Brian G. Rubin

Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms

PURPOSE Matrix metalloproteinases (MMPs) are considered to play a central role in the pathogenesis of abdominal aortic aneurysms (AAAs). Doxycycline (Dox) has direct MMP-inhibiting properties in vitro, and it effectively suppresses the development of elastase-induced AAAs in rodents. The purpose of this study was to determine if treatment with Dox suppresses MMPs within human aneurysm tissue and to elucidate the molecular mechanisms underlying this effect. METHODS Aneurysm tissues were obtained from 15 patients with an AAA, eight of whom had been treated with Dox before surgery (100 mg orally twice a day for 7 days). Protein extracts were examined by means of gelatin zymography and immunoblot analysis, and RNA was examined by means of reverse transcription-polymerase chain reaction (RT-PCR). The effects of Dox on MMP production were further examined in human THP-1 mononuclear phagocytes in vitro. RESULTS No detectable difference was found between groups by using substrate zymography as a means of assessing total MMP activity, but Dox treatment was associated with a slight (24.4%) reduction in the activated fraction of 72-kDa gelatinase (MMP-2; P <.05). In contrast, a 2.5-fold reduction in the amount of extractable 92-kDa gelatinase (MMP-9) protein in Dox-treated patients was revealed by means of immunoblot analysis (P <.05). Also, a 5.5-fold (81.9%) reduction in MMP-9 messenger RNA (mRNA) in Dox-treated patients was demonstrated by means of quantitative competitive RT-PCR (mean +/- SE, mol MMP-9/mol beta-actin: 1.3 +/- 0.5 vs 7.2 +/- 3.1; P <.04). There was no significant difference between groups in the relative expression of MMP-2 protein or mRNA. In cultured THP-1 monocytes stimulated with phorbol ester, the expression of MMP-9 protein and mRNA were both decreased after exposure to relevant concentrations of Dox in vitro. CONCLUSION In addition to its recognized effects as a direct MMP antagonist, Dox may influence connective tissue degradation within human aneurysm tissue by reducing monocyte/macrophage expression of MMP-9 mRNA and by suppressing the post-translational processing (activation) of proMMP-2. Through this complementary combination of mechanisms, treatment with Dox may be a particularly effective strategy for achieving MMP inhibition in patients with an AAA.

Transabdominal versus retroperitoneal incision for abdominal aortic surgery: Report of a prospective randomized trial ☆ ☆☆ ★

PURPOSE The purpose of this study was to perform a randomized, prospective trial that compares the transabdominal with the retroperitoneal approach to the aorta for routine infrarenal aortic reconstruction. METHODS From August 1990 through November 1993, patients undergoing surgery for abdominal aortic aneurysm (AAA) disease or aortoiliac occlusive disease (AIOD) were asked to participate in a randomized trial comparing the transabdominal incision (TAI) to the retroperitoneal incision (RPI) for aortic surgery. One hundred forty-five patients were randomized, with 75 (41 with AAA and 34 with AIOD) in the TAI group and 70 (40 with AAA and 30 with AIOD) in the RPI group. There were no significant differences between the groups in terms of age, sex, postoperative pain control (epidural vs patient-controlled analgesia), or comorbid conditions, except for a higher incidence of chronic obstructive pulmonary disease in the TAI group (21 vs 8 patients). RESULTS The incidence of intraoperative complications was similar for both groups. After surgery, the incidence of prolonged ileus (p = 0.013) and small bowel obstruction (p = 0.05) was higher in the TAI group. Overall, the RPI group had significantly fewer complications (p < 0.0001). The overall postoperative mortality rate (two deaths) was 1.4%, with both occurring in the TAI group (p = 0.507). The RPI group also had significantly shorter stays in the intensive care unit (p = 0.006), a trend toward shorter hospitalization (p = 0.10), lower total hospital charges (p = 0.019), and lower total hospital costs (p = 0.017). There was no difference in pulmonary complications (p = 0.71). In long-term follow-up (mean 23 months), the RPI group reported more incisional pain (p = 0.056), but no difference was found in incisional hernias or bulges (p = 0.297). CONCLUSIONS We conclude that the RPI approach for abdominal aortic surgery is associated with fewer postoperative complications, shorter stays in the hospital and intensive care unit, and lower cost. There is, however, an increase in long-term incisional pain. Current methods of postoperative pain control seem to decrease the incidence of pulmonary complications.

Spontaneous closure of selected iatrogenic pseudoaneurysms and arteriovenous fistulae

PURPOSE We report our approach to the management of postcatheterization femoral artery pseudoaneurysms and arteriovenous fistulae in an attempt to determine the frequency of spontaneous resolution of selected lesions. METHODS We studied 196 pseudoaneurysms, 81 arteriovenous fistulae, and 9 combined lesions that were identified by duplex scan. Indications for immediate surgical repair included pseudoaneurysm greater than 3 cm, enlarging hematoma, pain, groin infection, nerve compression, limb ischemia, concomitant surgical procedure, and patient refusal or inability to comply with follow-up. All other lesions were observed. RESULTS One hundred thirty-nine patients underwent prompt surgical repair, and 147 patients were initially managed without operation. There were no limb-threatening complications associated with nonoperative management in this subset of patients. Eighty-six percent of the lesions being observed resolved spontaneously within a mean of 23 days, whereas 14% required surgical closure for a variety of reasons (at a mean of 111 days after the initial diagnosis). There was no statistically significant difference in the rate of spontaneous pseudoaneurysm closure (89%) as opposed to fistulae (81%) (p < 0.17). By life-table analysis, 90% of selected pseudoaneurysms had resolved by 2 months. Patients selected for observation underwent an average of 2.6 duplex scans per patient versus 1.4 scans per patient for those treated with immediate surgery (p < 0.01). CONCLUSION The natural history of stable pseudoaneurysms and arteriovenous fistulae is benign and frequently results in spontaneous resolution, which allows properly selected patients to be managed without operation.

The influence of anesthetic technique on perioperative complications after carotid endarterectomy

Abstract Purpose: This study evaluated the influence of anesthetic techniques on perioperative complications after carotid endarterectomy. Methods: Perioperative complications, the use of a carotid artery shunt, the duration of the operative procedure and postoperative hospital course were retrospectively compared in 584 consecutive patients undergoing 679 carotid endarterectomies with use of either general anesthesia ( n = 361) or cervical block regional anesthesia ( n = 318). There was no significant difference in the preoperative medical characteristics between the two anesthetic groups. Symptomatic carotid artery disease was the indication for surgery in 247 (68.4%) patients receiving general anesthetics, whereas 180 (56.6%) patients treated with a cervical block anesthetic had a symptomatic carotid artery stenosis ( p = 0.02). Results: The perioperative stroke rate and stroke-death rate for the entire series was 2.4% and 3.2%, respectively, and was not significantly different between the anesthetic groups or between patients with symptomatic or asymptomatic disease. A carotid artery shunt was used in 61 (19.2%) patients receiving a cervical block anesthetic and 152 (42.1%) patients treated with a general anesthetic ( p p = 0.04). Conclusions: We conclude that cervical block anesthesia is safer and results in a more efficient use of hospital resources than general anesthesia in the treatment of patients undergoing carotid endarterectomy. (J VASC SURG 1994;19:834-43.)

Pharmacomechanical thrombolysis and early stent placement for iliofemoral deep vein thrombosis

PURPOSE To evaluate an approach to the treatment of iliofemoral deep vein thrombosis (DVT) that included pharmacomechanical catheter-directed thrombolysis with reteplase and the Helix mechanical thrombectomy device, followed by early stent placement. MATERIALS AND METHODS During 3-year period, 23 symptomatic limbs in 18 patients with iliofemoral DVT were treated with reteplase catheter-directed thrombolysis. After an initial infusion of 8 to 16 hours, any residual acute thrombus over a long segment (> 10 cm) was treated by maceration with use of the Helix thrombectomy device. Residual short-segment (< 10 cm) iliac vein thrombus and/or stenosis were treated with stent placement. Technical success, clinical success, complications, thrombolytic infusion time, total thrombolytic agent dose, fibrinogen level changes, and late limb status were retrospectively analyzed. RESULTS Technical success was achieved in 23 of 23 limbs (100%). Clinical success was achieved in 22 of 23 limbs (96%). Complete or partial thrombolysis was observed in 19 of 23 limbs (83%). Major bleeding was observed in one patient (6%) and necessitated blood transfusion. Mean per-limb thrombolytic infusion time and total dose were 19.6 hours +/- 8.1 and 13.8 U +/- 5.3 reteplase, respectively. Mean serum fibrinogen nadir and percentage drop in serum fibrinogen were 282 mg/dL +/- 167 and 47% +/- 24%, respectively. Late (mean, 19.8 +/- 11.6 months) modified Venous Disability Scores were 0 (none) for six limbs, 1 (mild) for 10 limbs, 2 (moderate) for two limbs, and 3 (severe) for no limbs. CONCLUSION In a preliminary experience, pharmacomechanical catheter-directed iliofemoral DVT thrombolysis with early stent placement was safe and effective.

Preservation of renal function in juxtarenal and suprarenal abdominal aortic aneurysm repair

PURPOSE Deterioration in renal function is a common cause of morbidity in patients treated surgically for juxtarenal and suprarenal abdominal aortic aneurysms. We reviewed our experience over the last 8 years with 65 consecutive patients undergoing juxtarenal (n = 31) or suprarenal (n = 34) abdominal aortic aneurysm repair. METHODS The aneurysms were repaired with a transabdominal (n = 8), thoracoabdominal (n = 4), retroperitoneal (n = 22), or thoracoretroperitoneal (n = 31) approach. Proximal aortic clamps were placed at the suprarenal, supra-superior mesenteric artery, or supraceliac level. Renal hypothermia with cold heparinized saline solution renal artery perfusion was used to protect renal function in 38 patients with either preoperative renal insufficiency or with anticipated prolonged renal ischemia (> 30 minutes). Concomitant renal artery reconstruction was required in 30 patients. RESULTS Significant operative morbidity developed in 23 (35.3%) patients. There was one (1.53%) perioperative death (0 to 90 days). Temporary dialysis was necessary in two patients. Preoperative renal insufficiency was a significant risk factor on multivariate analysis for a decline in renal function during the first postoperative week. However, serum creatinine concentration had returned to baseline or improved in all patients but two (3.1%) at the time of discharge. In spite of significantly longer renal ischemia, discharge creatinine levels were, on univariate analysis, statistically less than baseline creatinine levels in patients with suprarenal aneurysms, patients requiring renal reconstruction, and patients treated with renal hypothermia. The location of the proximal aortic clamp was not a factor in postoperative morbidity. There was no significant difference between juxtarenal and suprarenal aneurysms with respect to operating room time, transfusion requirements, days intubated, resumption of oral diet, or the length of hospitalization. CONCLUSIONS Careful consideration of the route of exposure, location of the proximal aortic clamp, and the preservation of renal function with renal hypothermia and with the repair of significant renal artery lesions will result in minimal morbidity and mortality in patients requiring surgery for juxtarenal or suprarenal abdominal aortic aneurysms.

Endoluminal graft repair for abdominal aortic aneurysms in high-risk patients and octogenarians: is it better than open repair?

ObjectiveTo analyze the short-term and midterm results of open and endoluminal repair of abdominal aortic aneurysms (AAA) in a large single-center series and specifically in octogenarians. MethodsBetween January 1997 and October 2000, 470 consecutive patients underwent elective repair of AAA. Conventional open repair (COR) was performed in 210 patients and endoluminal graft (ELG) repair in 260 patients. Ninety of the patients were 80 years of age or older; of these, 38 underwent COR and 52 ELG repair. ResultsPatient characteristics and risk factors were similar for both the entire series and the subgroup of patients 80 years or older. The overall complication rate was reduced by 70% or more in the ELG versus the COR groups. The postoperative death rate was similar for the COR and ELG groups in the entire series and lower (but not significantly) in the ELG 80 years or older subgroup versus the COR group. The 36-month rates of freedom from endoleaks, surgical conversion, and secondary intervention were 81%, 98.2%, and 88%, respectively. ConclusionThe short-term and midterm results of AAA repair by COR or ELG are similar. The death rate associated with this new technique is low and comparable, whereas the complication rate associated with COR in all patients and those 80 years or older in particular is greater and more serious than ELG repair. Long-term results will establish the role of ELG repair of AAA, especially in elderly and high-risk patients.

Outcomes of percutaneous endovascular intervention for type II endoleak with aneurysm expansion.

OBJECTIVE Type II endoleak (T2EL) with aneurysm expansion is believed to place patients at risk for aneurysm-related mortality (ARM). Treatment with glue and/or coil embolization of the aneurysm sac, inferior mesenteric artery (IMA), and lumbar branches via translumbar or transarterial approaches has been utilized to ablate such endoleaks, and thus decrease ARM. We evaluated the midterm results of percutaneous endovascular treatment of T2EL with aneurysm expansion. METHODS Single-institution, 5-year (January 2003 to August 2008) retrospective study of all endovascular interventions for T2EL with sac expansion. Blinded, independent review of all available pre- and post-T2EL intervention computed tomography (CT) scans was performed. Aneurysm sac maximal transverse diameters and aneurysm sac growth rates prior to and following T2EL intervention were analyzed. RESULTS Forty-two patients (34 male, eight female; mean age, 75) underwent T2EL intervention at 26 ± 20 months after endovascular aneurysm repair (EVAR) and were subsequently followed for 23 ± 20 months. Seven out of 42 patients (17%) underwent repeat T2EL intervention. Interventions included 44 translumbar sac embolizations, and transcatheter embolizations of nine IMAs and seven lumbar/hypogastric arteries. Aneurysm diameter was 6.1 ± 1.6 cm at EVAR, 6.6 ± 1.5 cm at initial T2EL treatment, and 6.9 ± 1.7 cm at last follow-up. There were no significant differences in the rates of aneurysm sac growth pre- and post-T2EL treatment. At last follow-up imaging, recurrent or persistent T2EL was noted in 72% of patients. Of 42 patients, nine (21%) received operative endoluminal correction of occult type I or type III endoleaks that were diagnosed during the T2EL angiographic intervention. There were no aneurysm ruptures or ARMs during follow-up; overall mortality for the 5-year study period was 24%. CONCLUSIONS In this series, percutaneous endovascular intervention for type II endoleak with aneurysm sac growth does not appear to alter the rate of aneurysm sac growth, and the majority of patients display persistent/recurrent endoleak. However, diagnostic angiographic evaluation may reveal unexpected type I and III endoleaks and is therefore recommended for all patients with T2EL and sac growth. While coil and glue embolization of aneurysm sac and selected branch vessels does not appear to yield benefit in our series, the diagnosis and subsequent definitive treatment of previously occult type I and III endoleaks may explain the absence of delayed rupture and ARM in our series.

Delayed paraplegia after thoracic and thoracoabdominal aneurysm repair: a continuing risk.

BACKGROUND Paraplegia or paraparesis after otherwise successful thoracic or thoracoabdominal aortic reconstruction is a devastating complication for patient and physician. Interventions for its prevention have focused primarily on the intraoperative period. We have recently noted a significant incidence of delayed-onset neurologic deficit. METHODS We reviewed our most recent 5-year experience with thoracic and thoracoabdominal reconstruction to examine the incidence of and potential contributors to delayed paraplegia or paraparesis. RESULTS Between June 1996 and June 2001, 60 patients (29 men, 31 women) underwent repair of isolated thoracic (n = 26) or thoracoabdominal aortic aneurysm (Crawford I, n = 7; Crawford II, n = 14; Crawford III, n = 12; Crawford IV, n = 1) by the cardiac and vascular surgical services collaboratively. Repair was performed endovascularly in 6, and open with either circulatory arrest in 12, partial left heart bypass in 37, or partial femorofemoral bypass in 5. Operative mortality was 9.3% (5 of 54 patients) for open repair and 0% for endovascular repair. Paraplegia or paraparesis occurred in 6 (10%) patients of which 83.3% (5 of 6) were delayed in onset. All patients with delayed paraplegia or paraparesis had degenerative aneurysms of Crawford extent II (n = 3) or III (n = 2), had intraoperative left heart bypass, and had perioperative spinal drainage. Delayed paraplegia or paraparesis occurred up to 27 days postoperatively, and was associated with a documented episode of hypotension in 60% (3 of 5) of patients. CONCLUSIONS Improvements in intraoperative management may have reduced immediate paraplegia or paraparesis among vulnerable patients only to leave them at risk of delayed-onset deficit. Postoperative care, including assiduous attention to avoidance of even transient hypotension, must be tailored to this patient population.

A Randomized, Placebo-Controlled Trial of Doxycycline after Endoluminal Aneurysm Repair

BACKGROUND The late durability of endovascular aneurysm repair (EVAR) has been limited by progressive aortic degeneration believed to be mediated by matrix metalloproteases (MMP). The goal of this study was to evaluate the effect of a MMP inhibitor, doxycycline, on EVAR. METHODS Patients undergoing EVAR were randomized to doxycycline (100 mg twice daily) or placebo for 6 months following the procedure. Clinical data, blood samples, and computed tomography (CT) scans were obtained preoperatively, postoperatively (blood only), and at 1- and 6-month follow-up. Forty-four subjects were analyzed based on intention-to-treat. RESULTS Plasma MMP-9 decreased significantly below baseline in the doxycycline (N = 20) treated patients at 6 months (-16.4% +/- 20.7%, P < .05) while there was a nonsignificant increase in the placebo (N = 24) group (128.1% +/- 73.5%). This was primarily related to changes between 1 and 6 months. In patients with endoleaks at 6 months, plasma MMP-9 increased in 83% of the placebo treated patients, but in only 14% of the doxycycline treated group (P < .03). Among endoleak-free patients with AneuRx or Excluder endografts, doxycycline treatment resulted in greater decreases in maximum aortic diameter than placebo treatment (-13.3% +/- 3.3% vs -3.8% +/- 3.0%, P < .05). Furthermore, doxycycline treatment significantly reduced the aortic neck dilatation at 6 months in Excluder treated patients. CONCLUSION There is evidence of persistent MMP release representing ongoing aortic degradation after endografting which can be inhibited by doxycycline therapy. In analyses based on the endograft used, treatment with doxycycline also demonstrated evidence of increased aortic dimensional stability, a surrogate marker for long-term success of EVAR. Although encouraging, these results require confirmation in larger patient populations. Doxycycline should undergo more thorough evaluation as a potential adjuvant treatment to improve the results of EVAR, particularly in certain subgroups.