Protocol for the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study: a pragmatic, randomised clinical trial.

INTRODUCTION: Postoperative delirium, arbitrarily defined as occurring within 5 days of surgery, affects up to 50% of patients older than 60 after a major operation. This geriatric syndrome is associated with longer intensive care unit and hospital stay, readmission, persistent cognitive deterioration and mortality. No effective preventive methods have been identified, but preliminary evidence suggests that EEG monitoring during general anaesthesia, by facilitating reduced anaesthetic exposure and EEG suppression, might decrease incident postoperative delirium. This study hypothesises that EEG-guidance of anaesthetic administration prevents postoperative delirium and downstream sequelae, including falls and decreased quality of life. METHODS AND ANALYSIS: This is a 1232 patient, block-randomised, double-blinded, comparative effectiveness trial. Patients older than 60, undergoing volatile agent-based general anaesthesia for major surgery, are eligible. Patients are randomised to 1 of 2 anaesthetic approaches. One group receives general anaesthesia with clinicians blinded to EEG monitoring. The other group receives EEG-guidance of anaesthetic agent administration. The outcomes of postoperative delirium (≤5 days), falls at 1 and 12 months and health-related quality of life at 1 and 12 months will be compared between groups. Postoperative delirium is assessed with the confusion assessment method, falls with ProFaNE consensus questions and quality of life with the Veteran's RAND 12-item Health Survey. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 95% CIs and will be considered statistically significant at a two-sided p<0.05. ETHICS AND DISSEMINATION: Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) is approved by the ethics board at Washington University. Recruitment began in January 2015. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media. TRIAL REGISTRATION NUMBER: NCT02241655; Pre-results.

Potential renal protective benefits of intra-operative BNP infusion during cardiac transplantation.

BACKGROUND: Recombinant BNP (nesiritide) is known to reduce endothelin levels, cause afferent arteriole vasodilation, and increase natriuresis and diuresis. We hypothesized that intraoperative infusion of BNP may benefit renal function in cardiac transplant patients. METHODS: From June 2003 to September 2005, 22 consecutive heart transplant patients received BNP at a dose of 0.01 microg/kg/min before initiation of cardiopulmonary bypass (group A). BNP infusion was continued for a mean of 3.3 +/- 1.9 days. Hemodynamics, urine output, and serum creatinine levels were prospectively collected and compared with 22 consecutive patients who underwent heart transplantation between May 2002 and June 2003 following the identical transplant protocol, but without BNP infusion (group B). RESULTS: At 24 hours postoperatively, mean blood pressure was comparable between groups (87 +/- 11 mm Hg vs 89 +/- 17 mm Hg, P = .7), but pulmonary artery pressure (18 +/- 5 mm Hg vs 24 +/- 5 mm Hg, P = .001) and central venous pressure (12 +/- 5 mm Hg vs 16 +/- 4 mm Hg, P = .01) were lower with BNP infusion, whereas cardiac index was augmented (2.8 +/- 0.5 vs 2.4 +/- 0.6, P = .03). Requirement of low-dose inotropic and vasopressor support was equally distributed between groups (P > or = .72). Postoperative urine output for the initial 24 hours was higher in group A (84 +/- 15 vs 55 +/- 36 mL/h, P = .01). None of the patients with BNP infusion required additional diuretics or renal replacement therapy during the first week after transplantation. Mean postoperative serum creatinine levels as compared with preoperative values remained unchanged within group A (P = .12), but increased significantly in group B (P < .001). CONCLUSIONS: Intraoperative BNP infusion in heart transplant recipients was associated with favorable postoperative hemodynamics, significantly improved urine output, and stable serum creatinine levels. A prospective, randomized, multicenter trial is warranted to evaluate the potential renal protective benefits of intraoperative BNP infusion in this patient population.

Surgical treatment of atrial fibrillation with bipolar radiofrequency ablation: mid-term results in one hundred consecutive patients.

AIM: The Cox-Maze procedure was introduced nearly two decades ago for the surgical treatment of atrial fibrillation (AF). Recently, our group has replaced most of the incisions of the Cox-Maze procedure with bipolar radiofrequency (RF) ablations (Cox-Maze IV procedure). The purpose of this study was to examine our midterm results with the Cox-Maze procedure using bipolar RF ablation. METHODS: From January 2002 to October 2005, 100 consecutive patients underwent a modified Cox-Maze procedure with bipolar RF ablation for AF; 32 were lone operations, and 68 were concomitant procedures. Follow-up was performed at 1, 3, 6, and 12 months, and then annually thereafter. Heart rhythm was confirmed by electrocardiography. RESULTS: The mean age of patients was 62+/-13 years; 57% were male. Duration of AF was 6.3+/-7.6 years (0.1 to 40 years), 59% had paroxysmal AF, and 34% had permanent AF. Follow-up was complete for all patients with a mean follow-up of 13+/-10 months. At 12-month follow-up, 91% (49/54) of patients were free of AF. Cross-clamp time in the lone Cox-Maze IV procedure patients was 42+/-15 minutes, while it was 101+/-29 minutes for the Cox-Maze IV with a concomitant procedure (compared to 93+/-34 minutes and 122+/-37 minutes for the traditional procedure, P<0.05). There were four operative deaths. CONCLUSIONS: The Cox-Maze IV procedure had good mid-term efficacy. The use of bipolar RF energy significantly decreased operative time and simplified the procedure compared to the traditional Cox-Maze procedure, potentially increasing utilization of the procedure among cardiac surgeons.

Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor.

The immune system, despite its complexity, is maintained at a relative steady state. Mechanisms involved in maintaining lymphocyte homeostasis are poorly understood; however, recent availability of transgenic (Tg) and knockout mouse models with altered balance of lymphocyte cell populations suggest that cytokines play a major role in maintaining lymphocyte homeostasis. We show here that transforming growth factor (TGF)-beta plays a critical role in maintaining CD8(+) T cell homeostasis in a Tg mouse model that specifically overexpresses a dominant negative TGF-beta II receptor (DNRII) on T cells. DNRII T cell Tg mice develop a CD8(+) T cell lymphoproliferative disorder resulting in the massive expansion of the lymphoid organs. These CD8(+) T cells are phenotypically "naive" except for the upregulation of the cell surface molecule CD44, a molecule usually associated with memory T cells. Despite their dominance in the peripheral lymphoid organs, CD8(+) T cells appear to develop normally in the thymus, suggesting that TGF-beta exerts its homeostatic control in the peripheral immune system.

Immediate and late outcomes after direct stent implantation without balloon predilation.

OBJECTIVES: The aim of our study was to compare the in-hospital and long-term clinical outcomes of direct coronary stenting with balloon predilation followed by stent placement. BACKGROUND: With improvement in stent designs, the practice of direct stenting without balloon predilation has become more widespread. METHODS: We analyzed the Mayo Clinic Coronary Intervention data base between January 1, 1995 and March 5, 1999 and identified 777 patients who were treated with direct stenting (DS) and 3,176 patients treated with balloon angioplasty plus stenting (BA+S). RESULTS: The procedural success rates between the DS and BA+S groups were not significantly different (96.3% vs. 96.4%). The ability to deliver the stent in a subgroup of patients who had DS was 95%, with 5% requiring crossover to predilation. Multivariate analysis showed no significant differences with respect to in-hospital death (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.5 to 1.8), in-hospital myocardial infarction (OR 0.9, 95% CI 0.6 to 1.2) or revascularization (OR 0.7, 95% CI 0.4 to 1.5) in the DS compared with the BA+S group. Long-term outcomes were not significantly different between the DS and BA+S groups. The procedural duration was significantly shorter in the DS group, and there was a decreased utilization of contrast agent, balloons and wires. CONCLUSIONS: The in-hospital and long-term clinical outcomes in patients undergoing a coronary intervention are equivalent when comparing stenting without balloon predilation with balloon angioplasty followed by stenting. Direct stenting is associated with decreased utilization of contrast agent and equipment and shorter procedure times. A randomized study should be performed to better determine the impact of this technique on short- and long-term procedural outcomes.

Clopidogrel versus ticlopidine after intracoronary stent placement.

OBJECTIVES: The study compared the safety and efficacy of ticlopidine with clopidogrel in patients receiving coronary stents. BACKGROUND: Stent thrombosis is reduced when ticlopidine is administered with aspirin. Clopidogrel is similar to ticlopidine in chemical structure and function but has fewer side effects; few data are available about its use in stent patients. METHODS: We compared 30-day event rates in 500 consecutive coronary stent patients treated with aspirin and clopidogrel (300 mg loading dose immediately prior to stent placement, and 75 mg/day for 14 days) to 827 consecutive stent patients treated with aspirin and ticlopidine (500 mg loading dose and 250 mg twice daily for 14 days). RESULTS: Patients treated with clopidogrel had more adverse clinical characteristics including older age, more severe angina, and more frequent infarction within the prior 24 h. Nonetheless, mortality was 0.4% in clopidogrel patients versus 1.1% in ticlopidine patients; nonfatal myocardial infarction occurred in 0% versus 0.5%, stent thrombosis in 0.2% versus 0.7%, bypass surgery or repeat angioplasty in 0.4% versus 0.5%, and any event occurred in 0.8% versus 1.6% of patients, respectively (p = NS). Based on the observed 30-day event rate of 1.6% with ticlopidine, the statistical power of the study was 43% to detect an even rate of 0.5% with clopidogrel, and 75% to detect an event rate with of 4% with clopidogrel, with a p value of 0.05. CONCLUSIONS: These data indicate that clopidogrel can be safely substituted for ticlopidine in patients receiving coronary stents.

Safety and efficacy of ticlopidine for only 2 weeks after successful intracoronary stent placement.

BACKGROUND: In patients receiving intracoronary stents, stent thrombosis is reduced when ticlopidine therapy is combined with aspirin after the procedure. However, ticlopidine causes neutropenia in 1% of patients when administered for >2 weeks, and little is known about the duration that ticlopidine needs be administered to prevent stent thrombosis. METHODS AND RESULTS: We analyzed 827 patients undergoing successful stent placement in 1061 coronary segments at Mayo Clinic who were treated between May 1, 1996, and October 31, 1997. Chronic warfarin therapy, cardiogenic shock, and enrollment in research protocols requiring 4 weeks of ticlopidine were exclusion criteria; ticlopidine was discontinued after 14 days in all remaining patients. The mean age of the study population was 64+/-11 years; 49% had suffered a prior infarction, 20% had undergone coronary artery bypass surgery, and 65% had multivessel disease. The indication for stent placement was dissection or abrupt closure in 31% of patients and suboptimal results from balloon angioplasty in 18%. Placement was elective in 51% of patients, and 10.3% of patients were treated within 12 hours of an acute myocardial infarction. Mean nominal stent size was 3.3+/-0.5 mm. High-pressure inflations (>/=12 atm) were performed in all patients (mean, 17+/-4 atm). Intravascular ultrasound was used to facilitate stent placement in 8.8% of patients. Abciximab was administered to 38% of patients; 11% of patients who were at increased risk of stent thrombosis were treated with enoxaparin for 10 to 14 days. Adverse cardiovascular events in the 14 days after stent placement occurred in 11 patients (1.3%). Two patients died of nonischemic causes (sepsis and renal failure) in the 15th through 30th days after ticlopidine was stopped. However, there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures between the 15th and 30th days; stent thrombosis did not occur in any patient after ticlopidine had been stopped. No patient developed neutropenia, although 1.8% of the first 489 patients who were closely monitored for side effects from ticlopidine developed side effects requiring its discontinuation, and milder side effects occurred in 4.7%. CONCLUSIONS: In patients receiving intracoronary stents, the discontinuation of ticlopidine therapy 14 days after stent placement is associated with a very low frequency of stent thrombosis and other adverse events.

Frequency of adverse clinical events in the 12 months following successful intracoronary stent placement in patients treated with aspirin and ticlopidine (without warfarin).

Little is known about the frequency of adverse events in the year following stent placement in patients treated with aspirin and ticlopidine, without warfarin. We analyzed the first such 234 consecutive patients treated at our hospital between October 1994 and December 1995. Their mean age was 62+/-12 years; 40% had had a prior myocardial infarction, 22% had undergone coronary artery bypass surgery, and 65% had multivessel disease. The indication for stent placement was dissection or abrupt closure in 24% of patients and suboptimal balloon angioplasty results in 14%; placement was elective in 62% of patients. Three hundred forty-five coronary segments were treated in the 234 patients; 305 stents (1.3 stents/patient) were placed. Palmaz-Schatz coronary stents (75%), Gianturco-Roubin stents (21%), and Johnson & Johnson biliary stents (4%) were used. Mean nominal stent size was 3.4+/-0.4 mm. High-pressure inflations (> or = 14 atm, mean 17+/-2) were performed in all patients. The mean residual stenosis was 3+/-5% by visual estimate. Intravascular ultrasound was utilized to facilitate stent placement in 53% of patients. Mean follow-up was 1.6+/-0.5 years. There were no deaths, Q-wave myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures required during the remainder of the hospitalization or in 30 days after stent placement; stent thrombosis did not occur. Kaplan-Meier analysis of adverse events in the 6 months following the procedure revealed a mortality rate of 0.9%; the rate of myocardial infarction (Q-wave or non-Q-wave) was 1.3%. Bypass surgery was performed in 0.9% and angioplasty for in-stent restenosis was performed in 9.5% of patients. Any 1 of these events occurred in 11.7% of patients in the 6 months after the procedure. The corresponding event rates at 1 year were 1.3%, 2.2%, 3.5%, and 12.2%, respectively; any 1 of these events occurred in 16.5% of patients. In patients receiving intracoronary stents of varying designs followed by high-pressure postdeployment inflations in whom an excellent visual angiographic result is achieved, antithrombotic therapy with aspirin and ticlopidine is associated with a very low frequency of adverse cardiovascular events in the 12 months following the procedure regardless of the indication for stent placement.

Clinical outcome of patients undergoing endoluminal coronary artery reconstruction with three or more stents.

OBJECTIVES: We sought to evaluate the outcome of patients undergoing multiple (three or more), contiguous stent implantation within a single native coronary artery. BACKGROUND: The implantation of multiple stents within a single coronary artery is increasing in frequency, although the outcome of such patients is not well described. METHODS: Forty-five patients without previous coronary artery bypass graft surgery (CABG) undergoing multiple, contiguous stent implantation in a single coronary artery were identified. Clinical and angiographic characteristics and outcomes were analyzed. RESULTS: The angiographic success rate was 97.8%. The procedural success rate was 91.1%; stent occlusion during the initial hospital period occurred in four patients (8.9%). Death, myocardial infarction (MI), CABG, repeat target vessel intervention or severe angina occurred in 10 (23.3%) of 43 hospital survivors at 6-months follow-up. The indication for stent placement was threatened or abrupt closure in 30 patients (66.7%). Of the 25 patients with abrupt or threatened closure whose clinical and angiographic data would have indicated emergent CABG had stents not been available, the frequency of in-hospital death and Q wave MI was similar to that of a matched consecutive series of patients at our institution who underwent emergent CABG after failed angioplasty. At 1 year, the frequency of death, Q wave MI, CABG and severe angina at 1 year was similar in the two groups; the need for repeat percutaneous intervention was more common in the stent group (25% vs. 0%, p = 0.01). CONCLUSIONS: Implantation of multiple, contiguous intracoronary stents was associated with a high initial success rate, although the incidence of early stent closure was relatively high. Adverse events at 6 months of follow-up were more frequent than previously reported for elective single-stent implantation; however, adverse angiographic characteristics such as dissection and thrombus were frequent in this group. In addition, the strategy of multiple stent implantation in the setting of failed angioplasty is a reasonable alternative to emergent CABG, although the need for further percutaneous intervention must be anticipated.