resection, 13 patients; cyst resection with bypass graft, 5 patients; cyst resection with patch, 2 patients). Two patients with upper extremity ACD underwent cyst drainage without resection or arterial reconstruction. Complications, including graft infection, thrombosis, hematoma, and wound dehiscence, occurred in 12% of patients. Mean lower extremity ankle‐brachial index at 3 months postoperatively improved to 1.07 (P < .001), with an overall mean follow‐up of 20 months (range, 0.33‐9 years). Eight patients (18%) with lower extremity arterial ACD required reintervention (redo cyst resection, one; thrombectomy, three; redo bypass, one; balloon angioplasty, three) after a mean of 70 days with symptom relief in 88%. Lower extremity patients who underwent cyst resection and interposition or bypass graft were less likely to require reintervention (P = .04). One patient with lower extremity ACD required an above‐knee amputation for extensive tissue loss. Conclusions: This multi‐institutional, contemporary experience of ACD examines the treatment and outcomes of ACD. The majority of patients can be identified preoperatively; surgical repair, consisting of cyst excision with arterial reconstruction or bypass alone, provides the best long‐term symptomatic relief and reduced need for intervention to maintain patency.

Rationale and design of the MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia in Subjects with Severe Peripheral Arterial Disease (MOBILE) trial investigating autologous bone marrow cell therapy for critical limb ischemia

Objective: Critical limb ischemia (CLI) continues to place a significant encumbrance on patients and the health care system as it progresses to limb loss and long‐term disability. Traditional methods of revascularization offer a significant benefit; however, for one‐third of CLI patients, these surgical options are not technically possible or patency is severely limited by disease burden (deemed “poor‐option” for revascularization). In a previous phase I trial, we demonstrated intramuscular injection of concentrated bone marrow aspirate (cBMA) via MarrowStim (Zimmer Biomet, Warsaw, Ind) harvest is safe and may decrease major amputation in patients with CLI unfit for surgical revascularization. Therefore, we describe and rationalize the MarrowStim PAD Kit for the Treatment of Critical Limb Ischemia in Subjects with Severe Peripheral Arterial Disease (MOBILE) trial, a study geared to provide the pivotal proof of efficacy of cBMA in CLI. Methods: MOBILE is a multicenter, randomized, double‐blind, placebo‐controlled trial designed to assess the efficacy of intramuscular injections of cBMA in promoting amputation‐free survival in patients with poor‐option CLI. Patients (aged >21 years) with rest pain or tissue loss resulting from advanced peripheral arterial disease, as characterized by ankle‐brachial index (<0.6), toe‐brachial index (<0.4), or transcutaneous pressure of oxygen (<50 mm Hg), were eligible for inclusion if surgical revascularization was not possible secondary to advanced disease. Results: Treatment and 1‐year follow‐up of 152 patients enrolled in MOBILE are completed. Long‐term follow‐up is ongoing. Currently, we are in the process of unblinding the initial results for preliminary data analysis. Conclusions: If successful, MOBILE could add definitive, high‐quality evidence in support of cBMA for the treatment of poor‐option CLI patients and provide an additional modality for patients who face amputation secondary to advanced limb ischemia.

Rationale and design of the Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial investigating the therapeutic mechanism of mesenchymal stromal cells in the treatment of critical limb ischemia

Objective: Currently, there are no accepted nonsurgical therapies that improve the delivery of blood‐derived nutrients to patients with critical limb ischemia. Here, we describe the ongoing phase 1/2 Clinical and Histologic Analysis of Mesenchymal Stromal Cells in AmPutations (CHAMP) trial, which will provide crucial evidence of the safety profile of mesenchymal stromal cells (MSCs) and explore their therapeutic mechanisms in the setting of critical limb ischemia requiring below‐knee amputation (BKA). Methods: In the CHAMP and the parallel marrowCHAMP trials (hereafter grouped together as CHAMP), a total of 32 extremities with rest pain or tissue loss requiring BKA will be enrolled to receive intramuscular injections of allogeneic MSCs (CHAMP; n = 16) or autogenous concentrated bone marrow aspirate (marrowCHAMP; n = 16) along the distribution of the BKA myocutaneous flap and proximal tibialis anterior. After treatment, subjects are randomized to BKA at four time points after injection (days 3, 7, 14, and 21). At the time of amputation, skeletal muscle is collected at 2‐cm increments from the tibialis injection site and used to determine proangiogenic cytokine description, MSC retention, quantification of proangiogenic hematopoietic progenitor cells, and histologic description. Clinical limb perfusion before and after treatment will be quantified using transcutaneous oximetry, toe‐brachial index, ankle‐brachial index, and indocyanine angiography. Additional clinical end points include all‐cause mortality, need for amputation revision, and gangrene incidence during the 6‐month post‐treatment follow‐up. Results: Enrollment is under way, with 10 patients treated per protocol thus far. We anticipate full conclusion of follow‐up within the next 24 months. Conclusions: CHAMP will be pivotal in characterizing the safety, efficacy, and, most important, therapeutic mechanism of allogeneic MSCs and autogenous concentrated bone marrow aspirate in ischemic skeletal muscle.

Institutional experience with the Zenith Fenestrated aortic stent graft

Objective: The Zenith Fenestrated (ZFEN; Cook Medical, Bloomington, Ind) aortic stent graft system was approved for commercial use by the Food and Drug Administration in April 2012. We report our single‐center experience of 100 consecutive patients treated with the ZFEN platform from October 2012 to March 2017. Methods: A retrospective review of our prospectively maintained fenestrated endovascular aneurysm repair (FEVAR) database at a tertiary care academic institution located in the Midwest United States was performed for descriptive analysis. All continuous variables are reported as a mean ± standard deviation and compared using two‐sided Student t‐tests. Categorical variables were compared using two‐sided Fisher exact tests. Results: All but one of the procedures were elective in nature. Overall intraoperative characteristics included a mean blood loss (estimated blood loss) of 388 ± 385 mL, fluoroscopy time of 63 ± 30 minutes, radiation dose of 437 ± 272 rad, contrast material volume of 99 ± 36 mL, and operative time of 236 ± 87 minutes. Average number of visceral arteries stented was 2.1 ± 0.5. Technical success was achieved in 98% of the patients. Statistically significant (P < .05) improvement in estimated blood loss (2.1‐fold) was observed in the second half of our series. Interestingly, no improvements were made in terms of fluoroscopy time, radiation exposure, contrast material use, or operative time. However, procedural difficulty increased in the last half by number of visceral arteries stented as a surrogate (1.9 vs 2.2; P < .05). Mean length of stay was 3.6 ± 4.3 days. Perioperative mortality at 30 days was 2%. Perioperative morbidity included a 5% incidence of any bowel ischemia, 1% of spinal cord ischemia, 3% of renal failure requiring hemodialysis, 1% of stroke, and 4% of myocardial infarction. Average follow‐up was 1.7 ± 1.4 years. Reintervention during the follow‐up phase was 20%. Of the 209 visceral arteries stented, we noted 6 instances of stent thrombosis, 6 of kinking or stenosis, and 1 of stent fracture in follow‐up. Endoleak, most commonly type II, was present or could not be excluded in 15% of all FEVARs at last available computed tomography angiography. Conclusions: In our experience, FEVAR with the ZFEN system continues to be safe and effective. There is a significant rate of reintervention observed, and close monitoring is fundamental to maintaining good clinical results.

Osteopontin may be a driver of abdominal aortic aneurysm formation

Objective: Previous in vitro and animal studies have suggested that osteopontin (OPN), an inflammatory extracellular matrix protein, is involved in the formation and growth of abdominal aortic aneurysms (AAAs). However, the mechanism by which this occurs continues to be nebulous. The relationship between OPN and inflammation‐suppressing lymphocytes present in the human AAA condition was investigated and presented herein. Methods: Serum OPN concentrations were measured in healthy, risk factor‐matched non‐AAA and AAA patients by enzyme‐linked immunosorbent assay (ELISA). Immunohistochemistry was used to determine the source of OPN secretion using aortic tissue collected from multiorgan donors and AAA patients undergoing open surgical repair. Vascular smooth muscle cells (VSMCs) were exposed to various inflammatory mediators, and OPN expression was evaluated by quantitative reverse transcriptase‐polymerase chain reaction and ELISA. The inflammatory nature of OPN and the aortic wall was determined using a TR1 suppressor cell induction assay as a surrogate and characterized by ELISA and fluorescence‐activated cell sorting. Results: OPN was found to be elevated in both the plasma and aortic homogenate of AAA patients compared with controls. On immunohistochemistry, OPN localized to the tunica media of the diseased aorta but was minimally expressed in healthy aorta. In vitro, cigarette smoke extract was the most potent stimulator of OPN secretion by VSMCs and increased both messenger RNA and supernatant concentrations. OPN demonstrated an ability to inhibit the induction of interleukin 10‐secreting TR1 lymphocytes, a depleted population in the AAA patient, from naive precursors. Last, neutralizing receptor targets of OPN in the setting of AAA homogenate coincubation abrogated the inhibition of TR1 induction. Conclusions: OPN, secreted by the VSMCs of the tunica media, is elevated in the circulating plasma and aortic wall of patients with AAA. It can inhibit the induction of the TR1 suppressor cell, leading to an overall proinflammatory state contributing to progressive aortic wall breakdown and dilation. Clinical Relevance: Little is known about the initiating event of abdominal aortic aneurysm formation. However, the early histology of the ectatic aorta is characterized by massive infiltration of mononuclear cells and elaboration of matrix metalloproteinases, collagenases, and elastases. This runaway inflammatory response directly leads to extracellular matrix degradation and loss of aortic integrity. In this study, we report elevations of osteopontin (OPN), an extracellular matrix glycoprotein associated with inflammation in other pathologic processes. In addition, OPN demonstrated an ability to inhibit the expression of the TR1 lymphocyte, a potent suppressor of inflammation. Therefore, we argue that accumulation of OPN in the aortic wall may be a potent driver for abdominal aortic aneurysm propagation.