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Background: Stress and negative emotions contribute to atrial fibrillation (AF). Mind-body practices decrease stress and negative emotions and may reduce AF episodes and improve quality of life for patients with AF. Objective: We examined the effects of a multimodal mind-body program, the SMART Program, on AF-related quality of life in patients with paroxysmal AF (PAF). Methods: In this randomized, waitlist-controlled pilot trial, 18 subjects with PAF participated in an 8-week SMART Program delivered online immediately or 3 months later. Validated measures were completed at baseline and at 3 and 6 months (waitlist group only). Results: Comparing pre- vs post-program scores among all 18 participants, subjects reported improvement in AF-related quality of life (Cohen’s d = 0.75, P = .005) and depression (d = 0.50, P = .05) but not anxiety (d = 0.35, P = .16). Subjects also reported improvements in AF symptom severity (P = .026), distress (P = .014), positive affect (P = .003), and ability to cope with stress (P = .001). Compared to waitlist control subjects, those in the immediate group reported improvement in positive affect (d = 1.20, P = .021) and coping with stress (d = 1.36, P = .011) after participating in the program. Conclusion: The SMART Program, delivered virtually, may enhance positive emotions and coping with stress as well as decrease negative emotions and AF symptoms. These results warrant a larger trial to better understand the potential benefits of such programs for patients with PAF.

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.

Background: Sugammadex, with its novel mechanism of action of encapsulation and noncompetitive binding of aminosteroid neuromuscular-blocking agents (rocuronium and vecuronium), may offer distinct advantage to pediatric patients where residual neuromuscular blockade may be poorly tolerated. Data describing its use in the pediatric population are limited, and no large-scale studies are available evaluating the occurrence of adverse event across the full spectrum of ages. We sought to measure the occurrence of adverse events, assess the severity and clinical significance of the events, and quantify a surrogate measure of efficacy of sugammadex compared to neostigmine in a large population and in the full age range of children., Methods: Beginning in September 2016 through initiation of data collection, we identified from our data warehouse that all patients were treated with sugammadex for reversal of neuromuscular blockade, from birth through adolescence, and retrospectively matched, by case type and age group, to historical neostigmine-treated controls. From subsequent chart review, we quantified occurrence of adverse events and administration of medications to treat adverse events. All cases in the originally identified cohort treated with epinephrine after administration of sugammadex underwent chart review to elicit the cause, in the event that an infrequently occurring event was not captured after the case-matching process. "End-Interval Time," the time from administration of reversal agent to time out of the procedure room, was measured as an indirect assessment of efficacy., Results: Fewer cases of bradycardia were observed in the sugammadex group compared to the neostigmine group in the overall cohort (P < .001) and in the subgroups of older children (P < .001) and adolescents (P < .001). End-interval time, the time measured from administration of neuromuscular blockade (NMB) reversal agent to time out of the operating room, was significantly shorter in sugammadex-treated groups in the overall cohort (mean difference, 2.8; 95% CI, 1.85-3.77; P < .001) and all age groups except for first year (31 days through 12 months). This observation was most pronounced in the neonatal subgroup (mean difference, 11.94 minutes; 95% CI, 4.79-19.1; P < .001). No other adverse events measured were found to be different between treatment groups., Conclusions: This study provides data supporting the safe and effective use of sugammadex for reversal of neuromuscular blockade throughout the entire range of ages in the pediatric population. Within age groups, sugammadex demonstrates faster completion of operation compared with neostigmine, with the greatest difference observed in the neonatal population.

Background: Noise in the operating room may cause distractions during critical periods and impair reliable communication between staff. Even momentary inefficiency while administering anesthesia can lead to errors and serious consequences for the patient. Distractions to an anesthesia provider during critical periods such as induction and emergence are a patient safety issue. Because of concerns regarding unacceptable noise levels and distractions during induction of general anesthesia, our institution developed a quality improvement initiative, the "Distraction-Free Induction Zone." The specific aim of this project was to decrease the percentage of cases with a distraction, described as music, unnecessary conversations, or loud noises, occurring during induction of general anesthesia in pediatric otolaryngology operating rooms from 61% to 15%., Methods: To complete this quality improvement initiative, a multidisciplinary team used improvement science methods, including The Model for Improvement with interventions tested via Plan-Do-Study-Act cycles. We used tools such as the Key Driver Diagram, Pareto Charts, Process Flow Chart, and Plan-Do-Study-Act worksheets. Data were manually collected and entered weekly in an Excel spreadsheet. Statistical process control methods, including a run chart and a P-control chart, were used for data analysis. Our measure was a composite measure in which observation of 1 of the 3 distractions during induction of general anesthesia categorized the case as a case with a distraction., Results: We tested and implemented several interventions via Plan-Do-Study-Act cycles in which 3 main interventions collectively were associated with an observed decrease in distractions during induction of general anesthesia. These included educating the perioperative staff present in the operating room to help them understand that distractions to anesthesia providers represent a patient safety issue, the operating room circulating nurse taking responsibility to pause any music on arrival to the operating room, and the anesthesiologist reminding the staff in the operating room of induction time and/or asking for quiet during induction if a distraction occurs. The percentage of cases with a distraction during induction of general anesthesia in our pediatric otolaryngology operating rooms decreased from 61% to 15% by April 15, 2017 and to 10% by June 5, 2017., Conclusions: Using improvement science methods, we observed a decrease in distractions during induction of general anesthesia, improved a process, and encouraged change in culture at a large academic children's hospital to enhance the quality and safety of the anesthetic care we provide our patients.

Objective: To evaluate the effect of dynamic ultrasound (US) on the need for surgical intervention to achieve successful arterial cannulation in the pediatric cardiac surgery population., Design: Retrospective, observational study., Setting: Single, academic, pediatric hospital in the United States., Participants: The study comprised 3,569 consecutive patients who had an arterial catheter placed in the operating room before undergoing congenital heart surgery between January 2004 and September 2016., Interventions: Dynamic US was used in 2,064 cases (57.83%) to obtain arterial access. Arterial cannulation by palpation was performed in the remaining 37.8% of cases. Surgical cutdown for arterial access was required in 192 cases after failed cannulation attempts by the anesthesia team., Measurements and Main Results: Use of US was associated with an overall decrease in the need for surgical access from 10.43% to 1.70% (p < 0.0001). In patients younger than 30 days, US decreased the rate of surgical access, from 19.62% to 2.65% (p < 0.0001). This significant decrease also was observed in patients 1 to 6 months old (13.93% v 3.73%; p < 0.0001), 7 to 12 months old (7.34% v 0.00%, p < 0.0001), and older than 2 years (1.12% v 0%; p = 0.0083). For children between 13 and 24 months old, there was no statistically significant benefit to using US for avoiding surgical access (3.33% v 0.79%; p = 0.1411). Throughout all age groups, use of US was associated with a significant improvement in optimal arterial line location, defined as placement in an upper extremity (73.75% v 91.13%; p < 0.0001)., Conclusions: Dynamic US resulted in a significant reduction in surgical intervention to achieve arterial cannulation in children presenting for cardiac surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To determine whether precardiopulmonary bypass (CPB) normalization of antithrombin levels in infants to 100% improves heparin sensitivity and anticoagulation during CPB and has beneficial effects into the postoperative period., Design: Randomized, double-blinded, placebo-controlled prospective study., Setting: Multicenter study performed in 2 academic hospitals., Participants: The study comprised 40 infants younger than 7 months with preoperative antithrombin levels <70% undergoing CPB surgery., Interventions: Antithrombin levels were increased with exogenous antithrombin to 100% functional level intraoperatively before surgical incision., Measurements and Main Results: Demographics, clinical variables, and blood samples were collected up to postoperative day 4. Higher first post-heparin activated clotting times (sec) were observed in the antithrombin group despite similar initial heparin dosing. There was an increase in heparin sensitivity in the antithrombin group. There was significantly lower 24-hour chest tube output (mL/kg) in the antithrombin group and lower overall blood product unit exposures in the antithrombin group as a whole. Functional antithrombin levels (%) were significantly higher in the treatment group versus placebo group until postoperative day 2. D-dimer was significantly lower in the antithrombin group than in the placebo group on postoperative day 4., Conclusion: Supplementation of antithrombin in infants with low antithrombin levels improves heparin sensitivity and anticoagulation during CPB without increased rates of bleeding or adverse events. Beneficial effects may be seen into the postoperative period, reflected by significantly less postoperative bleeding and exposure to blood products and reduced generation of D-dimers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias., Methods and Results: We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity., Conclusions: Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background/purpose: Patients with hypoplastic left heart syndrome (HLHS) experience a higher risk for complications from gastroesophageal reflux, prompting frequent need for fundoplication. Patients between stage I and II palliation ("interstage") are at particularly high operative risk because of the parallel nature of their pulmonary and systemic blood flow. Laparoscopic approach for fundoplication is common for pediatric patients. However, its safety in interstage HLHS is relatively unknown. We examined the perioperative physiologic burden of a laparoscopic fundoplication in HLHS patients., Methods: All patients who underwent open or laparoscopic fundoplication during the interstage period at our institution since 2006 were reviewed. Perioperative physiologic data, echocardiographic findings, survival, and complications were collected from the anesthetic record and patient chart., Results: Nineteen patients with HLHS had laparoscopic fundoplication, 13 (68%) during the interstage period, compared to 64 performed by the open approach. Ten (77%) of 13 interstage patients had perioperative hemodynamic instability. Incidence of instability between open and laparoscopic groups was not different. One laparoscopic patient required ECMO support for shunt thrombosis., Conclusions: Despite a high incidence of hemodynamic instability, overall outcomes are consistent with those reported in the literature for this high-risk patient population. Laparoscopic approach for fundoplication during the interstage period appears to be a relatively safe option for these patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Our objectives were to study risk factors and post-operative outcomes associated with excessive post-operative bleeding in pediatric cardiac surgeries performed using cardiopulmonary bypass (CPB) support. A retrospective observational study was undertaken, and all consecutive pediatric heart surgeries over 1 year period were studied. Excessive post-operative bleeding was defined as 10 ml/kg/h of chest tube output for 1 h or 5 ml/kg/h for three consecutive hours in the first 12 h of pediatric cardiac intensive care unit (PCICU) stay. Risk factors including demographics, complexity of cardiac defect, CPB parameters, hematological studies, and post-operative morbidity and mortality were evaluated for excessive bleeding. 253 patients were studied, and 107 (42 %) met the criteria for excessive bleeding. Bayesian model averaging revealed that greater volume of blood products transfusion during CPB was significantly associated with excessive bleeding. Multiple logistic regression analysis of blood products transfusion revealed that increased volume of packed red blood cells (PRBCs) administration for CPB prime and during CPB was significantly associated with excessive bleeding (p = 0.028 and p = 0.0012, respectively). Proportional odds logistic regression revealed that excessive bleeding was associated with greater time to achieve negative fluid balance, prolonged mechanical ventilation, and duration of PCICU stay (p < 0.001) after adjusting for multiple parameters. A greater volume of blood products administration, especially PRBCs transfusion for CPB prime, and during the CPB period is associated with excessive post-operative bleeding. Excessive bleeding is associated with worse post-operative outcomes.

Background: Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model., Methods and Results: We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P=0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P<0.0001)., Conclusions: We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies., (© 2015 American Heart Association, Inc.)

Objective: Children undergoing congenital cardiac surgery (CCS) are at increased risk for acute kidney injury (AKI) due to a number of factors. Recent evidence suggests AKI may influence mortality beyond the immediate postoperative period and hospitalization. We sought to determine the association between renal failure and longer-term mortality in children following CCS., Methods: Our Study population included all patients that underwent cardiac surgery at our institution during a period of 3 years from 2004 through 2006. The primary definition of acute renal injury was based on pRIFLE using estimated creatinine clearance (pRIFLE eCCL)., Results: Predictors of mortality. Age, single ventricle status, and renal failure as defined by pRIFLE stage F were associated with mortality. The hazard ratio for a patient with renal failure as defined by pRIFLE stage F was 3.82 (CI 1.89-7.75). Predictors of AKI as defined by pRIFLE. Duration of cardiopulmonary bypass (CPB) and age were the only variables associated with pRIFLE by univariate analysis. However, in the ordinal or survival model, age was the only variable associated with renal failure as defined by pRIFLE. As patient age increases from 0.30 to 3.5 years, the risks of having renal injury (pRIFLE stage I) or failure (pRIFLE stage F) decreases (OR 0.44, CI 0.21-0.94)., Conclusion: Mortality risk following CCS is increased in younger patients and those experiencing postoperative renal failure as defined by pRIFLE for a period of time that extends well beyond the immediate postoperative period and the time of hospitalization., (© 2014 John Wiley & Sons Ltd.)

Objective: Our primary aim was to study postoperative complications in pediatric cardiac surgery patients and their association with cardiopulmonary bypass (CPB) use. The secondary aim was to evaluate the association of postoperative complications with established outcome measures., Methods: A single-institution retrospective observational study was undertaken of consecutive pediatric cardiac surgery patients during a 1-year period. Five cardiac and 15 extracardiac complications were studied. CPB use, CPB parameters, demographics, and Risk Adjusted Classification for Congenital Heart Surgery (RACHS-1) levels were evaluated as risk factors for complications. Outcomes, including mechanical ventilation duration, pediatric cardiac intensive care unit stay, hospital stay, and mortality were studied., Results: A total of 325 patients were studied: 271 with CPB and 54 without CPB. Of the 325 patients, 141 (43%) had ≥1 complication (95% confidence interval, 38%-49%). Of the 325 patients, 82 (25%) developed cardiac and 120 (37%) developed extracardiac complications. The evidence from logistic regression analysis was insufficient to suggest a relationship between CPB support and the incidence of cardiac or extracardiac complications after adjusting for age, gender, previous sternotomy, and RACHS-1 levels. For patients receiving CPB, longer CPB times, higher RACHS-1 levels, and a lower temperature with CPB were associated with a greater number of cardiac complications (P < .01). Longer CPB times and higher RACHS-1 levels were associated with a greater number of extracardiac complications (P = .006). Postoperative complications were significantly associated with an increased mechanical ventilation duration, pediatric cardiac intensive care unit stay, and hospital stay and mortality (P < .01)., Conclusions: Postoperative complications occurred in 43% of pediatric cardiac surgeries performed both with and without CPB. The complications were associated with longer mechanical ventilation and pediatric cardiac intensive care unit and hospital stays, and increased mortality., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: Hemolysis, occurring during cardiopulmonary bypass, is associated with lipid peroxidation and postoperative acute kidney injury. Acetaminophen inhibits lipid peroxidation catalyzed by hemeproteins and in an animal model attenuated rhabdomyolysis-induced acute kidney injury. This pilot study tests the hypothesis that acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass., Design: Single-center prospective randomized double-blinded study., Setting: University-affiliated pediatric hospital., Patients: Thirty children undergoing elective surgical correction of a congenital heart defect., Interventions: Patients were randomized to acetaminophen (OFIRMEV [acetaminophen] injection; Cadence Pharmaceuticals, San Diego, CA) or placebo every 6 hours for four doses starting before the onset of cardiopulmonary bypass., Measurement and Main Results: Markers of hemolysis, lipid peroxidation (isofurans and F2-isoprostanes), and acute kidney injury were measured throughout the perioperative period. Cardiopulmonary bypass was associated with a significant increase in free hemoglobin (from a prebypass level of 9.8 ± 6.2 mg/dL to a peak of 201.5 ± 42.6 mg/dL postbypass). Plasma and urine isofuran and F2-isoprostane concentrations increased significantly during surgery. The magnitude of increase in plasma isofurans was greater than the magnitude in increase in plasma F2-isoprostanes. Acetaminophen attenuated the increase in plasma isofurans compared with placebo (p = 0.02 for effect of study drug). There was no significant effect of acetaminophen on plasma F2-isoprostanes or urinary makers of lipid peroxidation. Acetaminophen did not affect postoperative creatinine, urinary neutrophil gelatinase-associated lipocalin, or prevalence of acute kidney injury., Conclusion: Cardiopulmonary bypass in children is associated with hemolysis and lipid peroxidation. Acetaminophen attenuated the increase in plasma isofuran concentrations. Future studies are needed to establish whether other therapies that attenuate or prevent the effects of free hemoglobin result in more effective inhibition of lipid peroxidation in patients undergoing cardiopulmonary bypass.

Background: Postoperative atrial fibrillation (PoAF) after cardiac surgery is common and associated with increased morbidity and mortality. Increased sympathetic activation after surgery contributes to PoAF, and β-blockers are the first-line recommendation for its prevention. We examined the hypothesis that common functional genetic variants in the β1-adrenoreceptor, the mediator of cardiac sympathetic activation and drug target of β-blockers, are associated with the risk for PoAF and with the protective effect of β-blockers., Methods: In a prospective cohort study, we studied 947 adult European Americans who underwent cardiac surgery at Vanderbilt University between 1999 and 2005. We genotyped 2 variants in the β1-adrenoreceptor, rs1801253 (Arg389Gly) and rs1801252 (Ser49Gly), and used logistic regression to examine the association between genotypes and PoAF occurring within 14 days after surgery, before and after adjustment for demographic and clinical covariates., Results: Postoperative atrial fibrillation occurred in 239 patients (25.2%) and was associated with rs1801253 genotype (adjusted P = .008), with Gly389Gly having an odds ratio of 2.63 (95% CI 1.42-4.89) for PoAF compared to the common Arg389Arg (P = .002). In a predefined subgroup analysis, this association appeared to be stronger among patients without β-blocker prophylaxis (adjusted odds ratio 7.00, 95% CI 1.82-26.96, P = .005) compared to patients with β-blocker prophylaxis, among whom the association between rs1801253 genotype and PoAF was not statistically significant (adjusted P = .11)., Conclusion: The Gly389 variant in the β1-adrenoreceptor is associated with PoAF, and this association appears to be modulated by β-blocker therapy. Future studies of the association of other adrenergic pathway genes with PoAF will be of interest., (© 2014.)

Objective: The objective of this study was to examine the incidence and clinical outcomes of residual lesions in postoperative pediatric cardiac surgery patients receiving extracorporeal membrane oxygenation (ECMO) support., Methods: A retrospective observational study was undertaken at a pediatric heart institution. Postoperative pediatric cardiac surgery patients receiving ECMO support within 7 days of surgery during the past 7 years (2005-2011) were studied. A hemodynamically significant cardiac lesion on ECMO support that required intervention to decannulate successfully was defined as a residual lesion. Demographic data, complexity of cardiac defect, surgical data, indications for ECMO, echocardiographic findings, and cardiac catheterization results were studied. Evaluation of residual lesions based on duration of ECMO support, interventions undertaken, and clinical outcomes were also examined., Results: Residual lesions were evaluated in 43 of 119 postoperative patients placed on ECMO support. Lesions were detected in 35 patients (28%), predominantly in branch pulmonary arteries (n = 10), shunts (n = 7), and ventricular outflow tracts (n = 9). Echocardiography detected 7 residual lesions (20%) and cardiac catheterization detected 28 residual lesions (80%). Earlier detection of residual lesions during the first 3 days of ECMO support in 24 patients improved their rate of decannulation significantly (P = .004) and survival to hospital discharge (P = .035), compared with later detection (after 3 days of ECMO support) in 11 patients., Conclusions: Residual lesions are present in approximately one-quarter of postoperative cardiac surgery patients requiring ECMO support. All postoperative pediatric cardiac surgery patients unable to be weaned off ECMO successfully should be evaluated actively for residual lesions, preferably by cardiac catheterization imaging. Earlier detection of residual lesions and reintervention are associated with improved clinical outcome., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Children with complex congenital heart disease entail risk when undergoing noncardiac operations and other procedures requiring general anesthesia. To address concerns regarding intraoperative instability, need for postoperative mechanical ventilation, and postoperative hospital length of stay (LOS), we present our 5-year experience with 71 patients with complex congenital heart disease who underwent 252 surgical procedures., Methods: We reviewed the records of all patients from July 2006 to January 2011 who underwent a cardiac procedure with a Risk Adjustment for Congenital Heart Surgery-1 score of 6, and included all who underwent noncardiac procedures during this interval. Perioperative data were gathered to identify patients at risk for induction and maintenance instability, need for postoperative mechanical ventilation, and postoperative hospital LOS. Univariate predictors of these outcome variables were evaluated and entered into stepwise regression algorithms to determine independent variables., Results: We identified 252 procedures that were performed on 71 patients during the study interval. These procedures were performed under 173 general anesthesias. Using each general anesthesia as a case, induction instability was independently associated with stage of palliation before cavopulmonary shunt, case complexity, and preoperative use of angiotensin-converting enzyme inhibitor in a multivariate logistic regression. Maintenance instability was independently associated with case complexity and preoperative use of digoxin and inotropes. Among the 145 cases where the patient was not intubated before the procedure, postoperative need for mechanical ventilation was associated only with preoperative hospital LOS exceeding 14 days. Finally, the resulting linear regression model showed postoperative hospital LOS was independently associated with preoperative hospital LOS exceeding 14 days, presence of moderate ventricular dysfunction, preoperative use of an inotrope, and negatively associated with use of digoxin., Conclusions: Within this population, we have identified independent risk factors for specific clinical outcomes. Patients before stage II palliation, undergoing more invasive procedures, and receiving inotropes, angiotensin-converting enzyme inhibitors, or digoxin appear to be at risk for intraoperative hemodynamic instability. Patients with preoperative hospital LOS exceeding 14 days appear to be at greater risk for requiring postoperative mechanical ventilation. Patients with preoperative LOS exceeding 14 days, with ventricular dysfunction, receiving inotropes, and not receiving digoxin appear to be at risk for protracted hospitalization. Application of these results should assist clinicians in assessing perioperative risk., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Infants with hypoplastic left heart syndrome (HLHS) represent a high-risk population when they present for noncardiac surgery. To assist clinicians in the care of these infants, we present our experience of 36 HLHS patients who underwent abdominal surgery after stage I palliation. We reviewed patients with HLHS who underwent gastrostomy and/or fundoplication after stage I palliation during an 18-month period. We assessed the impact of preoperative echocardiographic predictors and regional anesthesia on use of intraoperative inotropes, extubation in the OR, perioperative instability, postoperative escalation of care, and length of hospital and intensive care unit stay. Of 39 abdominal operations, all but 2 were performed with open laparotomy. There was a positive association between regional anesthesia and instability during induction. Escalation of respiratory care occurred in 9 (23.1%) cases, and escalation of hemodynamic care occurred in 6 (15.4%) cases. Neoaortic valve insufficiency was associated with increased length of stay, and ventricular outflow obstruction was associated with escalation of hemodynamic care. Extubation in the OR was successful in 31 cases (79.5%). In-hospital death occurred in 1 patient (2.7%). HLHS infants often undergo abdominal surgery, but intraoperative instability and need for escalation of care is common. Specific echocardiographic findings were associated with length of stay and escalation of care. Regional anesthesia was associated with transient intraoperative instability but not with other adverse outcomes.

Cardiopulmonary bypass (CPB) produces inflammation and oxidative stress, which contribute to postoperative complications after cardiac surgery. F(2)-Isoprostanes (F(2)-IsoPs) are products of lipid oxidative injury and represent the most accurate markers of oxidative stress. In adults undergoing cardiac surgery, CPB is associated with elevated IsoPs. The relationship between F(2)-IsoPs and perioperative end-organ function in infants with single-ventricle physiology, however, has not been well studied. This study prospectively enrolled 20 infants (ages 3-12 months) with univentricular physiology undergoing elective stage 2 palliation (bidirectional cavopulmonary anastomosis). Blood samples were collected before the surgical incision (T0), 30 min after initiation of CPB (T1), immediately after separation from CPB (T2), and 24 h postoperatively (T3). Plasma F(2)-IsoP levels were measured at each time point and correlated with indices of pulmonary function and other relevant clinical variables. Plasma F(2)-IsoPs increased significantly during surgery, with highest levels seen immediately after separation from CPB (p < 0.001). After separation from CPB, increased F(2)-IsoP was associated with lower arterial pH (ρ = -0.564; p = 0.012), higher partial pressure of carbon dioxide (PaCO(2); ρ = 0.633; p = 0.004), and decreased lung compliance (ρ = -0.783; p ≤ 0.001). After CPB, F(2)-IsoPs did not correlate with duration of CPB, arterial lactate, or immediate postoperative outcomes. In infants with single-ventricle physiology, CPB produces oxidative stress, as quantified by elevated F(2)-IsoP levels. Increased F(2)-IsoP levels correlated with impaired ventilation in the postoperative period. The extent to which F(2)-IsoPs and other bioactive products of lipid oxidative injury might predict or contribute to organ-specific stress warrants further investigation.

Background: Postoperative ventricular dysfunction (VnD) occurs in 9-20% of coronary artery bypass graft (CABG) surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery., Methods: A genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed., Results: Over 100 SNPs were associated with VnD (P<10(-4)), with one SNP (rs17691914) encoded at 3p22.3 reaching genome-wide significance (P(additive model) = 2.14×10(-8)). Meta-analysis of validation and replication study data for 17 SNPs identified three SNPs associated with increased risk for developing postoperative VnD after adjusting for clinical risk factors. These SNPs are located at 3p22.3 (rs17691914, OR(additive model) = 2.01, P = 0.0002), 3p14.2 (rs17061085, OR(additive model) = 1.70, P = 0.0001) and 11q23.2 (rs12279572, OR(recessive model) = 2.19, P = 0.001)., Conclusions: No SNPs were consistently associated with strong risk (OR(additive model)>2.1) of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.

Background: Atrial fibrillation (AF) is the most common adverse event following coronary artery bypass graft surgery. A recent study identified chromosome 4q25 variants associated with AF in ambulatory populations. However, their role in postoperative AF is unknown. We hypothesized that genetic variants in the 4q25 chromosomal region are independently associated with postoperative AF after coronary artery bypass graft surgery., Methods and Results: Two prospectively collected cohorts of patients undergoing coronary artery bypass graft surgery, with or without concurrent valve surgery, at 3 US centers. From a discovery cohort of 959 patients, clinical and genomic multivariate predictors of postoperative AF were identified by genotyping 45 single-nucleotide polymorphisms (SNPs) encompassing the 4q25 locus. Three SNPs were then assessed in a separately collected validation cohort of 494 patients. After adjustment for clinical predictors of postoperative AF and multiple comparisons, rs2200733, rs13143308, and 5 other linked SNPs independently predicted postoperative AF in the discovery cohort. Additive odds ratios for the 7 associated 4q25 SNPs ranged between 1.57 and 2.17 (P=8.0x10(-4) to 3.4x10(-6)). Association with postoperative AF were measured and replicated for rs2200733 and rs13143308 in the validation cohort., Conclusions: In 2 independently collected cardiac surgery cohorts, noncoding SNPs within the chromosome 4q25 region are independently associated with postoperative AF after coronary artery bypass graft surgery after adjusting for clinical covariates and multiple comparisons.

Background: The angiotensin-converting enzyme (ACE) gene contains a common polymorphism based on the insertion (I) or deletion (D) of a 287-bp intronic DNA fragment. The D allele is associated with higher ACE activity and thus higher angiotensin II levels. Angiotensin II stimulates cardiac fibrosis and conduction heterogeneity., Objective: The purpose of this study was to determine whether the ACE I/D polymorphism modulates cardiac electrophysiology., Methods: Three different cohorts of patients were studied: 69 patients with paroxysmal lone atrial fibrillation (AF), 151 patients with structural heart disease and no history of AF, and 161 healthy subjects without cardiovascular disease or AF. Patients taking drugs that affect cardiac conduction were excluded from the study. ECG parameters during sinus rhythm were compared among the ACE I/D genotypes., Results: The ACE I/D polymorphism was associated with the PR interval and heart block in the lone AF cohort. In multivariable linear regression models, the D allele was associated with longer PR interval in the lone AF and heart disease cohorts (12.0-ms and 7.1-ms increase per D allele, respectively). P-wave duration showed a similar trend, with increase in PR interval across ACE I/D genotypes in the lone AF and heart disease cohorts., Conclusion: The ACE D allele is associated with electrical remodeling in patients with lone AF and in those with heart disease, but not in control subjects. ACE activity may play a role in cardiac remodeling after the development of AF and heart disease.

Background: We and others have reported mutations in the cardiac predominant sodium channel gene SCN5A in patients with atrial fibrillation (AF). We also have reported that SCN1B is associated with Brugada syndrome and isolated cardiac conduction disease. We tested the hypothesis that mutations in the 4 sodium channel beta-subunit genes SCN1B-SCN4B contribute to AF susceptibility., Methods and Results: Screening for mutations in the 4 beta-subunit genes was performed in 480 patients with AF (118 patients with lone AF and 362 patients with AF and cardiovascular disease) and 548 control subjects (188 ethnically defined anonymized subjects and 360 subjects without AF). The effects of mutant beta-subunits on SCN5A mediated currents were studied using electrophysiological studies. We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF. These occur at residues highly conserved across mammals and were absent in control subjects. In 3 of 4 mutation carriers, the ECGs showed saddleback-type ST-segment elevation in the right precordial leads. Transcripts encoding both SCN1B and SCN2B were detected in human atrium and ventricle. In heterologous expression studies using Chinese hamster ovary cells, the mutant beta1- or beta2-subunits reduced SCN5A-mediated current and altered channel gating compared with coexpression of wild-type subunits., Conclusions: Loss of function mutations in sodium channel beta-subunits were identified in patients with AF and were associated with a distinctive ECG phenotype. These findings further support the hypothesis that decreased sodium current enhances AF susceptibility.

Aims: A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts., Methods and Results: The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464., Conclusion: The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.

Genetic variants in the coagulation system have been known since antiquity. Today, because of modern improvements in diagnosis and medical management, the clinician is likely to encounter a spectrum of coagulation factor deficiencies and identified polymorphic variants in the surgical population. Because perioperative hemorrhagic and thrombotic complications are potentially serious, it is important to understand the role that these defects and variants may play in predicting risk and optimizing patient management. The implications of coagulation genetics on the perioperative management of the cardiac surgery patient are reviewed.

Background: The tissue factor (TF) factor (F) VIIa complex activates coagulation FIX and FX to initiate coagulation, and also cleaves protease activated receptors (PARs) to initiate inflammatory processes in vascular cells. Tissue factor pathway inhibitor (TFPI) is the only specific inhibitor of the TF-FVIIa complex, regulating both its procoagulant and pro-inflammatory properties. Upon heparin infusion during cardiopulmonary bypass (CPB), a heparin releasable pool of endothelial associated TFPI circulates in plasma. Following protamine neutralization of heparin, the plasma TFPI level decreases, but does not return completely to baseline, suggesting that during CPB a fraction of the plasma TFPI becomes heparin-independent. We have investigated the structural and functional properties of plasma TFPI during CPB to further characterize how TFPI is altered during this procedure., Methods: We enrolled 17 patients undergoing first-time cardiac surgery involving CPB. Plasma samples were obtained at baseline, 5 min and 1 h after start of CPB (receiving heparin), 10 min after protamine administration (off CPB) and 24 h following surgery. Samples were analyzed for full-length and free (non-lipoprotein bound) TFPI antigen by enzyme-linked immunosorbent assay (ELISA) and for TFPI anticoagulant activity using an amidolytic assay. Western blot analysis was used to identify TFPI species of varying molecular weights in three additional patients. Dunnett's test for post hoc comparisons was used for statistical analysis., Results: The ELISA and Western blot data indicated that an increase in full-length TFPI accounted for most of the heparin releasable TFPI. Following heparin neutralization with protamine, the full-length TFPI antigen returned to baseline levels while the free TFPI antigen and the total plasma TFPI activity remained elevated. This was associated with the appearance of a new 38 kDa form of plasma TFPI identified by Western blot analysis. The 38 kDa form of TFPI did not react with an antibody directed against the C-terminal region of TFPI indicating it has undergone proteolysis within this region. All TFPI measurements returned to baseline 24 h following CPB., Conclusions: During CPB the full-length form of TFPI is the predominant form in plasma because of its prompt release from the endothelial surface following heparin administration. Upon heparin neutralization with protamine, full-length TFPI redistributes back to the endothelial surface. However, a new 38 kDa TFPI fragment is generated during CPB and remains circulating in plasma, indicating that TFPI undergoes proteolytic degradation during CPB. This degradation may result in a decrease in endothelium-associated TFPI immediately post-CPB, and may contribute to the procoagulant and proinflammatory state that often complicates CPB.

Greater trait anger-out is associated with elevated pain responsiveness. Previous work suggests this effect may be mediated by deficient endogenous opioid analgesia, possibly reflecting diminished opioid receptor sensitivity. The A118G single nucleotide polymorphism (SNP) of the mu opioid receptor gene influences both opioid receptor sensitivity and clinical responsiveness to opioid analgesics. Therefore, this study tested whether this SNP either mediated or moderated the effects of anger-out on postsurgical pain outcomes. Forty-eight patients undergoing coronary artery bypass graft surgery provided genetic samples, and completed measures of anger-out and postsurgical pain. Postsurgical opioid analgesic use was also recorded. Anger-out was positively associated with postsurgical pain ratings (p < 0.05). Anger-out was not associated with A118G SNP status (p > 0.10), suggesting the latter is unlikely to mediate anger-out's pain-related effects. A significant anger-out x A118G interaction was observed on analgesic use (p < 0.05), due to a much stronger positive relationship between anger-out and analgesic demands in patient with the A118G SNP (b = 0.53) than those with the wild-type receptor (b = 0.07). These results suggest that the A118G SNP may moderate but not mediate the effects of anger-out on postoperative pain responses.

Objectives: Children with congenital heart disease experience both hemorrhagic and thrombotic complications. In this report the authors test the hypothesis that hypoxemia is associated with altered sensitivity to activated protein C (aPC) in pediatric patients with congenital heart lesions., Design: A retrospective genetic registry review, with statistical evaluation of factors contributing to the aPC ratio., Setting: Large university hospital., Participants: Cohort of 92 children with congenital heart disease undergoing cardiac catheterization procedures., Interventions: The authors measured the aPC ratio at cardiac catheterization and evaluated the contribution of independent variables using linear regression and classification tree approaches. Independent variables included age, gender, use of aspirin, history of thrombosis, room air arterial saturation, factor VIII:C levels, presence of congestive heart failure, and heterozygosity for factor V Leiden., Measurements and Main Results: At univariate analysis, factor V Leiden, female gender, room air arterial saturation, age greater than 6 months, and plasma factor VIII:C levels were associated with a lower aPC ratio (resistance to aPC). At stepwise linear regression, arterial saturation, factor VIII:C level, female gender, and factor V Leiden were independently associated with a lower aPC ratio, and these variables explained about 49% of the variability in aPC ratio. The classification tree approach confirmed the dependence of aPC ratio on factor V genotype and arterial saturation., Conclusions: The aPC ratio in this population is associated with hypoxemia, independent of factors previously observed in adults. Further studies are under way to determine how aPC resistance or sensitivity may independently affect perioperative hemostasis in this population.

Postoperative Atrial Fibrillation (PoAF) is the most common arrhythmia after heart surgery, and continues to be a major cause of morbidity. Due to the complexity of this condition, many genes and/or environmental factors may play a role in susceptibility. Previous findings have shown several clinical and genetic risk factors for the development of PoAF. The goal of this study was to determine whether interactions among candidate genes and a variety of clinical factors are associated with PoAF. We applied the Multifactor Dimensionality Reduction (MDR) method to detect interactions in a sample of 940 adult subjects undergoing elective procedures of the heart or great vessels, requiring general anesthesia and sternotomy or thoracotomy, where 255 developed PoAF. We took a random sample of controls matched to the 255 AF cases for a total sample size of 510 individuals. MDR is a powerful statistical approach used to detect gene-gene or gene-environment interactions in the presence or absence of statistically detectable main effects in pharmacogenomics studies. We chose polymorphisms in three (IL-6, ACE, and ApoE) candidate genes, all previously implicated in PoAF risk, and a variety of environmental factors for analysis. We detected a single locus effect of IL-6 which is able to correctly predict disease status with 58.8% (p<0.001) accuracy. We also detected an interaction between history of AF and length of hospital stay that predicted disease status with 68.34% (p<0.001) accuracy. These findings demonstrate the utility of novel computational approaches for the detection of disease susceptibility genes. While each of these results looks interesting, they only explain part of PoAF susceptibility. It will be important to collect a larger set of candidate genes and environmental factors to better characterize the development of PoAF. Applying this approach, we were able to elucidate potential associations with postoperative atrial fibrillation.

Voltage-gated potassium (K(V)) channels are modulated by at least three distinct classes of proteins including the KCNE family of single transmembrane accessory subunits. In the human genome, KCNE proteins are encoded by five genes designated KCNE1 through KCNE5. KCNE1 associates with KCNQ1 in vitro to generate a potassium current closely resembling the slowly activating delayed rectifier (I(Ks)). Other KCNE proteins also affect the activity of heterologously expressed KCNQ1. To investigate the potential physiological relevance of this gene family in human heart, we examined the relative expression of KCNQ1 and all five KCNE genes in samples derived from normal tissues representing major regions of human heart by real-time, quantitative RT-PCR. KCNE genes are expressed in human heart with a relative abundance ranking of KCNE1 > KCNE4 > KCNE5 approximately KCNE3 >> KCNE2. In situ hybridization revealed prominent expression of KCNE1 and KCNE3-5 in human atrial myocytes. In cardiomyopathic hearts, expression of KCNE1, KCNE3, KCNE4, and KCNQ1 was significantly increased, while KCNE2 and KCNE5 exhibited reduced expression. In a cell line stably expressing KCNQ1 and KCNE1, transient expression of KCNE3, KCNE4, or KCNE5 significantly altered I(Ks) current profiles. Even in the presence of additional KCNE1, KCNE4 and KCNE5 exert dominant effects on I(Ks). Although KCNE1 is the predominant KCNE family member expressed in human heart, the abundance of other KCNE transcripts including potential KCNQ1 suppressors (KCNE4 and KCNE5) and their altered expression patterns in disease lead us to speculate that a balance of KCNE accessory subunits may be important for cardiac K(V) channel function.

Activated protein C (aPC) resistance is a recognized hypercoagulable phenotype that is associated with increased risk for thrombosis in multiple clinical settings. Factor V Leiden (FVL) represents a specific inherited cause of aPC resistance, but the perioperative thrombotic risk of FVL is unclear. In this investigation, we sought to quantify whether cardiopulmonary bypass produces alterations in aPC resistance in FVL carriers and noncarrier controls, testing the hypothesis that FVL is associated with a relatively hypercoagulable postoperative state. Two-hundred-five adult cardiac surgery patients were prospectively enrolled into a genetic registry whose purpose was to study the impact of genetic variables on clinical outcomes. For this study, 8 subjects heterozygous for FVL were identified (group L), as well as 2 control groups: group MC, matched controls, 18 matched subjects without FVL; and group UC, unmatched controls, 11 consecutive subjects without FVL. Plasma was sampled at the beginning of surgery, 10 min after protamine administration, and on postoperative day 1, and assayed for resistance to aPC (normal aPC ratio is >2.0). Both MC and UC groups exhibited normal aPC ratio at baseline (2.40 and 2.36, respectively), which increased significantly (to 2.76 and 2.75, P = 0.007 and 0.021, respectively) on postoperative day 1, indicating increased postoperative sensitivity to aPC. Conversely, group L subjects exhibited aPC resistance at baseline (aPC ratio 1.80), and did not change significantly postoperatively (P = 0.867). Patients without FVL therefore show laboratory evidence consistent with relative protection from postoperative thrombosis, whereas FVL carriers do not. These findings provide mechanistic support for previous speculations of increased postoperative thrombotic risk associated with FVL.

Factor V Leiden (FVL) is the most common known inherited cause of thrombophilia; it is present in approximately 5% of the Caucasian population. Although the risk of venous thrombosis associated with this polymorphism in various medical settings is well described, its effect on perioperative risk is only beginning to be explored. Specifically, there are few studies addressing the potential risks of FVL in the surgical population, in which both hemorrhagic and thrombotic complications convey substantial clinical and economic significance. There are speculations and unproven hypotheses regarding FVL in this population, and these therefore highlight the need to comprehensively address this issue. This review will describe the physiology of the FVL mutation, briefly clarify its risk in the nonsurgical setting, and assess current data regarding FVL in noncardiac and cardiac surgery. Finally, a summary of current clinical evidence and a plan for more detailed investigation of this potentially significant risk factor will be proposed.

In this study of bioabsorbable screw fixation of free tendon grafts used in anterior cruciate ligament reconstruction, we performed load-to-failure and cyclic loading of tendon fixation in porcine bone. Bone density measurements from dual photon absorptometry scans were obtained to correlate bone density with fixation failure. The average density of porcine bone (1.42 g/cm2) was similar to that of young human bone (1.30 g/cm2) and significantly higher than that of elderly human cadaveric bone specimens (0.30 g/cm2). Cyclic loading was performed on free tendon grafts fixed with a bioabsorbable screw alone and on grafts fixed with a bioabsorbable screw and an anchor (polylactic acid ball or cortical bone disk). Stiffness of fixation increased substantially with the addition of a cortical bone disk anchor or polylactic acid ball compared with the interference screw alone. Tensile fixation strength of central quadriceps free tendon and hamstring tendon grafts were significantly superior in porcine bone of density similar to young human bone than in elderly human cadaveric bone. The bioabsorbable interference screw yielded loads at failure comparable with traditional bone-tendon-bone and hamstring tendon fixation when controlled for bone density. The addition of a cortical bone disk anchor provided the most optimal fixation of free tendon with the bioabsorbable screw and reduced slippage with cyclic loading to a very low level.