M. Burress Welborn

The relationship between visceral ischemia, proinflammatory cytokines, and organ injury in patients undergoing thoracoabdominal aortic aneurysm repair.

ObjectivesPlasma proinflammatory, anti-inflammatory cytokine, and soluble tumor necrosis factor (TNF) receptor concentrations were examined in hospitalized patients after abdominal and thoracoabdominal aortic aneurysm (TAAA) repair, with and without left atrial femoral bypass. Changes in plasma cytokine concentrations were related to the duration of visceral ischemia and the frequency rate of postoperative, single, or multiple system organ dysfunction (MSOD). DesignProspective, observational study. SettingTwo academic referral centers in the United States and The Netherlands. PatientsWe included 16 patients undergoing TAAA repair without left atrial femoral bypass, 12 patients undergoing TAAA repair with left atrial femoral bypass, and nine patients undergoing infrarenal aortic aneurysm repair. Measurements and Main ResultsTimed, arterial blood sampling for proinflammatory and anti-inflammatory cytokine and soluble TNF receptor concentrations (p55 and p75), and prospective assessment of postoperative single and MSOD. Plasma appearance of TNF-&agr;, interleukin (IL)-6, IL-8, and IL-10 peaked 1 to 4 hrs after TAAA repair, and concentrations were significantly elevated compared with infrarenal abdominal aortic aneurysm repair (p < .05). Left atrial femoral bypass significantly reduced the duration of visceral ischemia (p < .05) and the systemic TNF-&agr;, p75, and IL-10 responses (p < .05). Plasma TNF-&agr; concentrations >150 pg/mL were more common in patients with extended visceral ischemia times (>40 mins). Additionally, patients with early peak TNF-&agr; concentrations >150 pg/mL and IL-6 levels >1,000 pg/mL developed MSOD more frequently than patients without these elevated plasma cytokine levels (both p < .05). ConclusionsThoracoabdominal aortic aneurysm repair results in the increased plasma appearance of TNF-&agr;, IL-6, IL-8, IL-10, and shed TNF receptors. The frequency and magnitude of postoperative organ dysfunction after TAAA repair is associated with an increased concentration of the cytokines, TNF-&agr;, and IL-6 and the increased plasma levels of these cytokines appear to require extended visceral ischemia times.

Visceral ischemia-reperfusion injury promotes tumor necrosis factor (TNF) and interleukin-1 (IL-1) dependent organ injury in the mouse

Acute visceral ischemia and subsequent reperfusion injury, which accompanies the surgical repair of a thoracoabdominal aorta aneurysm, is associated with high rates of morbidity and mortality. The purpose of the present study was to determine whether endogenous tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) production contributes to organ dysfunction in animals subjected to visceral ischemia secondary to 30 min of supraceliac aortic occlusion. C57BL6/j mice were treated with either a TNF binding protein (TNF-bp-10 mg/kg) or an anti-IL-1 receptor type 1 antibody (150 μg) 2 h prior to 30 min of supraceliac aortic occlusion. An additional group of mice received 30 min of infrarenal aortic occlusion to determine the contribution of lower torso ischemia-reperfusion injury to the changes seen following supraceliac aortic occlusion. Visceral organ ischemia for 30 min produced by supraceliac aortic occlusion followed by 2 h of reperfusion produced measurable TNF-α in 38% of untreated mice, but TNF-α was undetectable in both sham-operated mice and following infrarenal aortic occlusion. After 2 h of reperfusion, lung myeloperoxidase levels were significantly elevated in the mice experiencing visceral ischemia-reperfusion compared with either a sham operation or infrarenal ischemia-reperfusion (11.6 ± 1.3 U/g vs. 3.4 ± .2 U/g and 3.7 ± 1.0 U/g, respectively, p < .05). Pretreatment with TNF-bp and anti-IL-1 antibody decreased lung neutrophil recruitment (7.2 ± 1.2 U/g and 4.6 ± 1.1 U/g) and capillary membrane permeability changes in mice following visceral ischemia-reperfusion. The present study demonstrates that brief (30 min) clinically relevant visceral ischemia produces TNF-α and IL-1 dependent lung injury.

Attenuation of skeletal muscle ischemia/reperfusion injury by inhibition of tumor necrosis factor

PURPOSE Tumor necrosis factor alpha (TNF-alpha) has been shown to play a role in pulmonary injury after lower-extremity ischemia/reperfusion (I/R). However, its role in direct skeletal muscle injury is poorly understood. The hypothesis that endogenous TNF production contributes to skeletal muscle injury after hindlimb I/R in rats was tested. METHODS Juvenile male Sprague-Dawley rats underwent 4 hours of bilateral hindlimb ischemia and 4 hours of reperfusion (IR) or sham operation (SHAM). A subset was treated with a soluble TNF receptor I construct (STNFRI, 10 mg/kg) 1 hour before ischemia (PRE) or at reperfusion (POST). Direct skeletal muscle injury (SMII) and muscle endothelial capillary permeability (MPI) were quantified by means of Tc99 pyrophosphate and I125 albumin uptake. Pulmonary neutrophil infiltration and hepatocellular injury were assessed by means of myeloperoxidase content (MPO) and aspartate aminotransferase (AST) concentrations, respectively. Serum TNF bioactivity was measured with the WEHI bioassay. RESULTS Hindlimb I/R (IR vs SHAM) resulted in a significant (P <.05) increase in the SMII (0.52 +/- 0.06 vs 0.07 +/- 0.01) and MPI (0.35 +/-.04 vs 0.06 +/- 0.01). Pretreatment with STNFRI (PRE vs IR) significantly ameliorated both SMII (0.30 +/- 0.05 vs 0.52 +/- 0.06) and MPI (0.23 +/- 0.02 vs 0.35 +/- 0.04), whereas treatment at reperfusion (POST vs IR) had no effect. Hindlimb I/R (IR vs SHAM) resulted in both significant pulmonary neutrophil infiltration (MPO 16.4 +/- 1.06 U/g vs 11.3 +/- 1.4 U/g) and hepatocellular injury (AST 286 +/- 45 U/mL vs 108 +/- 30 U/mL), but neither was inhibited by pretreatment with STNFRI before ischemia. Detectable levels of TNF were measured during ischemia in a significantly higher percentage of the IR group compared with SHAM (9 of 12 vs 3 of 12), and the maximal TNF values were also significantly greater (51.1 +/- 12.6 pg/mL vs 5.5 +/- 2.9 pg/mL). No TNF was detected in any treatment group during reperfusion nor after administration of the STNFRI. CONCLUSION Acute hindlimb IR initiates a systemic TNF response during the ischemic period that is partly responsible for the associated skeletal muscle injury.

Exogenously administered interleukin-10 decreases pulmonary neutrophil infiltration in a tumor necrosis factor–dependent murine model of acute visceral ischemia

INTRODUCTION Visceral ischemia and reperfusion associated with thoracoabdominal aortic aneurysm (TAAA) repair results in lung injury, which appears to be mediated in part by proinflammatory cytokines. The purpose of this study was to determine the effect of exogenous administration of the antiinflammatory cytokine, recombinant human IL-10 (rhIL-10), on proinflammatory cytokine production (IL-6 and TNF alpha) and pulmonary neutrophil infiltration after acute visceral ischemia-reperfusion. METHODS Two hours before 25 minutes of supraceliac aortic occlusion, 80 C57BL/6 mice (20 to 22 g) received an intraperitoneal injection of rhIL-10 (0.2 microgram [n = 20], 2 micrograms [n = 20], 5 micrograms [n = 25], or 20 micrograms [n = 15]), and 16 mice received murine anti-IL-10 IgM 200 micrograms. Twenty-five additional mice underwent visceral ischemia-reperfusion without treatment (controls), and 16 mice underwent laparotomy without aortic occlusion (sham). RESULTS Pretreatment with exogenous rhIL-10 resulted in significant reductions in lung neutrophil infiltration with 0.2 microgram, 2 micrograms, and 5 micrograms per mouse of rhIL-10 compared with lung neutrophil levels in control mice that underwent acute visceral ischemia-reperfusion alone (p < 0.05). In addition, serum TNF alpha was detected in 50% of control mice and in 75% of mice that received murine anti-IL-10, but in none of the mice that received rhIL-10 (2 micrograms per mouse) or the mice that underwent sham operative procedures (p < 0.05 by chi 2 analysis). CONCLUSION Exogenous IL-10 limits pulmonary neutrophil recruitment and the appearance of TNF alpha in this model of visceral ischemia-reperfusion injury. Thus the use of exogenous IL-10 may offer a novel therapeutic approach to decrease the complications that are associated with TAAA repair.

Emerging role of endovascular grafts in complex aortoiliac occlusive disease

BACKGROUND Aortobifemoral bypass is the standard therapy for complex aortoiliac occlusive disease. The purpose of this study was to examine the use of endovascular grafts as an alternative to aortobifemoral bypass in patients with advanced aortoiliac occlusive disease at high risk. METHODS Endovascular grafts were placed in 23 limbs in 22 patients with TransAtlantic Inter-Society Consensus document (TASC) type C and D lesions. All procedures were performed in the operating room, and images were obtained with portable digital fluoroscopy. Surgical exposure of the ipsilateral common femoral artery was performed to enable safe closure of 9F to 12F sheath sites and to facilitate ipsilateral interventions in the distal external iliac artery. Concomitant infrainguinal outflow procedures were performed in 6 patients. RESULTS Twenty of 22 patients were men; mean patient age was 63.2 +/- 3.2 years. Indications for intervention were rest pain in 12 of 23 limbs and tissue loss in 9 of 22 limbs. Risk factors included hostile abdomen or pelvis in 8 patients, coronary artery disease in 11 patients, end-stage renal disease in 3 patients, and severe chronic obstructive pulmonary disease in 3 patients. Each patient received a mean of 1.6 grafts. Initial technical success was 95.2%, with one technical failure. There was no 30-day mortality. All patients experienced at least one grade improvement per Society for Vascular Surgery reporting standards. Primary patency at 24 months was 84.2% +/- 8.0%, with a limb salvage rate of 95.3% +/- 5.0%. Mean (+/- SD) ankle brachial index improved from 0.49 +/- 0.22 to 0.87 +/- 0.26 (P <.001). CONCLUSION Endovascular grafting to treat advanced aortoiliac occlusive disease can be accomplished with good clinical outcome and acceptable short-term patency. This endovascular technique can be a viable alternative to conventional surgical revascularization in patients with advanced aortoiliac occlusive disease at high risk.

Endovascular repair of small abdominal aortic aneurysms: A paradigm shift?

Recent reports have documented poor long-term results following endovascular aneurysm repair (EVAR) of large abdominal aortic aneurysms (AAA). EVAR of small AAAs may result in improved long-term results compared to large AAAs. It is not known whether the frequency of anatomic suitability for EVAR is increased for small compared to large AAAs. This study compared the anatomic suitability of large and small AAAs for EVAR in an unselected patient population. Radiology reports for all computed tomography (CT) scans in a single hospital over a recent 3-year period were reviewed. AAAs diagnosed by contrasted CT scans with cuts >7 mm were excluded. Suitability for EVAR was determined by neck diameter, length, and angulation. In addition, iliac diameters and common iliac distal landing zone lengths were determined. Computerized 3-dimensional (3D) reconstruction was used to measure neck angulation and total aortic tortuosity. One hundred ninety-one patients were found to have AAAs with adequate CT scans for evaluation. Suitability for EVAR was highest in patients with AAA diameters of 3–4 cm and declined with increasing size of the AAA. Dividing AAAs into sizes greater than or less than 5.5 cm revealed that small AAAs had significantly longer necks, less neck angulation, longer common iliac landing zones, and less total aortic tortuosity. Multivariable analysis revealed that maximal aortic diameter was the only independent predictor of suitability for EVAR (p = 0.005, odds ratio 1.67, CI 95% = 1.17 to 2.38). The odds ratio predicts that with each 1 cm increase in size, the likelihood of suitability decreased by 5.3-fold. Small AAAs have less complex anatomy with longer aortic necks, less neck angulation, and less tortuosity. The poor outcomes following the treatment of large AAAs is thought to be due to complex anatomy. EVAR of less anatomically challenging small AAAs may improve longterm outcomes.

External-Beam Radiation Therapy for Improved Dialysis Access Patency: Feasibility and Early Safety

Abstract Rectenwald, J. E., Pretus, H. A., Seeger, J. M., Huber, T. S., Mendenhall, N. P., Zlotecki, R. A., Palta, J. R., Li, Z. F., Hook, S. Y., Sarac, T. P., Welborn, M. B., Klingman, N. V., Abouhamze, Z. S. and Ozaki, C. K. External-Beam Radiation Therapy for Improved Dialysis Access Patency: Feasibility and Early Safety. Radiat. Res. 156, 53–60 (2001). Prosthetic dialysis access grafts fail secondary to neointimal hyperplasia at the venous anastomosis. We hypothesized that postoperative single-fraction external-beam radiation therapy to the venous anastomosis of hemodialysis grafts can be used safely in an effort to improve access patency. Dogs (n = 8) underwent placement of expanded polytetrafluoroethylene grafts from the right carotid artery to the left jugular vein. Five dogs received single-fraction external-beam photon irradiation (8 Gy) to the venous anastomosis after surgery. Controls were not irradiated. Shunt angiograms were completed 3 and 6 months postoperatively. Anastomoses, mid-graft, and the surrounding tissues were analyzed. Immunohistochemistry for smooth muscle cell α-actin, proliferating cellular nuclear antigen (PCNA), and apoptosis was performed. Incisions healed well, though all animals developed wound seromas. One control suffered graft thrombosis 4 months postoperatively. Angiography/histology confirmed severe neointimal hyperplasia at the venous anastomosis. The remaining seven dogs developed similar amounts of neointimal hyperplasia. PCNA studies showed no accelerated fibroproliferative response at irradiated anastomoses compared to controls. Skin incisions and soft tissues over irradiated anastomoses revealed no radiation-induced changes or increase in apoptosis. Thus we conclude that postoperative single-fraction external-beam irradiation of the venous anastomosis of a prosthetic arteriovenous graft that mimics the situation in humans is feasible and safe with regard to early wound healing.