A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Preoperative Antithrombin Supplementation in Patients at Risk for Antithrombin Deficiency After Cardiac Surgery.

BACKGROUND: Antithrombin (AT) activity is reduced during cardiac operations with cardiopulmonary bypass (CPB), which is associated with adverse outcomes. Preoperative AT supplementation, to achieve >58% and <100% AT activity, may potentially reduce postoperative morbidity and mortality in cardiac operations with CPB. This prospective, multicenter, randomized, double-blind, placebo-controlled study was designed to evaluate the safety and efficacy of preoperative treatment with AT supplementation in patients at risk for low AT activity after undergoing cardiac surgery with CPB. METHODS: A total of 425 adult patients were randomized (1:1) to receive either a single dose of AT (n = 213) to achieve an absolute increase of 20% above pretreatment AT activity or placebo (n = 212) before surgery. The study duration was approximately 7 weeks. The primary efficacy end point was the percentage of patients with any component of a major morbidity composite (postoperative mortality, stroke, acute kidney injury [AKI], surgical reexploration, arterial or venous thromboembolic events, prolonged mechanical ventilation, and infection) in the 2 groups. Secondary end points included AT activity, blood loss, transfusion requirements, duration of intensive care unit (ICU), and hospital stays. Safety was also assessed. RESULTS: Overall, 399 patients (men, n = 300, 75.2%) with a mean (standard deviation [SD]) age of 66.1 (11.7) years, with the majority undergoing complex surgical procedures (n = 266, 67.9%), were analyzed. No differences in the percentage of patients experiencing morbidity composite outcomes between groups were observed (AT-treated 68/198 [34.3%] versus placebo 58/194 [29.9%]; P = .332; relative risk, 1.15). After AT infusion, AT activity was significantly higher in the AT group (108% [42-143]) versus placebo group (76% [40-110]), and lasted up to postoperative day 2. At ICU, the frequency of patients with AT activity ≥58% in the AT group (81.5%) was significantly higher ( P < .001) versus placebo group (43.2%). Secondary end point analysis did not show any advantage of AT over placebo group. There were significantly more patients with AKI ( P < .001) in the AT group (23/198; 11.6%) than in the placebo group (5/194, 2.6%). Safety results showed no differences in treatment-emergent adverse events nor bleeding events between groups. CONCLUSIONS: AT supplementation did not attenuate adverse postoperative outcomes in our cohort of patients undergoing cardiac surgery with CPB.

The perioperative significance of systemic arterial diastolic hypertension in adults.

PURPOSE OF REVIEW: Hypertension affects approximately one third of the U.S. population and is the most common preventable medical reason that surgical cases are postponed or cancelled. However, subtypes of hypertension and their perioperative risks are poorly studied and understood. We will review the natural history and pathophysiology of essential hypertension and discuss the perioperative significance of diastolic blood pressure elevation. RECENT FINDINGS: There is evidence that elevated preoperative diastolic blood pressures are associated with an increased perioperative risk of cardiovascular and cerebrovascular events and increased postoperatively 30-day mortality. However, lower preoperative diastolic blood pressures were found, in one study, to be associated with renal injury. SUMMARY: Diastolic hypertension and hypotension both carry perioperative risk. Further study needs to be dedicated to elucidating the risks and developing strategies for acute and chronic management of diastolic blood pressure changes in order to improve perioperative safety.

Levosimendan Reduces Mortality in Adults with Left Ventricular Dysfunction Undergoing Cardiac Surgery: A Systematic Review and Meta-analysis.

INTRODUCTION: Levosimendan is implemented in patients with low cardiac output after cardiac surgery. However, the strength of evidence is limited by randomized controlled trials enrolling a small number of patients. Hence we have conducted a systematic review to determine the role of levosimendan in adult cardiac surgery. METHODS: PUBMED, WoS, Cochrane database, and SCOPUS were systematically queried to identify original English language peer-reviewed literature (inception-October 2014) comparing clinical results of adult cardiac surgery between levosimendan and control. Pooled odds ratio (OR) was calculated using the Peto method; p < 0.05 is significant; results are presented within 95% confidence intervals. Continuous data was compared using standardized mean difference/mean difference. RESULTS: Fourteen studies were included in the analysis. Levosimendan reduced early mortality in patients with reduced ejection fraction (5.5% vs. 9.1%) (OR 0.48 [0.23-0.76]; p = 0.004). This result was confirmed using sensitivity analysis. Postoperative acute renal failure was lower with levosimendan therapy (7.4% vs. 11.5%). Intensive care unit stay was shorter in the levosimendan cohort comparable in both groups (standardized mean difference -0.31 [-0.53, -0.09]; p = 0.006; I(2) = 33.6%). Levosimendan-treated patients stayed 1.01 (1.61-0.42) days shorter when compared to control (p = 0.001). CONCLUSION: Our meta-analysis demonstrates that Levosimendan improves clinical outcomes in patients with left ventricular dysfunction undergoing cardiac surgery. Results of the ongoing multicenter randomized controlled trial are awaited to provide more conclusive evidence regarding the benefit of this drug.

Clevidipine compared with nitroglycerin for blood pressure control in coronary artery bypass grafting: a randomized double-blind study.

PURPOSE: We tested the hypothesis that clevidipine, a rapidly acting dihydropyridine calcium channel blocker, is not inferior to nitroglycerin (NTG) in controlling blood pressure before cardiopulmonary bypass (CPB) during coronary artery bypass grafting (CABG). METHODS: In this double-blind study from October 4, 2003 to April 26, 2004, 100 patients undergoing CABG with CPB were randomized at four centres to receive intravenous infusions of clevidipine (0.2-8 µg·kg(-1)·min(-1)) or NTG (0.4 µg·kg(-1)·min(-1) to a clinician-determined maximum dose rate) from induction of anesthesia through 12 hr postoperatively. The study drug was titrated in the pre-CPB period with the aim of maintaining mean arterial pressure (MAP) within ± 5 mmHg of a clinician-predetermined target. The primary endpoint was the area under the curve (AUC) for the total time each patient's MAP was outside the target range from drug initiation to the start of CPB, normalized per hour (AUCMAP-D). The predefined non-inferiority criterion for the primary endpoint was a 95% confidence interval (CI) upper limit no greater than 1.50 for the geometric means ratio between clevidipine and NTG. RESULTS: Total mean [standard deviation (SD)] dose pre-bypass was 4.5 (4.7) mg for clevidipine and 6.9 (5.4) mg for NTG (P < 0.05). The geometric mean AUCMAP-D for clevidipine was 283 mmHg·min·hr(-1) (n = 45) and for NTG was 292 mmHg·min·hr(-1) (n = 48); the geometric means ratio was 0.97 (95% CI 0.74 to 1.27). The geometric mean AUCMAP-D during aortic cannulation was 357.7 mmHg·min·hr(-1) for clevidipine compared with 190.5 mmHg·min·hr(-1) for NTG. Mean (SD) heart rate with clevidipine was 76.0 (13.8) beats·min(-1) compared with 81.5 (14.4) beats·min(-1) for NTG. There were no clinically important differences between groups in adverse events. CONCLUSION: During CABG, clevidipine was not inferior to NTG for blood pressure control pre-bypass.

Acute kidney injury following cardiac surgery: role of perioperative blood pressure control.

BACKGROUND/AIMS: Patients who develop acute kidney injury (AKI) after cardiac surgery continue to have a high mortality rate. Although factors that predispose to postoperative renal dysfunction have been identified, this knowledge has not been associated with a substantial reduction in the incidence of this serious adverse event. METHODS: This review uses the existing literature to explore the relationship between AKI and perioperative blood pressure (BP) control in cardiac surgery patients. The results of recent novel analyses are introduced, and the implications of these studies for the management of cardiac surgery patients in the perioperative period are discussed. RESULTS: Preexisting isolated systolic hypertension and wide pulse pressure increase the risk of postoperative renal dysfunction in the cardiac surgery population. New data suggest that BP lability (i.e., BP excursions outside an acceptable physiologic range) during cardiac surgery may also be an important predictor of subsequent renal dysfunction. CONCLUSION: Recently published data suggest that perioperative BP lability influences both the risk of postoperative renal dysfunction and 30-day mortality. Future studies will determine whether the use of agents that allow improved BP control within a desirable range will reduce the incidence of postoperative AKI in cardiac surgery patients.

Does perioperative systolic blood pressure variability predict mortality after cardiac surgery? An exploratory analysis of the ECLIPSE trials.

BACKGROUND: Few studies describe an association of perioperative blood pressure stability with postoperative outcome. We tested the hypothesis that systolic blood pressure (SBP) variability in patients undergoing cardiac surgery is associated with 30-day mortality. METHODS: Perioperative blood pressure variability was evaluated in the 1512 patients who were randomized and had perioperative hypertension in the ECLIPSE trials. Blood pressure variability was assessed as the product of magnitude × duration of SBP excursions outside defined SBP ranges (area under the curve). SBP ranges were analyzed from 65 to 135 mm Hg intraoperatively and 75 to 145 mm Hg pre- or postoperatively, up to 105 to 135 mm Hg intraoperatively and 115 to 145 mm Hg pre- or postoperatively, with the narrower ranges defined by progressively increasing the lower SBP limit by 10 mm Hg increments. Multiple logistic regression was used to assess the association of blood pressure variability with 30-day mortality obtained from the primary ECLIPSE trial results. RESULTS: Increased SBP variability outside a range of 75 to 135 mm Hg intraoperatively and 85 to 145 mm Hg pre- and postoperatively is significantly associated with 30-day mortality. The odds ratio was 1.16 (95% confidence interval, 1.04-1.30) for 30-day mortality risk per incremental SBP excursion of 60 mm Hg × min/h. The predicted probability of 30-day mortality increased for low-risk patients from 0.2% to 0.5%, and for high-risk patients from 42.4% to 60.7% if the area under the curve increased from 0 to 300 mm Hg × min/h. CONCLUSIONS: Perioperative blood pressure variability is associated with 30-day mortality in cardiac surgical patients, proportionate to the extent of SBP excursions outside the range of 75 to 135 mm Hg intraoperatively and 85 to 145 mm Hg pre- and postoperatively. Predicted mortality was greater for high-risk patients than for low-risk patients.

Troponin is superior to electrocardiogram and creatinine kinase MB for predicting clinically significant myocardial injury after coronary artery bypass grafting.

AIMS: Cardiac biomarkers are routinely elevated after uncomplicated cardiac surgery to levels considered diagnostic of myocardial infarction in ambulatory populations. We investigated the diagnostic power of electrocardiogram (ECG) and cardiac biomarker criteria to predict clinically relevant myocardial injury using benchmarks of mortality and increased hospital length of stay (HLOS) in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS: Perioperative ECGs, creatinine kinase MB fraction, and cardiac troponin I (cTnI) were assessed in 545 primary CABG patients. None of the ECG criteria for myocardial injury predicted mortality or HLOS. However, post-operative day (POD) 1 cTnI levels independently predicted 5-year mortality (hazard ratio = 1.42; 95% CI 1.14-1.76 for each 10 microg/L increase; P = 0.009), while adjusting for baseline demographic characteristics and perioperative risk factors. Moreover, cTnI was the only biomarker that significantly improved the prediction of 5-year mortality estimated by the logistic Euroscore (P = 0.02). Furthermore, the predictive value of cTnI for 5-year mortality was replicated in a separately collected cohort of 1031 CABG patients using cardiac troponin T. CONCLUSION: Electrocardiogram diagnosis of post-operative myocardial injury after CABG does not independently predict an increased risk of 5-year mortality or HLOS. Conversely, cTnI is independently associated with an increased risk of mortality and prolonged HLOS.

Successful use of bivalirudin for combined carotid endarterectomy and coronary revascularization with the use of cardiopulmonary bypass in a patient with an elevated heparin-platelet factor 4 antibody titer.

We report a combined carotid endarterectomy and coronary revascularization surgery with cardiopulmonary bypass using bivalirudin for systemic anticoagulation in a patient with a positive titer for the heparin-platelet factor 4 antibody. The patient experienced procedural success for both the carotid and coronary surgeries. Increased blood and blood product transfusion was required postoperatively.

Changes in mitral regurgitation after replacement of the stenotic aortic valve.

BACKGROUND: Concomitant mitral regurgitation (MR) is frequently seen in patients undergoing aortic valve replacement (AVR) for aortic stenosis. This study was undertaken to characterize the magnitude of MR in these patients and identify factors associated with significant postoperative change. METHODS: Between 2002 and 2006, 391 patients with stenotic AV disease but no structural mitral valve disease underwent AVR without coronary artery bypass grafting. Excluded were 164 patients with combined aortic and mitral intervention, right heart surgery, or moderate to severe aortic insufficiency, to yield a final study group of 227 patients. Follow-up echographic evaluation of MR was obtained in 87 of 219 patients (40%) discharged alive without mitral valve intervention. RESULTS: Overall mortality was 3.5%. After AVR, intraoperative MR severity improved in 66% of patients. Independent predictors of lower postoperative MR were small left atrial size (p = 0.03), the presence of aortic insufficiency (p < 0.01), and preoperative congestive heart failure (p = 0.04). Prosthetic valve type or size was not an independent predictor of postoperative MR. After adjustment for intraoperative underestimation of MR grade, there was no difference between the postprocedural MR grade and the early or late follow-up MR grade (p = 0.6 and p = 0.8, respectively). CONCLUSIONS: The results of this study support a conservative, tailored approach to concomitant mitral surgery in patients presenting for correction of aortic stenosis who demonstrate functional mitral regurgitation. Characteristics associated with resolution may allow for identification of patients most likely to benefit from mitral valve repair or replacement.

Prevalence of heparin/platelet factor 4 antibodies before and after cardiac surgery.

BACKGROUND: The clinical significance of heparin/platelet factor 4 (PF4) antibodies in subjects undergoing cardiac surgery has not been systematically studied. We prospectively investigated whether the presence of heparin/PF4 antibodies would predict clinical thrombosis in this population. METHODS: In 299 patients scheduled for cardiac surgery between October 2003 and March 2005, the heparin/PF4 antibodies and platelet count were measured immediately prior to, and 5 days after, surgery. The patients were followed up at 30 days for thrombotic complications. RESULTS: The prevalence of the heparin/PF4 antibodies was 4.3% (13 of 299) prior to surgery and increased more than fivefold to 22.4% (62 of 277) postoperatively (p < 0.0001). Thromboembolic events occurred in 8.8% of patients with negative antibody and in 6.3% of patients with positive antibody (p = 0.77). Of the 62 patients with positive heparin/PF4 antibodies postoperatively, 22 (35.5%) were treated with a nonheparin anticoagulant. There was a trend toward higher rates of thromboembolic events in subjects who were thrombocytopenic compared with those who were not (17.1% and 6.7%, respectively, p = 0.06), regardless of antibody status. Two out of 8 patients (25%) with both thrombocytopenia and a positive antibody (clinical heparin-induced thrombocytopenia [HIT]) suffered a thromboembolic event, compared with 17 of 222 (7.7%) without clinical HIT (p = 0.13). CONCLUSIONS: The high prevalence of antibodies to the heparin/PF4 complex after cardiac surgery and the low rate of thromboembolic complications in this population suggest that the antibody alone does not confer an increased risk of thrombotic complications. Monitoring for thrombocytopenia is recommended.

Arrested paradoxical emboli in transit diagnosed by intraoperative transesophageal echocardiography.

IMPLICATIONS: We describe a patient who developed a deep venous thrombosis that subsequently embolized to both the pulmonary and systemic arterial circulations. The diagnosis of arrested paradoxical embolus in transit at two separate and unique anatomic locations was made with intraoperative transesophageal echocardiography, and the patient did not suffer organ damage as a result of the paradoxical emboli.