Perioperative Ischemic Injury Research Articles

Perioperative infarction and myocardial injury: risk factors, mechanisms of development and clinical and epidemiological features

Тhe concept, risk factors, mechanisms, clinical and epidemiological, and angiographic features of perioperative ischemic injury and myocardial infarction were considered. Perioperative myocardial infarction is one of the most common complications (up to 3.6%) in non-cardiac surgical interventions and is characterized by high in-hospital mortality, reaching 25%. Most patients with this pathology (up to 65%) do not have typical symptoms of myocardial ischemia due to anesthesia and sedation. Pathogenetic mechanisms of perioperative myocardial infarction development continues to be actively studied. A critical increase in myocardial oxygen demand is indicated as the leading cause in some studies. Angiography reveals rupture of the coronary plaque and atherothrombosis in more than half of patients, according to other data. These contradictions point to the need for further epidemiological studies using coronary angiography with a focus on risk factors and triggers of this complication. In addition, the concept of perioperative myocardial injury in recent years has been formulated in the scientific literature. This is understood as ischemic damage that occurs in the first 30 days after surgery. Recent studies have shown that it can occur in 16% of surgical patients and is associated with a 6-fold increase in mortality within 1 month after surgery and a 2.5-fold increase within a year. It is important that perioperative myocardial injury does not include cases of non-ischemic etiology myocardial injury, for example, due to pulmonary embolism, sepsis, or electrical cardioversion. Thus, the assessment and understanding of risk factors for the development of perioperative myocardial ischemia is of great practical importance in optimizing the patient selection and preparation for surgical treatment.

The immunometabolite S-2-hydroxyglutarate exacerbates perioperative ischemic brain injury and cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity

BackgroundMetabolic dysregulation and disruption of immune homeostasis have been widely associated with perioperative complications including perioperative ischemic stroke. Although immunometabolite S-2-hydroxyglutarate (S-2HG) is an emerging regulator of immune cells and thus triggers the immune response, it is unclear whether and how S-2HG elicits perioperative ischemic brain injury and exacerbates post-stroke cognitive dysfunction.MethodsPerioperative ischemic stroke was induced by transient middle cerebral artery occlusion for 60 min in C57BL/6 mice 1 day after ileocecal resection. CD8+ T lymphocyte activation and invasion of the cerebrovascular compartment were measured using flow cytometry. Untargeted metabolomic profiling was performed to detect metabolic changes in sorted CD8+ T lymphocytes after ischemia. CD8+ T lymphocytes were transfected with lentivirus ex vivo to mobilize cell proliferation and differentiation before being transferred into recombination activating gene 1 (Rag1−/−) stroke mice.ResultsThe perioperative stroke mice exhibit more severe cerebral ischemic injury and neurological dysfunction than the stroke-only mice. CD8+ T lymphocyte invasion of brain parenchyma and neurotoxicity augment cerebral ischemic injury in the perioperative stroke mice. CD8+ T lymphocyte depletion reverses exacerbated immune-mediated cerebral ischemic brain injury in perioperative stroke mice. Perioperative ischemic stroke triggers aberrant metabolic alterations in peripheral CD8+ T cells, in which S-2HG is more abundant. S-2HG alters CD8+ T lymphocyte proliferation and differentiation ex vivo and modulates the immune-mediated ischemic brain injury and post-stroke cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity.ConclusionOur study establishes that S-2HG signaling-mediated activation and neurotoxicity of CD8+ T lymphocytes might exacerbate perioperative ischemic brain injury and may represent a promising immunotherapy target in perioperative ischemic stroke.

Development and Validation of a Diagnostic Model to Predict the Risk of Ischemic Liver Injury After Stanford A Aortic Dissection Surgery.

Objective: To define the risk factors of ischemic liver injury (ILI) following Stanford A aortic dissection surgery and to propose a diagnostic model for individual risk prediction.Methods: We reviewed the clinical parameters of ILI patients who underwent cardiac surgery from Beijing Anzhen Hospital, Capital Medical University between January 1, 2015 and October 30, 2020. The data was analyzed by the use of univariable and multivariable logistic regression analysis. A risk prediction model was established and validated, which showed a favorable discriminating ability and might contribute to clinical decision-making for ILI after Stanford A aortic dissection (AAD) surgery. The discriminative ability and calibration of the diagnostic model to predict ILI were tested using C statistics, calibration plots, and clinical usefulness.Results: In total, 1,343 patients who underwent AAD surgery were included in the study. After univariable and multivariable logistic regression analysis, the following variables were incorporated in the prediction of ILI: pre-operative serum creatinine, pre-operative RBC count <3.31 T/L, aortic cross-clamp time >140 min, intraoperative lactic acid level, the transfusion of WRBC, atrial fibrillation within post-operative 24 h. The risk model was validated by internal sets. The model showed a robust discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.718. The calibration plots for the probability of perioperative ischemic liver injury showed coherence between the predictive probability and the actual probability (Hosmer-Lemeshow test, P = 0.637). In the validation cohort, the nomogram still revealed good discrimination (C statistic = 0.727) and good calibration (Hosmer-Lemeshow test, P = 0.872). The 10-fold cross-validation of the nomogram showed that the average misdiagnosis rate was 9.95% and the lowest misdiagnosis rate was 9.81%.Conclusion: Our risk model can be used to predict the probability of ILI after AAD surgery and have the potential to assist clinicians in making treatment recommendations.

Effects of High Dose of Atorvastatin for Preventing Periprocedural Ischemic Brain Damage in Patients Undergoing Carotid Artery Stenting (PICAS) in China: A Randomized Controlled Clinical Trial.

Background: Research conducted in Western countries has suggested that high-dose statin therapy can lead to the regression of carotid atherosclerotic plaques and can reduce periprocedural ischemic complication rates in individuals undergoing carotid artery stenting (CAS). However, whether this same therapeutic approach is of value in patients of Chinese ethnicity is not as well-established.Methods: This is a single-center, prospective, parallel-controlled, intervention-based efficacy study that will enroll a total of 130 Chinese patients with cervical carotid stenosis who are scheduled to undergo CAS. These patients will be randomly divided into a routine treatment group and a high-dose atorvastatin group. Individuals in the routine treatment group will be administered standard of care 20 mg/day atorvastatin treatment. Individuals in the high-dose atorvastatin group will be administered 80 mg/day atorvastatin for 3 days prior to and following CAS. The primary outcome of this study will be the cumulative incidence of new cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging (DW-MRI) within 5 days following CAS, and of transient ischemic attacks (TIAs) or ischemic stroke within 30 days after CAS.Discussion: This study is the first to assess whether high-dose atorvastatin treatment is capable of reducing the incidence of perioperative cerebral ischemic injury in patients of Chinese ethnicity undergoing CAS. These results will offer evidence regarding which statin treatment regimens are more appropriate when treating Chinese patients undergoing CAS in an effort to minimize their risk of any perioperative cerebral ischemic injury.Trial Registration: ClinicalTrials.gov NCT03079115; registered March 14, 2017.

Perioperative Ischemic Reperfusion Injury, Aggravated by Prolonged Cardiac Ischemic Time, May Cause Temporary Deterioration of Allograft Function

Perioperative Ischemic Reperfusion Injury, Aggravated by Prolonged Cardiac Ischemic Time, May Cause Temporary Deterioration of Allograft Function

Computational evaluation of aortic occlusion and the proposal of a novel, improved occluder: Constrained endo-aortic balloon occlusion.

Because aortic occlusion is arguably one of the most dangerous aortic manipulation maneuvers during cardiac surgery in terms of perioperative ischemic neurological injury, the purpose of this investigation is to assess the structural mechanical impact resulting from the use of existing and newly proposed occluders. Existing (clinically used) occluders considered include different cross-clamps (CCs) and endo-aortic balloon occlusion (EABO). A novel occluder is also introduced, namely, constrained EABO (CEABO), which consists of applying a constrainer externally around the aorta when performing EABO. Computational solid mechanics are employed to investigate each occluder according to a comprehensive list of functional requirements. The potential of a state of occlusion is also considered for the first time. Three different constrainer designs are evaluated for CEABO. Although the CCs were responsible for the highest strains, largest deformation, and most inefficient increase of the occlusion potential, it remains the most stable, simplest, and cheapest occluder. The different CC hinge geometries resulted in poorer performance of CC used for minimally invasive procedures than conventional ones. CEABO with a profiled constrainer successfully addresses the EABO shortcomings of safety, stability, and positioning accuracy, while maintaining its complexities of operation (disadvantage) and yielding additional functionalities (advantage). Moreover, CEABO is able to achieve the previously unattainable potential to provide a clinically determinable state of occlusion. CEABO offers an attractive alternative to the shortcomings of existing occluders, with its design rooted in achieving the highest patient safety. Copyright © 2016 John Wiley & Sons, Ltd.

Troponin-I Level After Major Noncardiac Surgery and Its Association With Long-Term Mortality

Individuals with intermediate to high cardiac risk for major noncardiac surgery suffer from perioperative myocardial ischemic injury. The purpose of this study was to evaluate the long-term impact of postoperative cardiac troponin elevation on clinical outcome after major noncardiac surgery.Patients (n = 750) aged ≥ 50 years who underwent major noncardiac surgery were eligible for the study. Postoperative cardiac troponin-I data were collected retrospectively and consecutively. The primary outcome measure was allcause mortality. The median follow-up period was 1727 days in all patients.Among 750 patients, 92 (12.2%) showed elevated postoperative troponin-I above 0.10 ng/mL. Operative mortality was 4.1% (31 subjects), and patients with troponin-I elevation showed a higher operative mortality rate (RR: 4.23, 95% CI: 2.67-11.31, P < 0.001). In multivariate Cox regression analysis, a troponin-I concentration above 0.10 ng/mL was associated with all-cause mortality (RR: 1.73, 95% CI: 1.27-2.36, P < 0.001). It should be noted that there was a significant difference between patients with elevated and non-elevated troponin-I in the rate of mortality until 6 months. However, these differences disappeared after 6 months.An elevated troponin-I level conferred an increase in mortality during the 7 year follow-up period after major noncardiac surgery. This difference in mortality was mainly derived from the result within the first 6 months.

Evaluation of postoperative myocardial injury by heart-type fatty acid-binding protein in off-pump coronary artery bypass grafting surgery

Background and goal of studyPostoperative myocardial infarction is a serious and frequent complication of cardiac surgery. Nonetheless, diagnosis in this context is occasionally challenging. We sought to evaluate the kinetics and diagnostic accuracy of the new biomarker “heart-type fatty acid-binding protein” (h-FABP) in the early detection of myocardial injury in patients undergoing off-pump coronary artery bypass grafting, compared with classical biomarkers. Materials and methodsA prospective study was conducted on 17 consecutive patients who underwent off-pump coronary artery bypass grafting during a 2-month period. Blood samples were drawn for measurement of myocardial ischemic injury biomarkers (h-FABP, troponin, creatine kinase [CK] and CK-MB), at baseline (T1), immediate post-coronary artery bypass grafting (T2), on ICU admission (T3), and after 4 (T4), 8 (T5), 24 (T6) and 48h (T7). Perioperative ischemic complications, defined according to electrocardiographic, echocardiographic and hemodynamic criteria, were recorded. ResultsEarlier peak biochemical marker plasma values occurred at T4 with troponin (2.9±5.2ng/mL), and at T5 with h-FABP (37.9±55.5ng/mL). Maximum values of CK and CK-MB occurred later, both in T6 (741±779 and 37±51U/L, respectively). The optimized cut-off obtained for h-FABP was 19ng/mL, providing a sensitivity and specificity of 77 and 75%, respectively, for diagnosis of perioperative ischemic injury, with an area under the ROC curve for h-FABP of 0.83 (95% CI 0.6–1.0) vs. 0.63 (95% CI 0.33–0.83) for troponin. This cut-off value for h-FABP is reached on average at T2 (mean value of h-FABP at T2: 18.9±21.5ng/mL). ConclusionThis is the first study evaluating the kinetics of h-FABP biomarker in perioperative off-pump coronary artery bypass grafting, and the cut-off value established could help to extend earlier detection of myocardial ischemia in this context.

Anesthetic Neuroprotection: Antecedents and An Appraisal of Preclinical and Clinical Data Quality

Anesthetics have been studied for nearly fifty years as potential neuroprotective compounds in both perioperative and resuscitation medicine. Although anesthetics present pharmacologic properties consistent with preservation of brain viability in the context of an ischemic insult, no anesthetic has been proven efficacious for neuroprotection in humans. After such effort, it could be concluded that anesthetics are simply not neuroprotective in humans. Moreover, pharmacologic neuroprotection with non-anesthetic drugs has also repeatedly failed to be demonstrated in human acute brain injury. Recent focus has been on rectification of promising preclinical neuroprotection data and subsequent failed clinical trials. This has led to consensus guidelines for the process of transferring purported therapeutics from bench to bedside. In this review we first examined the history of anesthetic neuroprotection research. Then, a systematic review was performed to identify major clinical trials of anesthetic neuroprotection. Both the preclinical neuroprotection portfolio cited to justify a clinical trial and the design and conduct of that clinical trial were evaluated using modern standards that include the Stroke Therapy Academic Industry Roundtable (STAIR) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. In publications intended to define anesthetic neuroprotection, we found overall poor quality of both preclinical efficacy analysis portfolios and clinical trial designs and conduct. Hence, using current translational research standards, it was not possible to conclude from existing data whether anesthetics ameliorate perioperative ischemic brain injury. Incorporation of advances in translational neuroprotection research conduct may provide a basis for more definitive and potentially successful clinical trials of anesthetics as neuroprotectants.

Valoración del daño miocárdico mediante la medición de la heart-fatty acid-binding protein en cirugía de revascularización coronaria sin circulación extracorpórea. Estudio preliminar

Background and goal of studyPostoperative myocardial infarction is a serious and frequent complication of cardiac surgery. Nonetheless, diagnosis in this context it is occasionally challenging. We sought to evaluate the kinetics and diagnostic accuracy of the new biomarker «heart-type fatty acid-binding protein» (h-FABP) in the early detection of myocardial injury in patients undergoing off-pump coronary artery bypass grafting, compared with classical biomarkers. Materials and methodsA prospective study was conducted on 17 consecutive patients who underwent off-pump coronary artery bypass grafting during a 2 month period. Blood samples were drawn for measurement of myocardial ischemic injury biomarkers (h-FABP, troponin, creatine kinase [CK] and CK-MB), at baseline (T1), immediate post-coronary artery bypass grafting (T2), on ICU admission (T3), and after 4 (T4), 8 (T5), 24 (T6) and 48h (T7). Perioperative ischemic complications, defined according to electrocardiographic, echocardiographic and hemodynamic criteria, were recorded. ResultsEarlier biomarkers peak plasma values occurred at T4 with troponin (2.9±5.2ng/mL), and at T5 with h-FABP (37.9±55.5ng/mL). Maximum values of CK and CK-MB occurred later, both in T6 (741±779 and 37±51U/L, respectively). The optimized cut-off obtained for h-FABP was 19ng/mL, providing a sensitivity and specificity of 77 and 75%, respectively, for diagnosis of perioperative ischemic injury, with an area under the ROC curve for h-FABP of 0.83 (95% CI 0.6-1.0) vs. 0.63 (95% CI 0.33-0.83) for troponin. This cut-off value for h-FABP is reached on average at T2 (mean value of h-FABP at T2: 18.9±21.5ng/mL). ConclusionThis is the first study evaluating the kinetics of h-FABP biomarker in perioperative off-pump coronary artery bypass grafting, and the cut-off value established could help to extend earlier detection of myocardial ischemia in this context.

Cognitive dysfunction after on-pump operations: neuropsychological characteristics and optimal core battery of tests.

Postoperative cognitive dysfunction (POCD) is a mild form of perioperative ischemic brain injury, which emerges as memory decline, decreased attention, and decreased concentration during several months, or even years, after surgery. Here we present results of our three neuropsychological studies, which overall included 145 patients after on-pump operations. We found that the auditory memory span test (digit span) was more effective as a tool for registration of POCD, in comparison with the word-list learning and story-learning tests. Nonverbal memory or visuoconstruction tests were sensitive to POCD in patients after intraoperative opening of cardiac chambers with increased cerebral air embolism. Psychomotor speed tests (digit symbol, or TMT A) registered POCD, which was characteristic for elderly atherosclerotic patients. Finally, we observed that there were significant effects of the order of position of a test on the performance on this test. For example, the postoperative performance on the core tests (digit span and digit symbol) showed minimal impairment when either of these tests was administered at the beginning of testing. Overall, our data shows that the selection of tests, and the order of which these tests are administered, may considerably influence the results of studies of POCD.

Perioperative Ischemic Injury and Fibrotic Degeneration of Muscle in a Forearm Allograft

Allografts of the forearm are still uncommon in the field of composite tissue allograft transplantation. In November 2007, a right-hand allograft and a left-hand/full-length forearm allograft were transplanted in a 30-year-old man who lost both hands and the vision in his left eye due to an explosion. The patient underwent alemtuzumab and steroid induction therapy. Tacrolimus, mycophenolate mofetil, and low doses of steroids were given to prevent rejection. The allografts were rejected 3 times, but these episodes were controlled successfully. The immunosuppressive regimen was switched from tacrolimus to sirolimus because of increased serum creatinine. The left allograft showed a flexion contracture due to muscle fibrosis that was conjectured to be associated with a perioperative ischemic injury and permitted only a Moberg-type key pinch. In contrast, an excellent grade of function was observed in the right allograft. The Disabilities of the Shoulder, Arm, and Hand score improved from 70.83 to 36.6 and intrinsic musculature returned to both allografts. The patient was able to work 2 years after transplantation. This is the first report of an ischemic injury related to the successful allotransplantation of a composite tissue.

Revised Cardiac Risk Index (Lee) and Perioperative Cardiac Events as Predictors of Long-Term Mortality in Patients Undergoing Endovascular Abdominal Aortic Aneurysm Repair

Conclusion: Long-term mortality is high after endovascular repair of abdominal aortic aneurysm (AAA). In the setting of endovascular AAA repair, the Lee Index may be useful for stratifying short-term and long-term mortality in high-risk patients. Summary: Perioperative myocardial infarction remains a vexing problem. In very high-risk vascular surgical patients, perioperative myocardial ischemic injury may be as high as 18% to 35% (J Vasc Surg 2006;43:533-538). Although a large majority of patients survive a perioperative myocardial ischemic event, they are at risk of increased late mortality (J Vasc Surg 1994;20:598-604). Because it appears long-term survival is not improved by endovascular aneurysm repair (EVAR) vs conventional open AAA repair, it is reasonable to investigate whether patients undergoing EVAR can be stratified according to the Revised Cardiac Risk Index (Lee). This was a retrospective review from a single academic medical center involving 225 patients with AAA treated with EVAR between 1999 and 2006. The goal was to determine if the Lee Index is useful is stratifying patients by risk of both perioperative cardiac morbidity and long-term all-cause mortality. Data were collected from physician quality assurance databases, office records, and medical records. There were no in-hospital cardiac deaths. The major cardiac adverse event (MACE) rate perioperatively was 6.2%. Long-term all-cause mortality was 23%. By univariate analysis, a history of coronary artery disease (likelihood ratio [LR], 8.7; P = .023), history of congestive heart failure (LR, 4; P = .042), and a Revised Cardiac Risk Index (RCRI) ≥3 (LR, 8.6; P = .004) were all predictors of perioperative MACE. Long-term all-cause mortality was associated with a history of coronary artery disease (LR, 10.7; P = .002), perioperative cardiac events (LR, 15.9; P < .0001), echocardiographic evidence of myocardial infarction (LR, 8.5; P = .006), and exercise tolerance of only on block (LR, 8.4; P = .005). Long-term mortality is increased after perioperative cardiac events within the RCRI ≥3 subgroup (LR, 6.1; P = .019). Comment: It would seem logical that a patient who develops a myocardial ischemic event after EVAR should undergo further evaluation for coronary artery disease. Long-term survival appears significantly impaired after EVAR, and more so after even a minor myocardial infarction following EVAR. Whether the minor perioperative myocardial event is a cause of long-term mortality or merely a marker of long-term increased cardiac risk is a question that deserves further investigation.

36: Pattern and Evolution of C4d Staining in Perioperative Ischemic Myocyte Injury Post Transplantation

Perioperative ischemic myocyte injury post-transplantation (PIMI) may overlap morphologically with antibody mediated rejection (AMR). Immunohistochemical staining of endomyocardial biopsies for C4d has shown to correlate with AMR,especially microvascular endothelial staining. Ischemically injured myocytes may also stain with C4d. We examine pattern and evolution of myocytic and microvascular staining in a group of patients with PIMI.

Perioperative myocardial ischemic injury in high-risk vascular surgery patients: Incidence and clinical significance in a prospective clinical trial

Perioperative myocardial ischemic injury in high-risk vascular surgery patients: Incidence and clinical significance in a prospective clinical trial

IL-1α and IL-1β Are Endogenous Mediators Linking Cell Injury to the Adaptive Alloimmune Response

Preoperative or perioperative ischemic injury of allografts predisposes to graft arteriosclerosis, the major cause of late graft failure. We hypothesize that injured tissues release mediators that increase the production of pathogenic cytokines by alloreactive T cells. We find that freeze-thaw lysates of human endothelial cells (EC) increase both IFN-gamma and IL-17 production by human CD4(+) T cells activated by HLA-DR(+) allogeneic EC. Immunoadsorption of high-mobility group box 1 protein (HMGB1) reduces this activity in the lysates by about one-third, and recombinant HMGB1 increases T cell cytokine production. HMGB1 acts by inducing IL-1beta secretion from contaminating monocytes via TLR4 and CD14. Upon removal of contaminating monocytes, the remaining stimulatory activity of EC lysates is largely attributable to IL-1alpha. Recombinant IL-1 directly augments IFN-gamma and IL-17 production by activated memory CD4(+) T cells, which express IL-1R1. Furthermore, IL-1 increases the frequency of alloreactive memory CD4(+) T cells that produce IL-17, but not those that produce IFN-gamma, in secondary cultures. Our results suggest that IL-1, released by injured EC or by HMGB1-stimulated monocytes, is a key link between injury and enhanced alloimmunity, offering a new therapeutic target for preventing late graft failure.

Perioperative myocardial ischemic injury in high-risk vascular surgery patients: Incidence and clinical significance in a prospective clinical trial

The purpose of this study was to assess prospectively the incidence, health care resource utilization, and economic burden associated with perioperative myocardial ischemic injury (PMII) in high-risk patients undergoing noncardiac vascular surgery. Two hundred thirty-six patients consented to participate in a pharmacoeconomic substudy as part of a randomized, multicenter clinical trial. Patients were assessed for myocardial ischemic injury by using clinical, biochemical, and electrocardiographic criteria. PMII was defined as fatal or nonfatal myocardial infarction, new or worsened congestive heart failure, or new arrhythmias. Resource utilization parameters were compared for patients with and without PMII. Patients underwent the following index procedures: open abdominal aortic aneurysm repair (n = 44), bypass for aortoiliac disease (n = 29), bypass for femoropopliteal disease (n = 62), bypass for femorotibial disease (n = 71), extra-anatomic bypass (n = 23), and miscellaneous (n = 7). Patients undergoing carotid endarterectomy or only endovascular interventions were excluded. The incremental cost of PMII was estimated by applying the average costs (adjusted to 2004 US dollars) of the hospital ward (dollar 700.00/d) or intensive care unit (dollar 2500.00/d) to the length of stay differences for patients with and without PMII. The overall mortality was 3.4% (8/236), and 7 of 8 deaths were related to PMII. PMII occurred in 42 (17.8%) of 236 patients: 22 myocardial infarctions, 11 congestive heart failures, and 12 new arrhythmias (3 patients had 2 PMII events). There was no evidence of differences in the incidence of PMII among the various index procedures. PMII was associated with a dramatic increase in resource utilization. The mean length of stay was 16.8 and 10.0 days for patients with and without PMII, respectively (P < .001). Intensive care unit care was required by 35 (83.3%) of 42 patients with and 121 (62.4%) of 194 patients without PMII (P < .009). The mean intensive care unit length of stay was 6.6 and 3.7 days for patients with and without PMII, respectively (P < .009). Ten (23.8%) of 42 patients with and 20 (10.3%) of 194 patients without PMII returned to the emergency department for care after discharge (P < .02). In modern vascular surgery practice, PMII remains common despite the availability of beta-blockers and other preventative strategies. PMII is associated with dramatic increases in resource utilization and cost. The increase in resource utilization associated with PMII resulted in an estimated incremental cost per patient of dollar 9980.00. If 250,000 high-risk open vascular operations are performed annually in the United States, the economic burden of PMII in these procedures alone approximates dollar 444 million. Strategies to decrease PMII incidence and severity should be evaluated in large-scale prospective trials.

Efficacy of Zoniporide, an Na/H Exchange Ion Inhibitor, for Reducing Perioperative Cardiovascular Events in Vascular Surgery Patients

To determine whether a novel Na+/H+ exchange ion inhibitor, zoniporide, is associated with reduced perioperative myocardial ischemic injury in high-risk surgery patients. Randomized double-blind placebo-controlled multidose trial. Multicenter worldwide (105 centers) trial. Patients with known or multiple risk factors for coronary artery disease undergoing noncardiac vascular surgery. Four parallel groups received 1 of 3 doses of zoniporide or placebo, delivered as a 60-minute loading dose immediately before surgery, and followed by a continuous intravenous infusion for up to 7 days. A total of 824 subjects were randomized into the study from 105 centers worldwide. Of these, 784 subjects received study drug infusion in the 3-mg/kg/d, 6-mg/kg/d, and 12-mg/kg/d groups and the placebo group, and 769 satisfied the criteria for the primary efficacy analysis population. This is 68% of the planned sample size of 1125 subjects. Anesthetic management and perioperative cardiac medications were at the discretion of the attending anesthesiologists, surgeons, and cardiologists. The proportion of subjects who experienced the composite endpoint event (death, myocardial infarction, congestive heart failure, arrhythmia) by postsurgical day 30 was 18.5% in the 12-mg/kg/d group, compared with 15.7% in the placebo group, resulting in a relative risk (RR) of 1.17% (95% confidence interval [CI], 0.80-1.72; p = NS) favoring placebo. The proportions in the lower 2 zoniporide dose groups were slightly lower than in the placebo group, although the sample size is inadequate to reach any firm conclusions. The results fail to demonstrate the efficacy of zoniporide in reducing the proportion of patients at high risk undergoing noncardiac vascular surgery who experience a composite cardiovascular endpoint, which led the corporate sponsor to stop enrollment early on the basis of a futility analysis of the chance of demonstrating efficacy with a larger sample size.

3'-Aminoadenosine-5'-uronamides: discovery of the first highly selective agonist at the human adenosine A3 receptor.

Selective adenosine A(3) agonists have potential utility for the prevention of perioperative myocardial ischemic injury. Herein, we report on the discovery and synthesis of compound 7. This amino nucleoside agonist possesses unprecedented levels of selectivity for the human adenosine A(3) receptor.

Surgical Treatment of Nonatherosclerotic Lesions of the Extracranial Carotid Artery

Nonatherosclerotic disorders of the extracranial carotid artery, such as dissections, aneurysms, and carotid body tumors, are diverse in their causes, presentations, and modes of treatment. The surgical treatment of these lesions often will require a higher exposure of the extracranial carotid than is typical for a carotid endarterectomy. The prevention of perioperative ischemic injury assumes a major role in determining the surgical strategy for treating these lesions. This article offers a brief description of several of these disorders, a review of the general surgical approach to the high cervical artery, and a brief description of lesion-specific surgical techniques.