Retrospective Analysis of the Safety and Efficacy of Sugammadex Versus Neostigmine for the Reversal of Neuromuscular Blockade in Children.

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.

Distraction-Free Induction Zone: A Quality Improvement Initiative at a Large Academic Children's Hospital to Improve the Quality and Safety of Anesthetic Care for Our Patients.

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.

Evaluation of Dynamic Ultrasound for Arterial Access in Children Undergoing Cardiac Surgery.

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.

Double-Blind, Randomized, Placebo-Controlled Trial Comparing the Effects of Antithrombin Versus Placebo on the Coagulation System in Infants with Low Antithrombin Undergoing Congenital Cardiac Surgery.

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.

Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes.

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.

Laparoscopic Nissen fundoplication in infants with hypoplastic left heart syndrome.

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.

Genetic and clinical risk prediction model for postoperative atrial fibrillation.

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.

Association of blood products administration during cardiopulmonary bypass and excessive post-operative bleeding in pediatric cardiac surgery.

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.

Long-term mortality associated with acute kidney injury in children following congenital cardiac surgery.

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.

Acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass.

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.

Residual lesions in postoperative pediatric cardiac surgery patients receiving extracorporeal membrane oxygenation support.

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.

Genetic variation in the ß1-adrenergic receptor is associated with the risk of atrial fibrillation after cardiac surgery.

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 ß-blockers are the first-line recommendation for its prevention. We examined the hypothesis that common functional genetic variants in the ß1-adrenoreceptor, the mediator of cardiac sympathetic activation and drug target of ß-blockers, are associated with the risk for PoAF and with the protective effect of ß-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 ß1-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 ß-blocker prophylaxis (adjusted odds ratio 7.00, 95% CI 1.82-26.96, P = .005) compared to patients with ß-blocker prophylaxis, among whom the association between rs1801253 genotype and PoAF was not statistically significant (adjusted P = .11). CONCLUSION: The Gly389 variant in the ß1-adrenoreceptor is associated with PoAF, and this association appears to be modulated by ß-blocker therapy. Future studies of the association of other adrenergic pathway genes with PoAF will be of interest.