Magruder C. Donaldson

Ex-vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial

BACKGROUND Cell-cycle blockade by ex-vivo gene therapy of experimental vein grafts inhibits the neointimal hyperplasia and subsequent accelerated atherosclerosis that lead to human bypass-graft failure. In a prospective, randomised, controlled trial, we investigated the safety and biological efficacy of intraoperative gene therapy in patients receiving bypass vein grafts. METHODS We studied gene therapy that uses decoy oligodeoxynucleotide, which binds and inactivates the pivotal cell-cycle transcription factor E2F. 41 patients were randomly assigned untreated (16), E2F-decoy-treated (17), or scrambled-oligodeoxynucleotide-treated (eight) human infrainguinal vein grafts. Oligonucleotide was delivered to grafts intraoperatively by ex-vivo pressure-mediated transfection. The primary endpoints were safety and inhibition of target cell-cycle regulatory genes and of DNA synthesis in the grafts. Analysis was by intention to treat. FINDINGS Mean transfection efficiency was 89.0% (SD 1.9). Proliferating-cell nuclear antigen and c-myc mRNA concentrations and bromodeoxyuridine incorporation were decreased in the EF2-decoy group by medians of 73% [IQR 53-84], 70% [50-79], and 74% [56-83], respectively) but not in the scrambled-oligodeoxynucleotide group (p<0.0001). Groups did not differ for postoperative complication rates. At 12 months, fewer graft occlusions, revisions, or critical stenoses were seen in the E2F-decoy group than in the untreated group (hazard ratio 0.34 [95% CI 0.12-0.99]). INTERPRETATION Intraoperative transfection of human bypass vein grafts with E2F-decoy oligodeoxynucleotide is safe, feasible, and can achieve sequence-specific inhibition of cell-cycle gene expression and DNA replication. Application of this genetic-engineering strategy may lower failure rates of human primary bypass vein grafting.

Health-Related Quality of Life After Elective Surgery

Objective:To examine the responsiveness of the 36-Item Short Form Health Survey (SF-36) to clinical changes in three surgical groups and to study how health-related quality of life (HRQL) changes with time among patients who undergo total hip arthroplasty, thoracic surgery for treatment of non-small-cell lung cancer, or abdominal aortic aneurysm (AAA) repair.Design:Prospective cohort study with serial evaluations of HRQL preoperatively and at 1, 6, and 12 months after surgery.Setting:University tertiary care hospital.Patients:Of 528 patients, more than 50 years of age, who were admitted for these elective procedures, 454 (86%) provided preoperative health status data and are members of the study cohort. At 12 months after surgery, 439 (93%) of the cohort was successfully contacted and 390 (90%) provided follow-up interviews.Measurements and main results:The Medical Outcomes Study SF-36, the Specific Activity Scale, five validated health transition questions, and a 0 to 100 scale measure of global health were used to assess changes in health status at 1, 6, and 12 months after surgery. Change in health status as measured by the SF-36 demonstrated that physical function and role limitations due to physical health problems were worse 1 month after these three surgeries. However, by 6 months after surgery, most patients experienced significant gains in the majority of the dimensions of health, and these gains were sustained at 12 months after surgery. Longitudinal changes in the SF-36 were positively associated with responses to the five health transition questions, to changes on the Specific Activity Scale and global health rating question, and to clinical parameters for persons who had AAA repair. These findings indicate that the SF-36 has evidence of validity and is responsive to expected changes in HRQL after elective surgery for these procedures.Conclusions:For the total hip arthroplasty patients, responsiveness was greatest for the SF-36 scales that measure physical constructs. However, for the two other procedures and at various points of recovery, significant changes were observed for all eight subscales, suggesting that responsiveness was dependent on the type of surgery and the timing of follow-up, and that multidimensional measures are needed to fully capture changes in HRQL after surgery.

Selective evaluation and management of coronary artery disease in patients undergoing repair of abdominal aortic aneurysms. A 16-year experience.

Reduction of cardiac mortality associated with abdominal aortic aneurysm (AAA) repair remains an important goal. Five hundred consecutive urgent or elective operations for infrarenal nonruptured AAA were reviewed. Patients were divided into three groups based on preoperative cardiac status: group I (n = 260, 52%), no clinical or electrocardiographic (ECG) evidence of coronary artery disease (CAD); group II (n = 212, 42.2%), clinical or ECG evidence of CAD considered stable after further evaluation with studies such as dipyridamole-thallium scanning, echocardiography, or coronary arteriography; group III (n = 28, 5.6%), clinical or ECG evidence of CAD considered unstable after further evaluation. Group I had no further cardiac evaluation and groups I and II underwent AAA repair without invasive treatment of CAD. Group III underwent repair of cardiac disease before (n = 21) or coincident with (n = 7) AAA repair. In all instances, perioperative fluid volume management was based on left ventricular performance curves constructed before operation. The 30-day operative mortality rate for AAA repair in all 500 patients was 1.6% (n = 8). There was one (0.4%) cardiac-related operative death in group I, which was significantly less than the five (2.4%) in group II (p less than 0.02). Total mortality for the two groups were also significantly different, with one group I death (0.4%) and seven group II deaths (3.3%), (p less than 0.02). These data support the conclusions that (1) the leading cause of perioperative mortality in AAA repair is myocardial infarction, (2) correction of severe or unstable CAD before or coincident with AAA repair is effective in preventing operative mortality, (3) patients with known CAD should be investigated more thoroughly to identify those likely to develop perioperative myocardial ischemia so that their CAD can be corrected before AAA repair, and (4) patients with no clinical or ECG evidence of CAD rarely die of perioperative myocardial infarction, and thus selective evaluation of CAD based on clinical grounds in AAA patients is justified.

Causes of primary graft failure after in situ saphenous vein bypass grafting

In situ saphenous vein bypass grafts originating in the groin were performed in 455 consecutive patients. Primary failure occurred in 92 grafts during follow-up, including 22 (4.8%) with nonocclusive stenosis and 70 (15.4%) with occlusion. The cause for failure could not be determined in seven grafts; 104 contributory causes were identified in the remaining 85 grafts. Among the 104 likely causes, 66 (63%) were intrinsic to the graft itself and contributed to failure of 55 (12.1%) of 455 grafts. These causes included perianastomotic stenosis (48), vein stricture (14), focal vein stenosis (10), valvulotome injury (9), kink (6), retained valve leaflet (4), intimal flap (3), and residual arteriovenous fistula (2). Among these intrinsic causes, 20 were directly related to the in situ technique, contributing to failure of 15 (3.3%) of 455 grafts. Thirty-eight (37%) of the 104 causes were extrinsic to the graft, including compromised inflow (2) or outflow (19), hypercoagulability (9), systemic hypotension (6), and graft sepsis (2). Hypothetically, improvements in technique, patient selection, and perioperative management might have eliminated 46 (44%) of 104 causes of primary graft failure. Delayed graft and anastomotic stenosis and late progression of outflow disease remain resistant to modern therapy.

What is the proper role of polytetrafluoroethylene grafts in infrainguinal reconstruction

Polytetrafluoroethylene grafts have been used extensively for infrainguinal vascular reconstruction either as the conduit of choice or as a substitute when saphenous vein is unavailable. Although numerous studies have shown satisfactory early patency rates, the long-term efficacy of these grafts in a large number of patients for specific indications and in various positions has been less well defined. From 1977 to 1987 we used four PTFE grafts from three different manufacturers to perform 300 infrainguinal reconstructions on 240 patients on our vascular service. The indications for surgery were disabling claudication in 28% and limb salvage in 72%. The 30-day operative mortality of 1% was not different from the 1.4% associated with infrainguinal autogenous vein grafting. The 5-year cumulative patency rate achieved with all infrainguinal polytetrafluoroethylene grafts was 35%, significantly higher for grafts placed for claudication (57%) than those placed for limb salvage (24%). There were no significant differences between the above-knee and below-knee locations for distal anastomoses regardless of indication, but femoropopliteal grafts provided significantly higher 5-year patency (37%) than infrapopliteal grafts (12%). Comparison of the 5-year patency rates among the three manufacturers of polytetrafluoroethylene grafts showed no significant differences. Fifty-four polytetrafluoroethylene grafts that failed underwent 67 revisions after catheter thrombectomy or thrombolysis, which resulted in a minimal 11% 5-year patency rate. Based on this experience, it is concluded that infrainguinal polytetrafluoroethylene prostheses provide significantly inferior results when compared with autogenous reconstruction.

Observations on the use of thrombolytic agents for thrombotic occlusion of infrainguinal vein grafts

Vein graft failure remains a major challenge for the vascular surgeon. Thrombolysis of occluded vein grafts has shown promising short-term results in restoring vein graft patency, however, the long-term results are not established. This study examines the long-term patency and limb salvage after successful thrombolysis and revision of 22 thrombosed vein grafts in 21 patients. There were 17 men and four women with an average age of 60 years (38 to 77 years). Failed vein grafts had an average primary patency of 19 months (1 to 84 months) and included eight in situ grafts and 14 non-in situ grafts. Twelve grafts were to the popliteal level, whereas 10 were infrapopliteal. Thrombolytic agents used included urokinase (15), tissue plasminogen activator (5), and streptokinase (2). After successful thrombolysis, 19 grafts underwent 26 additional procedures including percutaneous transluminal angioplasty (9), vein patch angioplasty (4), vein interposition or jump extension graft (9), or other procedures (4). Three patients had no additional procedure, but one was placed on sodium warfarin (Coumadin). After successful initial vein graft salvage, life-table analysis revealed a 36.6% +/- 11.9% patency at 1 year and a 22.9% +/- 11.6% patency at 3 years. After secondary failure six patients had further interventions contributing to an improved limb salvage of 66.9% +/- 11.6% at 1 year and 60.3% +/- 19.0% at 3 years. The results suggest that thrombosed vein grafts initially salvaged with thrombolysis and revision do not have a favorable long-term patency, and that a premium must be placed on the detection of the failing vein graft before thrombosis.

Femoral-distal bypass with in situ greater saphenous vein. Long-term results using the Mills valvulotome.

During a 7-year period, 440 consecutive in situ saphenous vein grafts originating in the groin were performed in 371 patients, exposing the entire vein for valvulotomy with a modified Mills valvulotome. critical ischemia was the indication for bypass in 68%, and the distal anastomosis was to an infrapopliteal artery in 46%. Thirty-day operative mortality was 2.0%. Postoperative surveillance identified 18 stenotic grafts (4.1%), which were revised while still patent (primary revised patency); 36 grafts (8.2%) underwent revision after graft occlusion (secondary patency). Five-year life-table analysis showed overall primary revised patency of 78%, secondary patency of 83%, limb salvage of 88%, and patient survival of 66%. Femoroperoneal and inframalleolar bypasses fared well. The presence of diabetes did not diminish late graft patency. In contrast to reversed vein grafts, long infrapopliteal in situ grafts had long-term secondary patency similar to shorter femoropopliteal bypass grafts (p greater than 0.05). These results, coupled with the versatility and simplicity of the technique as used in the present series, suggest that in situ vein grafting is the procedure of choice for long infrapopliteal bypass.

Infrainguinal arterial reconstruction with nonreversed greater saphenous vein

PURPOSE This study was undertaken to examine the effectiveness and the possible advantages of infrainguinal arterial reconstruction with nonreversed greater saphenous vein (NRGSV) grafts. We reviewed the results achieved with 189 consecutive NRGSV bypass procedures from July 1, 1985, to August 31, 1995, and compared them with 568 consecutive in situ greater saphenous vein (INGSV) bypass procedures completed over the same interval. METHODS NRGSV bypass procedures were performed by selecting the optimum inflow and outflow vessels and then excising the best available appropriate-length segment of greater saphenous vein. The valves were lysed with a Mills valvulotome using gentle antegrade distention with an isotonic electrolyte solution containing heparin (1000 U/500 ml) and papaverine (60 mg/500 ml). The graft was then translocated to the inflow site, where the proximal and distal anastomoses were sequentially completed, followed by a completion arteriography. RESULTS Demographic and risk factor characteristics did not differ between patients who underwent NRGSV and those who underwent INGSV bypass. Compared with INGSV bypasses, NRGSV bypasses were more commonly secondary procedures (26% vs 8%; p < 0.001) and were more often performed for limb salvage indications (89% vs 68%; p < 0.001). NRGSV bypasses also had more distal inflow vessels (23% superficial femoral artery [SFA] and 28% popliteal artery [POP] vs 10% SFA and 1% POP; p < 0.001) and more distal outflow vessels (52% tibial and 22% pedal artery vs 47% tibial and 3% pedal artery; p < 0.001) than did INGSV bypasses. Despite the higher incidence of secondary bypass procedures and more distal outflow vessels in the NRGSV group, the overall results achieved at 5 years did not differ between the two groups. The 5-year primary patency rates were 65% +/- 5% for NRGSV and 72% +/- 3% for INGSV (p < 0.12), and the 5-year secondary patency rates were 74% +/- 5% and 82% +/- 2% (p < 0.08), respectively. Similarly, the 5-year limb salvage rate among bypass procedures performed for limb salvage indications did not differ for NRGSV (82% +/- 5%) and INGSV (90% +/- 2%; p < 0.06). CONCLUSIONS The application of the NRGSV bypass graft preserves the INGSVs main advantage of optimal size match between artery and vein at each anastomosis, but facilitaties the tailoring of the procedure to the patients anatomy and the completion of the bypass with the shortest, best-quality conduit available. Our application of the NRGSV in a more challenging series of bypass procedures produced equivalent results to those achieved in a concurrent series of INGSV bypass procedures.

Preoperative risk factors for carotid endarterectomy: defining the patient at high risk ☆

PURPOSE The efficacy of carotid endarterectomy (CEA) for prevention of stroke has been demonstrated in randomized trials; however, the optimal approach in patients excluded from these trials or who have other significant comorbid conditions remains controversial, particularly with the advent of percutaneous interventions. We examined the influence of putative risk factors on outcome of CEA in a single-center experience. METHODS A retrospective analysis of 1370 consecutive CEA performed from 1990 to 1999 was undertaken. Preoperative risk factors examined included age older than 80 years, congestive heart failure, chronic obstructive pulmonary disease, renal failure (serum creatinine concentration > 2.0 mg/dL), contralateral carotid artery occlusion, recurrent ipsilateral carotid artery stenosis, ipsilateral hemispheric symptoms within 6 weeks, and recent coronary bypass grafting (CABG). The Fisher exact test was used to identify baseline variables associated with perioperative (30 days) risk for stroke or death. Multivariate analysis with Poisson regression was used to study the effect of all univariate criteria in combination. RESULTS In the overall cohort, there were 32 adverse events (2.3%), including 11 deaths (0.8%), 6 disabling strokes (0.4%), and 10 nondisabling strokes (0.7%). There was no significant difference in incidence of perioperative stroke or death between patients with one or more risk factors (n = 689) and those with no risk factors (low risk, n = 681). Thirty-day mortality was significantly greater in patients with two or more risk factors compared with patients with no risk factors (2.8% vs 0.3%; P =.04), but no significant difference was noted in perioperative stroke rate (2.3% vs 1.0%). Univariate analysis demonstrated that contralateral carotid occlusion (n = 75) was the only significant predictor of adverse outcome (5 events, 6.7%) among the variables tested; this was confirmed with multivariate analysis (relative risk, 4.3; 95% confidence interval, 1.2-12.3; P =.01). Five-year survival for patients with two or more risk factors was notably diminished compared with that for patients with no risk factors (38.7% +/- 5.9% vs 75.0% +/- 2.6%; P <.001). Contralateral occlusion was also associated with reduced 5-year survival (38 +/- 11% vs 67 +/- 2%; P <.004). CONCLUSION CEA can be safely performed in patients deemed at high risk, including those aged 80 years or older and others with significant comorbid conditions, with combined stroke and mortality rates comparable to those found in randomized trials, ie, the Asymptomatic Carotid Atherosclerosis Study and the North American Symptomatic Carotid Endarterectomy Trial. Contralateral occlusion may be a predictor for moderately increased perioperative risk and for reduced long-term survival. Caution may be warranted in asymptomatic patients with multiple risk factors, in whom presumed long-term benefit of CEA may be compromised by markedly reduced 5-year survival.

Body mass index as a correlate of postoperative complications and resource utilization

PURPOSE To describe the relationship of body mass index (BMI) with postoperative complications and resource utilization. PATIENTS AND METHODS Two thousand nine hundred and sixty-four patients 50 years or older undergoing elective noncardiac surgery with an expected length of stay > or = 2 days were enrolled in a prospective cohort study to measure major cardiac complications, noncardiac complications, length of stay, and costs. The setting was an urban teaching hospital. A preoperative history, physical, electrocardiogram (ECG), and chart review were performed by study personnel. Postoperative complications were detected by ECGs, creatine kinase and creatine kinase MB levels, and daily chart review. Total costs were obtained from the hospitals computerized database. RESULTS Complication rates were not different among BMI groups (underweight < 20, normal 20 to 29, overweight 30 to 34, most overweight > 34), but patients with BMI 30 to 34 and > 34 who underwent abdominal or gynecologic procedures had significantly higher wound infection rates (11% each) than normal weight patients (4.7%) or the underweight (0%). After adjusting for age, race, gender, smoking history, comorbid diseases, procedure type, and insurance status, there were nonsignificant trends toward increased resource utilization by the most overweight patients (BMI > 34). These patients stayed 0.8 days longer (P = 0.13) and had total costs that were