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OBJECTIVE: Cardiac surgery utilizing circulatory arrest is most commonly performed under deep hypothermia (~18°C) to suppress tissue oxygen demand and provide neuroprotection during operative circulatory arrest. Studies investigating the effects of deep hypothermic circulatory arrest (DHCA) on neurodevelopmental outcomes of patients with congenital heart disease give conflicting results. Here, we address these issues by quantifying changes in cerebral oxygen saturation, blood flow, and oxygen metabolism in neonates during DHCA and investigating the association of these changes with post-operative brain injury. METHODS: Neonates with critical congenital heart disease undergoing DHCA were recruited for continuous intraoperative monitoring of cerebral oxygen saturation (ScO(2)) and an index of cerebral blood flow (CBF(i)) using two non-invasive optical techniques, diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS). Pre- and post-operative brain magnetic resonance imaging (MRI) was performed to detect white matter injury (WMI). RESULTS: Fifteen neonates were studied, and 11/15 underwent brain MRI. During DHCA, ScO(2) decreased exponentially in time with a median decay rate of −0.04 min(−1). This decay rate was highly variable between subjects. Subjects who had larger decreases in ScO(2) during DHCA were more likely to have post-operative WMI (p=0.02). CONCLUSIONS: Cerebral oxygen extraction persists during DHCA and varies widely from patient-to-patient. Patients with a higher degree of oxygen extraction during DHCA were more likely to show new WMI in post-operative MRI. These findings suggest cerebral oxygen extraction should be monitored during DHCA to identify patients at risk for hypoxic-ischemic injury, and that current commercial cerebral oximeters may underestimate cerebral oxygen extraction.

We investigated the incidence and predictors of failure to undergo the Fontan in children with hypoplastic left heart syndrome who survived superior cavopulmonary connection.The cohort consists of all patients with hypoplastic left heart syndrome who survived to hospital discharge after superior cavopulmonary connection between 1988 and 2017. The primary outcome was attrition, which was defined as death, nonsuitability for the Fontan, or cardiac transplantation before the Fontan. Subjects were excluded if they were awaiting the Fontan, were lost to follow-up, or underwent biventricular repair. The study period was divided into 4 eras based on changes in operative or medical management. Attrition was estimated with 95% confidence intervals, and predictors were identified using adjusted, logistic regression models.Of the 856 hospital survivors after superior cavopulmonary connection, 52 died, 7 were deemed unsuitable for Fontan, and 12 underwent or were awaiting heart transplant. Overall attrition was 8.3% (71/856). Attrition rate did not change significantly across eras. A best-fitting multiple logistic regression model was used, adjusting for superior cavopulmonary connection year and other influential covariates: right ventricle to pulmonary artery shunt at Norwood (P .01), total support time at superior cavopulmonary connection (P .01), atrioventricular valve reconstruction at superior cavopulmonary connection (P = .02), performance of other procedures at superior cavopulmonary connection (P = .01), and length of stay after superior cavopulmonary connection (P .01).In this study spanning more than 3 decades, 8.3% of children with hypoplastic left heart syndrome failed to undergo the Fontan after superior cavopulmonary connection. This attrition rate has not decreased over 30 years. Use of a right ventricle to pulmonary artery shunt at the Norwood procedure was associated with increased attrition.

OBJECTIVES The objective of this study was to estimate hospital mortality and length of stay (LOS) for children with hypoplastic left heart syndrome undergoing superior cavopulmonary connection (SCPC). METHODS All hypoplastic left heart syndrome interstage survivors who underwent SCPC between 1 January 1988 and 31 December 2017 were included. The study period was divided into 4 eras based on changes in operative or medical management. Mortality rates were estimated using standard binomial proportions. Adjusted and unadjusted logistic regression models were used to identify risk factors for mortality and LOS. RESULTS The most common procedures for the cohort (n = 958) were Hemi-Fontan (57.3%) or Bidrectional Glenn shunt (35.7%). The mortality was 4.1% overall and decreased in all 3 later eras compared to era 1. Factors associated with mortality in a multiple covariate model included longer total support time, earlier gestational age, longer LOS at the Norwood Procedure and need for additional procedures. Overall, the median LOS was 7.0 days with a decrease from eras 1 to 2 and plateaued in eras 3 and 4. Predictors of longer LOS included genetic anomaly, longer Norwood LOS, additional procedures, lower weight at surgery and longer total support time. The type of SCPC was not associated with mortality or LOS. CONCLUSIONS In this large cohort of patients with hypoplastic left heart syndrome undergoing SCPC, hospital mortality has decreased significantly. LOS initially declined but plateaued in recent eras. The risk factors for mortality and longer LOS are related to patient and procedural complexity, especially the need for additional procedures at the time of SCPC.

Dexmedetomidine (DEX) is a sedative used in combination with other drugs in neonates and infants undergoing cardiac surgery using cardiopulmonary bypass (CPB). This study aimed to evaluate the disposition of DEX after administration to the ex vivo CPB circuits following different bolus doses and continuous infusion of DEX, including the effect of circuit coating, temperature, and modified ultrafiltration (MUF). Cardiopulmonary bypass circuits were setup ex vivo and primed with reconstituted blood. Dexmedetomidine was administered to the circuit (as a single bolus or single bolus along with continuous infusion). The circuit was allowed to equilibrate during the first 5 minutes, blood samples were collected at multiple time points (5-240 minutes). Blood samples were processed to collect plasma and analyzed for DEX with a validated assay. The majority of DEX sequestration in ex vivo CPB circuits occurred within the first 15 minutes. The percent of DEX remained in plasma pre-MUF (16-71%) and post-MUF (22-92%) varied depending on the dose and dosing scheme. Modified ultrafiltration significantly increased the plasma concentration of DEX in 19 of 23 circuits by an average of 12.1 ± 4.25% (p < 0.05). The percent sequestration of DEX was lower in CPB circuits at lower DEX doses compared to higher doses. A combination of DEX initial loading dose and continuous infusion resulted in steady concentrations of DEX over 4 hours. At therapeutically relevant concentrations of DEX (485-1,013 pg/ml), lower sequestration was observed in ex vivo CPB circuits compared to higher doses. The sequestration of DEX to circuits should be considered to achieve the optimal concentration of DEX during CPB surgery.

Objective To determine the impact of damaging genetic variation in proangiogenic pathways on placental function, complications of pregnancy, fetal growth, and clinical outcomes in pregnancies with fetal congenital heart defect. Study design Families delivering a baby with a congenital heart defect requiring surgical repair in infancy were recruited. The placenta and neonate were weighed and measured. Hemodynamic variables were recorded from a third trimester (36.4 ± 1.7 weeks) fetal echocardiogram. Exome sequencing was performed on the probands (N = 133) and consented parents (114 parent-child trios, and 15 parent-child duos) and the GeneVetter analysis tool used to identify damaging coding sequence variants in 163 genes associated with the positive regulation of angiogenesis (PRA) (GO:0045766). Results In total, 117 damaging variants were identified in PRA genes in 133 congenital heart defect probands with 73 subjects having at least 1 variant. Presence of a damaging PRA variant was associated with increased umbilical artery pulsatility index (mean 1.11 with variant vs 1.00 without; P = .01). The presence of a damaging PRA variant was also associated with lower neonatal length and head circumference for age z score at birth (mean −0.44 and −0.47 with variant vs 0.23 and −0.05 without; P = .01 and .04, respectively). During median 3.1 years (IQR 2.0-4.1 years) of follow-up, deaths occurred in 2 of 60 (3.3%) subjects with no PRA variant and in 9 of 73 (12.3%) subjects with 1 or more PRA variants (P = .06). Conclusions Damaging variants in proangiogenic genes may impact placental function and are associated with impaired fetal growth in pregnancies involving a fetus with congenital heart defect.

The Pediatric Heart Network Collaborative Learning Study (PHN CLS) successfully changed practice at four hospitals to increase the rate of early extubation within 6 hours after infant heart surgery. It is unknown whether this practice continued after study completion.We linked the PHN CLS dataset to the Pediatric Cardiac Critical Care Consortium registry to compare outcomes at four active hospitals between the study period (post-clinical practice guideline [CPG]) and the first year after study completion (follow-up) after a 3-month washout. Inclusion and exclusion criteria were the same across eras. Primary outcome was early extubation rate after tetralogy of Fallot or aortic coarctation repair. Secondary outcomes included time to first extubation and intensive care and hospital lengths of stay.There were 121 patients in the post-CPG era and 139 patients in the follow-up era with no difference in patient characteristics or operation subtypes. Post-CPG early extubation rate declined from 67% to 30% in follow-up (p0.0001); time to first extubation increased (4.5 versus 13.5 hours, p0.0001). One hospital maintained the rate of early extubation (72% versus 67%), whereas the other three hospitals had significantly lower rates in follow-up (p0.02 for each). Intensive care (2.8 versus 2.9 days) and postoperative hospital (6 versus 5 days) stays did not differ between eras (p0.05 for both). Findings were consistent across operation subtypes.Extubation practice in the first year of follow-up after the PHN CLS reverted toward prestudy levels. One of four hospitals maintained its early extubation strategy, suggesting that specific implementation and maintenance approaches may effectively sustain impact from quality initiatives.

Background The Pediatric Heart Network Collaborative Learning Study (PHN CLS) increased early extubation after infant tetralogy of Fallot (TOF) and coarctation repair overall at participating sites through implementing a clinical practice guideline (CPG). We evaluated variability across sites in CPG implementation and outcomes. Methods Patient characteristics and outcomes (time to extubation, length of stay [LOS]) were compared across sites, including pre-CPB to post-CPG changes. Semistructured interviews were analyzed to assess similarities and differences in implementation strategies across sites. Results A total of 322 patients were included (4 active sites, 1 model site). Patient characteristics were similar across active sites, whereas pre-CPG median time to extubation varied from 15.4 to 35.5 hours. All active sites had a significant post-CPG decline (p Conclusions All PHN CLS sites successfully reduced time to extubation. The magnitude of change varied and may be partly explained by different CPG implementation strategies. These data can guide CPG dissemination and design of future improvement projects.

OBJECTIVES Controversy exists in ascertaining the ideal location for adults with congenital heart disease requiring surgical intervention. In this study, we sought to compare the perioperative management between our paediatric and adult hospitals and to determine how clinical factors and the location affect the length of stay after pulmonary valve replacement. METHODS A retrospective analysis of patients, ≥18 years of age, undergoing pulmonary valve replacement was conducted at our paediatric and adult hospitals between 1 January 2000 and 30 October 2014. Patients with previous Ross or concomitant left heart procedures were excluded. Descriptive statistics were used to assess demographics and clinical characteristics. Inverse probability weight-adjusted models were used to determine differences in the number of surgical complications, duration of mechanical ventilation and postoperative length of stay between paediatric and adult hospitals. Additional models were calculated to identify factors associated with prolonged length of stay. RESULTS There were altogether 98 patients in the adult (48 patients) and paediatric (50 patients) hospitals. Patients in the adult hospital were older with more comorbidities (arrhythmia, hypertension, depression and a history of cardiac arrest, all P CONCLUSIONS Pulmonary valve replacement may be performed safely with no deaths and with a comparable complication rate at both hospitals. Patients undergoing surgery at the adult hospital have longer intubation times and length of stay. Opportunities exist to streamline management strategies.

Objectives The Pediatric Heart Network Collaborative Learning Study used collaborative learning strategies to implement a clinical practice guideline that increased rates of early extubation after infant repair of tetralogy of Fallot and coarctation of the aorta. We assessed early extubation rates for infants undergoing cardiac surgeries not targeted by the clinical practice guideline to determine whether changes in extubation practices spilled over to care of other infants. Design Observational analyses of site's local Society of Thoracic Surgeons Congenital Heart Surgery Database and Pediatric Cardiac Critical Care Consortium Registry. Setting Four Pediatric Heart Network Collaborative Learning Study active-site hospitals. Patients Infants undergoing ventricular septal defect repair, atrioventricular septal defect repair, or superior cavopulmonary anastomosis (lower complexity), and arterial switch operation or isolated aortopulmonary shunt (higher complexity). Interventions None. Measurements and main results Aggregate outcomes were compared between the 12 month pre-clinical practice guideline and 12 months after study completion (Follow Up). In infants undergoing lower complexity surgeries, early extubation increased during Follow Up compared with Pre-Clinical Practice Guideline (30.2% vs 18.8%, p = 0.006), and hours to initial postoperative extubation decreased. We observed variation in these outcomes by surgery type, with only ventricular septal defect repair associated with a significant increase in early extubation during Follow Up compared with Pre-Clinical Practice Guideline (47% vs 26%, p = 0.006). Variation by study site was also seen, with only one hospital showing an increase in early extubation. In patients undergoing higher complexity surgeries, there was no difference in early extubation or hours to initial extubation between the study eras. Conclusions We observed spillover of extubation practices promoted by the Collaborative Learning Study clinical practice guideline to lower complexity operations not included in the original study that was sustainable 1 year after study completion, though this effect differed across sites and operation subtypes. No changes in postoperative extubation outcomes following higher complexity surgeries were seen. The significant variation in outcomes by site suggests that center-specific factors may have influenced spillover of clinical practice guideline practices.

Background The superior cavo‐pulmonary connection was introduced at our institution in 1988 for infants undergoing surgery for hypoplastic left heart syndrome. Patients with hypoplastic left heart syndrome remain at high risk for mortality in the time period between the Norwood procedure and the superior cavo‐pulmonary connection. The primary objectives of this study were to compare interstage mortality across 4 eras and analyze factors that may impact interstage mortality. Methods and Results Patients with hypoplastic left heart syndrome who underwent the Norwood procedure, were discharged from the hospital, and were eligible for superior cavo‐pulmonary connection between January 1, 1988, and December 31, 2017, were included. The study period was divided into 4 eras based on changes in operative or medical management. Mortality rates were estimated with 95% CIs. Adjusted and unadjusted logistic regression models were used to identify risk factors for mortality. There were 1111 patients who met the inclusion criteria. Overall, interstage mortality was 120/1111 (10.8%). Interstage mortality was significantly lower in era 4 relative to era 1 (4.6% versus 13.4%; P =0.02) during the time that age at the superior cavo‐pulmonary connection was the lowest (135 days; P P =0.02) and was more routinely practiced in era 4. Conclusions During this 30‐year experience, the risk of interstage mortality decreased significantly in the most recent era. Factors that coincide with this finding include younger age at superior cavo‐pulmonary connection, introduction of an interstage monitoring program, and increased use of the right ventricle to pulmonary artery shunt.

Objectives In-hospital complications after the Norwood operation for single ventricle heart defects account for the majority of morbidity and mortality. Inpatient care variation occurs within and across centers. This multidisciplinary quality improvement project standardized perioperative management in a large referral center. Design Quality improvement project. Setting High volume cardiac center, tertiary care children's hospital. Patients Neonates undergoing Norwood operation. Interventions The quality improvement team developed and implemented a clinical guideline (preoperative admission to 48 hr after surgery). The composite process metric, Guideline Adherence Score, contained 13 recommendations in the guideline that reflected consistent care for all patients. Measurements and main results One-hundred two consecutive neonates who underwent Norwood operation (January 1, 2013, to July 12, 2016) before guideline implementation were compared with 50 consecutive neonates after guideline implementation (July 13, 2016, to May 4, 2018). No preguideline operations met the goal Guideline Adherence Score. In the first 6 months after guideline implementation, 10 of 12 operations achieved goal Guideline Adherence Score and continued through implementation, reaching 100% for the last 10 operations. Statistical process control analysis demonstrated less variability and decreased hours of postoperative mechanical ventilation and cardiac ICU length of stay during implementation. There were no statistically significant differences in major hospital complications or in 30-day mortality. A higher percentage of patients were extubated by postoperative day 2 after guideline implementation (67% [30/47] vs 41% [41/99], respectively; p = 0.01). Of these patients, reintubation within 72 hours of extubation significantly decreased after guideline implementation (0% [0/30] vs 17% [7/41] patients, respectively; p = 0.02). Conclusions This initiative successfully implemented a standardized perioperative care guideline for neonates undergoing the Norwood operation at a large center. Positive statistical process control centerline shifts in Guideline Adherence Score, length of postoperative mechanical ventilation, and cardiac ICU length of stay were demonstrated. A higher percentage were successfully extubated by postoperative day 2. Establishment of standard processes can lead to best practices to decrease major adverse events.

The coronavirus disease 2019 (COVID-19) pandemic has impacted congenital cardiac surgical programs with significant reduction in case load, implementation of patient triage strategies, and development of personal protective equipment (PPE) guidelines. This document summarizes current status and implications of COVID-19 in congenital cardiac surgery outlining recommendations from the Congenital Cardiac Anesthesia Society (CCAS). [...]

BackgroundVeno-arterial extracorporeal membrane oxygenation is frequently used in patients with cardiac disease. We evaluated short-term outcomes and identified factors associated with hospital mortality in cardiac patients supported with veno-arterial extracorporeal membrane oxygenation.MethodsA retrospective review of patients supported with veno-arterial extracorporeal membrane oxygenation at a university-affiliated children’s hospital was performed.ResultsA total of 253 patients with cardiac disease managed with extracorporeal membrane oxygenation were identified; survival to discharge was 48%, which significantly improved from 39% in an earlier era (1995–2001) (p=0.01). Patients were categorised into surgical versus non-surgical groups on the basis of whether they had undergone cardiac surgery before or not, respectively. The most common indication for extracorporeal membrane oxygenation was extracorporeal cardiopulmonary resuscitation: 96 (51%) in the surgical group and 45 (68%) in the non-surgical group. In a multiple covariate analysis, single-ventricle physiology (p=0.01), duration of extracorporeal membrane oxygenation (pConclusionWe report improvement in survival compared with an earlier era in cardiac patients supported with extracorporeal membrane oxygenation. Single-ventricle physiology continues to negatively impact survival, along with evidence of organ dysfunction during extracorporeal membrane oxygenation, duration of extracorporeal membrane oxygenation, and length of stay.

Background Hypoxic-ischemic white matter brain injury commonly occurs in neonates with critical congenital heart disease. Recent work has shown that longer time to surgery is associated with increased risk for this injury. In this study we investigated changes in perinatal cerebral hemodynamics during the transition from fetal to neonatal circulation to ascertain mechanisms that might underlie this risk. Methods Neonates with either transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS) were recruited for preoperative noninvasive optical monitoring of cerebral oxygen saturation, cerebral oxygen extraction fraction, and cerebral blood flow using diffuse optical spectroscopy and diffuse correlation spectroscopy, 2 noninvasive optical techniques. Measurements were acquired daily from day of consent until the morning of surgery. Temporal trends in these measured parameters during the preoperative period were assessed with a mixed effects model. Results Forty-eight neonates with TGA or HLHS were studied. Cerebral oxygen saturation was significantly and negatively correlated with time, and oxygen extraction fraction was significantly and positively correlated with time. Cerebral blood flow did not significantly change with time during the preoperative period. Conclusions In neonates with TGA or HLHS, increasing cerebral oxygen extraction combined with an abnormal cerebral blood flow response during the time between birth and heart surgery leads to a progressive decrease in cerebral tissue oxygenation The results support and help explain the physiological basis for recent studies that show longer time to surgery increases the risk of acquiring white matter injury.

The recent adoption of an improved lymphatic access technique coupled with Dynamic Contrast-enhanced Magnetic Resonance Lymphangiography has introduced the ability to diagnose and treat severe lymphatic disorders unresponsive to other therapies. All pediatric patients presenting for lymphatic procedures require general anesthesia presenting challenges in managing highly morbid and comorbid conditions both from logistical as well as medical aspects. General anesthesia is used because of the procedural requirement for immobility to accurately place needles and catheters, treat pain secondary to contrast and glue injections, and to accommodate additional procedures. We reviewed a one-year cohort of all pediatric patients in a newly created Center for Lymphatic Imaging and Intervention at a tertiary care children's hospital presenting for lymphatic procedures. The patients ranged in age from 4 days to 17 years and weighed from 2.5 to 92 kg. There were 106 anesthetics for 68 patients. Patients were functionally impaired (98% ASA 3 or 4) and included significant comorbidities (79.4%). Concurrent with lymphatic imaging and intervention additional procedures were frequently performed (76%). They included cardiac catheterization, bronchoscopy, endoscopy, and drain placement (thoracic or abdominal). Paralysis and controlled ventilation was used for all interventions. Reversal of paralysis and tracheal extubation occurred in all patients not previously managed by invasive respiratory support. All patients having an intervention were admitted to intensive care for observation where escalation of care or complications (fever, hypotension, bleeding, or stroke) occurred in 25% in the first 24 hours.

IntroductionThe right ventricular adaptations early after surgery in infants with tetralogy of Fallot are important to understand the changes that occur later on in life; this physiology has not been fully delineated. We sought to assess early postoperative right ventricular remodelling in patients with tetralogy of Fallot by cardiac MRI.Materials and methodSubjects with tetralogy of Fallot under 1 year of age were recruited following complete surgical repair for tetralogy of Fallot. Protocol-based cardiac MRI to assess anatomy, function, and flows was performed before hospital discharge using the feed and sleep technique, an unsedated imaging technique.ResultsMRI was completed in 16 subjects at a median age of 77 days (interquartile range 114). There was normal ventricular ejection fraction and indexed right ventricular end-diastolic volume (48±13 cc/m2), but elevated right ventricular mass (z score 6.2±2.4). Subjects requiring a transannular patch or right ventricle to pulmonary artery conduit had moderate pulmonary insufficiency (regurgitant fraction 27±16%).DiscussionEarly right ventricular remodelling after surgical repair for tetralogy of Fallot is characterised by significant pulmonary regurgitation, right ventricular hypertrophy, and lack of dilation. Performing cardiac MRI using the feed and sleep technique is feasible in infants younger than 5 months. These results might open new avenues to study longitudinal right ventricular changes in tetralogy of Fallot and to further explore the utility of unsedated MRI in patients with other types of CHDs.

OBJECTIVESControversy remains regarding the use of deep hypothermic circulatory arrest (DHCA) in neonatal cardiac surgery. Alterations in cerebral mitochondrial bioenergetics are thought to contribute to ischaemia–reperfusion injury in DHCA. The purpose of this study was to compare cerebral mitochondrial bioenergetics for DHCA with deep hypothermic continuous perfusion using a neonatal swine model.METHODSTwenty-four piglets (mean weight 3.8 kg) were placed on cardiopulmonary bypass (CPB): 10 underwent 40-min DHCA, following cooling to 18°C, 10 underwent 40 min DHCA and 10 remained at deep hypothermia for 40 min; animals were subsequently rewarmed to normothermia. 4 remained on normothermic CPB throughout. Fresh brain tissue was harvested while on CPB and assessed for mitochondrial respiration and reactive oxygen species generation. Cerebral microdialysis samples were collected throughout the analysis.RESULTSDHCA animals had significantly decreased mitochondrial complex I respiration, maximal oxidative phosphorylation, respiratory control ratio and significantly increased mitochondrial reactive oxygen species (P CONCLUSIONSDHCA is associated with disruption of mitochondrial bioenergetics compared with deep hypothermic continuous perfusion. Preserving mitochondrial health may mitigate brain injury in cardiac surgical patients. Further studies are needed to better understand the mechanisms of neurological injury in neonatal cardiac surgery and correlate mitochondrial dysfunction with neurological outcomes.

BackgroundWe have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival.MethodsThis study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike’s information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model.ResultsGenetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011).ConclusionsThese data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype–phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.

Background Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing. Methods We included 122 neonates and infants (0–180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200–300 pg ml−1), medium (400–500 pg ml−1), and high (600–700 pg ml−1) DEX plasma concentrations. Results Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8–9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min−1 70 kg−1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th–95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml−1. Conclusions When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection. Clinical trials registration NCT01915277.

OBJECTIVE: The Pediatric Heart Network sponsored the multicenter Collaborative Learning Study that implemented a clinical practice guideline to facilitate early extubation in infants after repair of isolated coarctation of the aorta and Tetralogy of Fallot. We sought to compare the anesthetic practice in the operating room and sedation-analgesia management in the ICU before and after the implementation of the guideline that resulted in early extubation. DESIGN: Secondary analysis of data from a multicenter study from January 2013 to April 2015. Predefined variables of anesthetic, sedative and analgesia exposure were compared before and after guideline implementation. Propensity score weighted logistic regression analysis was used to determine the independent effect of intraoperative dexmedetomidine administration on early extubation. SETTING: Five children’s hospitals. PATIENTS: 240 study subjects who underwent repair of coarctation of the aorta or Tetralogy of Fallot (119 pre and 121 post-guideline implementation). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical practice guideline implementation was accompanied by a decrease in the median total intraoperative dose of opioids (49.7 vs 24.0 mcg/kg of Fentanyl Equivalents, p

Background Little is known of baseline anatomic, hemodynamic, and fluid dynamic cardiac magnetic resonance data in single-ventricle patients immediately after Fontan. A comparison from that time point to the teen years can demonstrate clinical course, potentially predict future events, and may shed some light regarding how to optimize outcome. This cross-sectional study is meant to characterize these variables from just after Fontan to the teenage years. Methods The anatomy, flows, and computational fluid dynamic modeling of 22 patients 3 to 9 months after Fontan (age 3 ± 1.1 years) and 25 teens (age 16 ± 1.8 years) were compared. Significance was defined as P less than .05. Results The percentage of Fontan pathway stenosis was greater with cardiac index and fenestration flow while caval return was lower in teens than in younger patients (for Fontan pathway stenosis, 43% vs 21%, P = .009); however, hepatic flow distribution was more evenly distributed in older patients. Pulmonary artery size kept up with somatic growth. In the teen group, indexed power loss (R = .39), percentage of Fontan pathway stenosis (R = .62), and particle resident time (R = .42) deteriorated as time from Fontan increased (P Conclusions There are mostly aspects of deterioration with a few bright spots of stability in anatomy, blood flow, and fluid dynamic variables in Fontan patients from the postoperative period to the teenage years. Most notably, Fontan pathway stenosis increases with decreasing flows while pulmonary artery size and hepatic flow distribution remain stable or improved. These data may be aid in designing improved Fontan reconstruction to optimize clinical outcome and to understand future complications.

To determine whether a collaborative learning strategy-derived clinical practice guideline can reduce the duration of endotracheal intubation following infant heart surgery.Prospective and retrospective data collected from the Pediatric Heart Network in the 12 months pre- and post-clinical practice guideline implementation at the four sites participating in the collaborative (active sites) compared with data from five Pediatric Heart Network centers not participating in collaborative learning (control sites).Ten children's hospitals.Data were collected for infants following two-index operations: 1) repair of isolated coarctation of the aorta (birth to 365 d) and 2) repair of tetralogy of Fallot (29-365 d). There were 240 subjects eligible for the clinical practice guideline at active sites and 259 subjects at control sites.Development and application of early extubation clinical practice guideline.After clinical practice guideline implementation, the rate of early extubation at active sites increased significantly from 11.7% to 66.9% (p0.001) with no increase in reintubation rate. The median duration of postoperative intubation among active sites decreased from 21.2 to 4.5 hours (p0.001). No statistically significant change in early extubation rates was found in the control sites 11.7% to 13.7% (p = 0.63). At active sites, clinical practice guideline implementation had no statistically significant impact on median ICU length of stay (71.9 hr pre- vs 69.2 hr postimplementation; p = 0.29) for the entire cohort. There was a trend toward shorter ICU length of stay in the tetralogy of Fallot subgroup (71.6 hr pre- vs 54.2 hr postimplementation, p = 0.068).A collaborative learning strategy designed clinical practice guideline significantly increased the rate of early extubation with no change in the rate of reintubation. The early extubation clinical practice guideline did not significantly change postoperative ICU length of stay.

There is increasing interest in reducing the duration of mechanical ventilation after pediatric cardiac operations. However, the contemporary use of an early extubation strategy and its effect on clinical outcomes is poorly understood.Data from The Society of Thoracic Surgeons Congenital Heart Surgery Database (2010 to 2013) were analyzed to determine the association of early extubation with postoperative length of stay (PLOS). Two operations were analyzed: complete repair of tetralogy of Fallot (TOF) in patients older than 45 days and the Fontan procedure. Centers were stratified into tertiles by frequency of early extubation, defined as less than 6 hours after leaving the operating room. Patients extubated after 48 hours were excluded.Among 92 centers, early extubation was performed in 31.5% (478 of 1,519) of children undergoing TOF repair and in 69.8% (1,153 of 1,653) of those undergoing the Fontan procedure. Early extubation after TOF repair was associated with heavier weight at operation (p0.001) and fewer preoperative risk factors (p = 0.016). After adjustment for covariates, average PLOS after TOF repair was shorter for centers in the highest tertile of early extubation rate than for the lowest tertile centers, which have low early extubation rate (p = 0.04). No association was found between center early extubation rate and PLOS for Fontan procedures (p = 0.08).Early extubation is common after repair of TOF and the Fontan procedure. A high institutional rate of early extubation after TOF repair is associated with shorter PLOS. Further analysis is needed to understand what effect early extubation might have on other meaningful measures such as resource use.

Dexmedetomidine is a highly selective α2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day-1 month) and 36 evaluable infants (age, 1 month-24 months) after open heart surgery.Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 μg/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 μg/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 μg/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 μg/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics.Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated a plasma drug clearance of 657 × (weight/70) mL/min, intercompartmental clearance of 6780 × (weight/70) mL/min, central volume of distribution of 88 × (weight/70) L and peripheral volume of distribution of 112 × (weight/70) L for a typical subject with age1 month with a cardiopulmonary bypass time of 60 minutes and without right-to-left intracardiac shunt. Dexmedetomidine pharmacokinetics may be influenced by age during the neonatal period, weight, total bypass time, and presence of intracardiac shunt.Dexmedetomidine clearance is significantly diminished in full-term newborns and increases rapidly in the first few weeks of life. The dependence of clearance on age during the first few weeks of life reflects the relative immaturity of metabolic processes during the newborn period. Continuous infusions of up to 0.3 μg/kg/h in neonates and 0.75 μg/kg/h in infants were well tolerated after open heart surgery.

BACKGROUND: The Pediatric Heart Network Collaborative Learning Study (PHN CLS) increased early extubation rates after infant tetralogy of Fallot (TOF) and coarctation of the aorta (CoA) repair across participating sites by implementing a clinical practice guideline (CPG). The impact of the CPG on hospital costs has not been studied. METHODS: PHN CLS clinical data were linked to cost data from Children’s Hospital Association by matching on indirect identifiers. Hospital costs were evaluated across active and control sites in the pre- and post-CPG periods using generalized linear mixed-effects models. A difference-in-difference approach was used to assess whether changes in cost observed in active sites were beyond secular trends in control sites. RESULTS: Data were successfully linked on 410 of 428 eligible patients (96%) from four active and four control sites. Mean adjusted cost per case for TOF repair was significantly reduced in the post-CPG period at active sites ($42,833 vs $56,304, p < 0.01) and unchanged at control sites ($47,007 vs $46,476, p = 0.91), with an overall cost reduction of 27% in active versus control sites (p = 0.03). Specific categories of cost reduced in the TOF cohort included clinical (−66%, p < 0.01), pharmacy (−46%, p = 0.04), lab (−44%, p < 0.01), and imaging (−32%, p < 0.01). There was no change in costs for CoA repair at active or control sites. CONCLUSIONS: The early extubation CPG was associated with a reduction in hospital costs for infants undergoing repair of TOF but not CoA. This CPG represents an opportunity to both optimize clinical outcome and reduce costs for certain infant cardiac surgeries.

Objective Hypoplastic left heart syndrome is one of the most common and challenging lesions requiring surgical intervention in the neonatal period. The Norwood procedure for hypoplastic left heart syndrome was first reported in 1983. The objective of this study was to describe early outcomes after the Norwood procedure at a single institution over 30 years. Methods This retrospective cohort study included all patients with hypoplastic left heart syndrome (and variants) who underwent the Norwood procedure between January 1984 and May 2014 at a single institution. The study period was divided into 6 eras: era 1, 1984 to 1988; era 2, 1989 to 1993; era 3, 1994 to 1998; era 4, 1999 to 2003; era 5, 2004 to 2008; and era 6, 2009 to 2014. The primary outcome was in-hospital mortality after the Norwood procedure. Binomial point estimates complete with 95% confidence intervals (CL0.95) were computed for the entire cohort and by era. Results During the study period, 1663 infants underwent the Norwood procedure. Overall in-hospital mortality was 25.9% (CL0.95, 23.8-28.0). Mortality by chronologic era was 40.4% (CL0.95, 34.9-45.9), 33.6% (CL0.95, 29.2-37.9), 28.7% (CL0.95, 22.8-34.6), 14.9% (CL0.95, 10.4-19.3), 11.2% (CL0.95, 7.4-15.0), and 15.7% (CL0.95, 10.3-21.1). Survival was improved in eras 4 to 6 compared with eras 1 to 3 (P all Conclusions Survival after the Norwood procedure has plateaued despite improvements in diagnosis, perioperative care, and surgical techniques. Nonmodifiable patient characteristics are important determinants of the risk of mortality.

OBJECTIVES: Pregnancies with congenital heart disease in the foetus have an increased prevalence of pre-eclampsia, small for gestational age and preterm birth, which are evidence of an impaired maternal–foetal environment (MFE). METHODS: The impact of an impaired MFE, defined as pre-eclampsia, small for gestational age or preterm birth, on outcomes after cardiac surgery was evaluated in neonates (n = 135) enrolled in a study evaluating exposure to environmental toxicants and neuro-developmental outcomes. RESULTS: The most common diagnoses were transposition of the great arteries (n = 47) and hypoplastic left heart syndrome (n = 43). Impaired MFE was present in 28 of 135 (21%) subjects, with small for gestational age present in 17 (61%) patients. The presence of an impaired MFE was similar for all diagnoses, except transposition of the great arteries (P

Background Remote ischemic preconditioning (RIPC) is a mechanism to protect tissues from injury during ischemia and reperfusion. We investigated the neuroprotective effects of RIPC in neonates undergoing cardiac surgery. Methods The outcome was white matter injury (WMI), assessed by the change in volume of WMI from preoperative to postoperative brain magnetic resonance imaging (MRI). Patients were randomized to RIPC or SHAM. RIPC was induced prior to cardiopulmonary bypass by four 5-minute cycles of blood pressure cuff inflation to produce ischemia of the lower extremity. For patients randomized to SHAM, the cuff was positioned, but not inflated. Results The study included 67 patients, with 33 randomized to RIPC and 34 randomized to SHAM. Preoperative and postoperative MRIs were available in 50 patients, including 26 of the 33 RIPC patients and 24 of the 34 SHAM patients. There were no differences in baseline and operative characteristics for either the overall study group or the group with evaluable MRIs. WMI was identified in 28% of the patients preoperatively and in 62% postoperatively. There was no difference in the prevalence of WMI by treatment group ( p > 0.5). RIPC patients had an average change in WMI of 600 mL 3 , and SHAM subjects had an average WMI change of 107 mL 3 . There was no significant difference in the mean value of WMI change between patients who received RIPC and those who received SHAM treatments ( p = 0.178). Conclusions In this randomized, blinded clinical trial, there was no evidence that use of RIPC provides neuroprotection in neonates undergoing repair of congenital heart defects with cardiopulmonary bypass.

Summary Background Surgical site infection (SSI) prevention for children with congenital heart disease is imperative and methods to assess and evaluate the tissue concentrations of prophylactic antibiotics are important to help maximize these efforts. Aim The purposes of this study were to determine the plasma and tissue concentrations with standard of care, perioperative cefazolin dosing in an immature porcine model of pediatric cardiac surgery, and to determine the feasibility of this model. Methods Piglets (3–5 days old) underwent either median sternotomy (MS) or cardiopulmonary bypass with deep hypothermic circulatory arrest (CPB + DHCA) and received standard of care prophylactic cefazolin for the procedures. Serial plasma and microdialysis sampling of the skeletal muscle and subcutaneous tissue adjacent to the surgical site was performed. Cefazolin concentrations were measured, noncompartmental pharmacokinetic analyses were performed, and tissue penetration of cefazolin was assessed. Results Following the first intravenous dose, maximal cefazolin concentrations in the subcutaneous tissue and skeletal muscle were similar between groups with peak tissue concentrations 15–30 min after administration. After the second cefazolin dose given with the initiation of CPB, total plasma cefazolin concentrations remained relatively constant until the end of DHCA and then decreased while muscle- and subcutaneous-unbound cefazolin concentrations showed a second peak during or after rewarming. For the MS group, 60–67% of the intraoperative time showed subcutaneous and skeletal muscle concentrations of cefazolin >16 μg·ml−1 while this percentage was 78–79% for the CPB + DHCA group. There was less tissue penetration of cefazolin in the group that underwent CBP + DHCA (P = 0.03). Conclusions The cefazolin dosing used in this study achieves plasma and tissue concentrations that should be effective against methicillin-sensitive Staphylococcus aureus but may not be effective against some gram-negative pathogens. The timing of the cefazolin administration prior to incision and a second dose given during cardiopulmonary bypass may be important factors for achieving goal tissue concentrations.

Objectives The American Clinical Neurophysiology Society recommends continuous electroencephalographic monitoring after neonatal cardiac surgery because seizures are common, often subclinical, and associated with worse neurocognitive outcomes. We performed a quality improvement project to monitor for postoperative seizures in neonates with congenital heart disease after surgery with cardiopulmonary bypass. Methods We implemented routine continuous electroencephalographic monitoring and reviewed the results for an 18-month period. Clinical data were collected by chart review, and continuous electroencephalographic tracings were interpreted using standardized American Clinical Neurophysiology Society terminology. Electrographic seizures were classified as electroencephalogram-only or electroclinical seizures. Multiple logistic regression was used to assess associations between seizures and potential clinical and electroencephalogram predictors. Results A total of 161 of 172 eligible neonates (94%) underwent continuous electroencephalographic monitoring. Electrographic seizures occurred in 13 neonates (8%) beginning at a median of 20 hours after return to the intensive care unit after surgery. Neonates with all types of congenital heart disease had seizures. Seizures were electroencephalogram only in 11 neonates (85%). Status epilepticus occurred in 8 neonates (62%). In separate multivariate models, delayed sternal closure or longer deep hypothermic circulatory arrest duration was associated with an increased risk for seizures. Mortality was higher among neonates with than without seizures (38% vs 3%, P Conclusions Continuous electroencephalographic monitoring identified seizures in 8% of neonates after cardiac surgery with cardiopulmonary bypass. The majority of seizures had no clinical correlate and would not have been otherwise identified. Seizure occurrence is a marker of greater illness severity and increased mortality. Further study is needed to determine whether seizure identification and management lead to improved outcomes.

The inclusion of dexmedetomidine in the operative and postoperative management of infants with congenital heart defects has lessened the need for opioids that may cause respiratory depression. Our objective was to show that a dexmedetomidine bolus at or about the time of sternal closure is associated with a decrease in the use of mechanical ventilation in the immediate postoperative period.Retrospective cohort study.Single pediatric tertiary cardiac center.Infants undergoing surgical intervention for congenital heart defects requiring cardiopulmonary bypass, age 30-365 days in a 5-year time period from June 1, 2008, to December 31, 2012.None.Of 1,057 total encounters, 441 met inclusion criteria and were evenly distributed over the 5-year time period. Dexmedetomidine had been given at or about the time of sternal closure in 57% of patients. When the exposed and unexposed groups were compared in terms of mechanical ventilation immediately postoperative, there was a statistically significant effect of using dexmedetomidine on the odds of receiving mechanical ventilation (p = 0.0019). This difference remained significant after adjusting for covariates affecting the decision for mechanical ventilation, including year of the procedure, age and weight of subject, cardiopulmonary bypass time, the use of deep hypothermic circulatory arrest, intraoperative fentanyl dose, and the Risk Adjustment for Congenital Heart Surgery Score 1 (p = 0.0317). The odds of receiving mechanical ventilation are estimated to be two times higher for patients who did not receive dexmedetomidine than for patients who received dexmedetomidine after adjusting for variables.The use of dexmedetomidine bolus in the operating room at the time of sternal closure in infants undergoing open heart surgery is associated with reduced need for mechanical ventilation in the immediate postoperative period.

Pulse-wave velocity (PWV), a measure of arterial stiffness, is a known independent risk factor for cardiovascular events. Patients with single ventricle who undergo aortic to pulmonary anastomosis (recon) have noncompliant patch material inserted into the neoaorta, possibly increasing vessel stiffness and afterload. The purpose of this study is to determine if PWV in patients with single ventricle differed between those who did and those who did not undergo aortic reconstruction (nonrecon). We retrospectively reviewed cardiac magnetic resonance anatomic, cine, and phase contrast evaluations in the ascending aorta and descending aorta (DAo) at the level of the diaphragm data from 126 patients with single ventricle (8.6 ± 8.0 years) from January 2012 to May 2013. Significance = p0.05. Seventy-five patients underwent recon and 51 did not. PWV in recon was significantly higher than in nonrecon (3.9 ± 0.9 m/s vs 3.2 ± 1.0 m/s, p = 0.008); in recon, patients13 years old had a higher PWV than those7 years (4.5 ± 0.6 vs 3.5 ± 0.7 m/s, p = 0.004). Whether7 or13 years old, PWV of those with recon was higher than nonrecon DAo distensibility was similar between both groups. There was no difference in age, body surface area, or cardiac index between recon and nonrecon. No correlations between various hemodynamic and ventricular function parameters with PWV were noted. In conclusion, PWV in recon is higher than in nonrecon with similar DAo distensibility implicating the aortic reconstruction as a possible cause of increased afterload; older recon patients have stiffer aortas than younger ones, possibly imposing an additional cardiovascular risk in the future. Other biomaterials may potentially moderate PWV if clinical outcome is adversely affected.

Objective To describe the pharmacokinetics and tissue disposition of prophylactic cefazolin into skeletal muscle in a pediatric population undergoing cardiac surgery. Methods The subjects included 12 children, with a median age of 146 days (interquartile range, 136-174) and median weight of 5.5 kg (interquartile range, 5.2-7.3) undergoing cardiac surgery and requiring cardiopulmonary bypass with or without deep hypothermic circulatory arrest. Institutional cefazolin at standard doses of 25 mg/kg before incision and 25 mg/kg in the bypass prime solution were administered. Serial plasma and skeletal muscle microdialysis samples were obtained intraoperatively and the unbound cefazolin concentrations measured. Noncompartmental pharmacokinetic analyses were performed and the tissue disposition evaluated. Results After the first dose of cefazolin, the skeletal muscle concentrations peaked at a median microdialysis collection interval of 30 to 38.5 minutes. After the second dose, the peak concentrations were delayed a median of 94 minutes in subjects undergoing deep hypothermic circulatory arrest. Skeletal muscle exposure to cefazolin measured by the area under concentration time curve 0-last measurement was less in the subjects who underwent deep hypothermic circulatory arrest than in those who received cardiopulmonary bypass alone (P = .04). The skeletal muscle concentrations of cefazolin exceeded the goal concentrations for methicillin-sensitive Staphylococcus aureus prophylaxis; however, the goal concentrations for gram-negative pathogens associated with surgical site infections were achieved only 42.1% to 84.2% and 0% to 11.2% of the intraoperative time in subjects undergoing cardiopulmonary bypass alone or deep hypothermic circulatory arrest, respectively. Conclusions This cefazolin dosing strategy resulted in skeletal muscle concentrations that are likely not effective for surgical prophylaxis against gram-negative pathogens but are effective against methicillin-sensitive S aureus in infants undergoing cardiac surgery.

Anaphylactic reaction to gelatin-containing hemostatic agents has been reported in the orthopedic literature, most commonly during scoliosis repair in adolescents. However, the risk, differential diagnosis, and management of anaphylaxis in patients with complex congenital heart disease undergoing noncardiac procedures have not been previously reported. We describe the case of an adolescent with a history of repaired truncus arteriosus undergoing posterior spinal fusion who developed sudden and profound hypotension that was ultimately confirmed to be an anaphylactic reaction to Surgiflo. Echocardiography was used to aid in diagnosis and management of the cardiovascular effects of anaphylaxis in this patient with residual cardiac pathophysiology.

Pediatric cardiac anesthesiology has evolved as a subspecialty of both pediatric and cardiac anesthesiology and is devoted to caring for individuals with congenital heart disease ranging in age from neonates to adults. Training in pediatric cardiac anesthesia is a second-year fellowship with variability in both training duration and content and is not accredited by the Accreditation Council on Graduate Medical Education. Consequently, in this article and based on the Accreditation Council on Graduate Medical Education Milestones Model, an expert panel of the Congenital Cardiac Anesthesia Society, a section of the Society of Pediatric Anesthesiology, defines 18 milestones as competency-based developmental outcomes for training in the pediatric cardiac anesthesia fellowship.

Background Preoperative brain injury is common in neonates with complex congenital heart disease. Increasing evidence suggests a complex interaction of prenatal and postnatal risk factors for development of brain white matter injury, called periventricular leukomalacia (PVL), in neonates with complex congenital heart disease. To date, there remains a limited understanding of the risk factors contributing to preoperative PVL in hypoplastic left heart syndrome (HLHS). Methods Neonates with HLHS or HLHS variants from 3 prospective magnetic resonance imaging studies (2003-2010) were selected for this cohort. Preoperative brain magnetic resonance imaging was performed the morning of the surgery. Stepwise multilogistic regression of patient characteristics, mode of delivery (cesarean section vs vaginal), time of diagnosis (prenatal vs postnatal), HLHS subtypes, brain total maturation score, time to surgery, individual averaged daily preoperative blood gases, and complete blood cell count values was used to determine significant associations. Results A total of 57 neonates with HLHS were born at 38.7 ± 2.3 weeks; 86% (49/57) had a prenatal diagnosis, with 31% (18/57) delivered by cesarean section. HLHS with aortic atresia (AA) was common in this cohort, 71% (41/57). Preoperative PVL was identified in 19% (11/57). Male patients with AA ( P = .004) were at higher risk for PVL. Lower total brain maturation score was also identified as a strong predictor for preoperative PVL ( P = .005). Conclusions In neonates with HLHS, nonmodifiable patient-related factors, including male sex with AA (lack of antegrade blood flow) and lower total brain maturation score, placed neonates at the greatest risk for preoperative white matter injury.

Background— There are limited follow-up studies examining surgical and catheter-based reinterventions in long-term survivors of the Fontan operation. Methods and Results— All 773 patients who underwent Fontan at our institution between 1992 and 2009 were retrospectively reviewed. Current information regarding post-Fontan intervention was available for 70%. By 20 years after Fontan, 65% of patients had experienced either surgical or transcatheter intervention. The median time to first reintervention was 9.8 years. Freedom from reoperation was 69% at 15 years and 63% at 20 years. The most common operations were pacemaker placement and Fontan revision. Risk factors for pacemaker placement included systemic left ventricle (hazard ratio [HR], 2.2; P =0.006) and lateral tunnel Fontan (HR, 4.3; P =0.001). Freedom from interventional catheterization was 53% at 15 years and 50% at 20 years. The most common procedures performed were fenestration closure and pulmonary artery intervention. Catheter intervention for anatomic indications was associated with Fontan after 2002 (HR, 2.1; P =0.007), Norwood operation (HR, 2.3; P =0.001), and longer cardiopulmonary bypass time (HR, 1.1 per 10 minutes; P =0.001). Catheter intervention for physiological indications was associated with prolonged post-Fontan pleural drainage (HR, 4.0; P P =0.01). Conclusions— In this study of Fontan survivors, two thirds of patients required surgical or catheter-based reintervention by 20 years. Families should be counseled that the Fontan is typically not the final stage of single-ventricle palliation.

Although survival after the Fontan operation has improved, little is known about the burden of major medical morbidities associated with the modern total cavopulmonary connection (TCPC). A total of 773 consecutive patients who underwent a first Fontan operation at our institution between 1992 and 2009 were retrospectively reviewed. All subjects underwent TCPC (53% lateral tunnel, 47% extracardiac conduit). Median length of follow-up was 5.3 years (interquartile range 1.4 to 11.2), and 30% had follow-up >10 years. Freedom from a composite medical morbidity outcome (protein-losing enteropathy, plastic bronchitis, serious thromboembolic event, or tachyarrhythmia) was 47% at 20 years (95% confidence interval [CI] 38 to 55). Independent risk factors for morbidity included pre-Fontan atrioventricular valve regurgitation (hazard ratio [HR] 1.7, 95% CI 1.2 to 2.4, p = 0.001), pleural drainage >14 days (HR 1.5, 95% CI 1.01 to 2.2, p = 0.04), and longer cross-clamp time (HR 1.2 per 10 minutes, 95% CI 1.06 to 1.3, p = 0.004) at the time of TCPC. Surgical era, Fontan type, and ventricular morphology were not associated with the composite outcome. Presence of Fontan-associated morbidity was associated with a 36-fold increase in the risk of subsequent Fontan takedown, heart transplantation, or death (95% CI 17 to 76, p

Objective The occurrence of an electroencephalographic (EEG) seizure after surgery for complex congenital heart defects has been associated with worse neurodevelopmental (ND) outcomes. We previously identified postoperative seizures documented by 48-hour EEG monitoring in 11% of 178 neonates and infants. Evaluation at 1 year of age did not identify an adverse effect of an EEG seizure on ND outcomes. The current study was undertaken to determine if testing in the preschool period would identify deficits that become apparent as children develop. Methods The ND outcomes assessed at 4 years of age included cognition, language, attention, impulsivity, executive function, behavior problems, academic achievement, and visual and fine motor skills. Results Developmental evaluations were performed in 132 (87%) of 151 survivors. For the entire cohort, the Full-Scale IQ was 95.0 ± 18.5. IQ was 95.1 ± 18.7 for patients without a history of seizure and 93.6 ± 16.7 for those with a history of seizure. After covariate adjustment, occurrence of an EEG seizure was associated with worse executive function ( P = .037) and impaired social interactions/restricted behavior ( P = .05). Seizures were not significantly associated with worse performance for cognition, language, attention, impulsivity, academic achievement, or motor skills (all P > .1). Conclusions The occurrence of a postoperative seizure is a biomarker of brain injury. This study confirms that postoperative EEG seizures are associated with worse ND outcomes, characterized by impairments of executive function and a higher prevalence of deficits in social interactions and repetitive/restricted behaviors in preschool survivors of cardiac surgery in infancy. However, EEG seizures were not associated with worse cognitive, language, or motor skills.

Objective To evaluate the dose-response relationship of dexmedetomidine in infants with congenital heart disease postoperative from open heart surgery. Design Prospective open-label dose-escalation pharmacokinetic-pharmacodynamic study. Setting Tertiary pediatric cardiac ICU. Patients Thirty-six evaluable infants, 1-24 months old, postoperative from open heart surgery requiring mechanical ventilation. Interventions Cohorts of 12 infants were enrolled sequentially to one of the three IV loading doses of dexmedetomidine (0.35, 0.7, and 1 mcg/kg) over 10 minutes followed by respective continuous infusions (0.25, 0.5, and 0.75 mcg/kg/hr) for up to 24 hours. Measurements and main results Dexmedetomidine plasma concentrations were obtained at timed intervals during and following discontinuation of infusion. Pharmacodynamic variables evaluated included sedation scores, supplemental sedation and analgesia medication administration, time to tracheal extubation, respiratory function, and hemodynamic parameters. Infants achieved a deeper sedation measured by the University of Michigan Sedation Scale score (2.6 vs 1) despite requiring minimal supplemental sedation (0 unit doses/hr) and fewer analgesic medications (0.07 vs 0.15 unit doses/hr) while receiving dexmedetomidine compared with the 12-hour follow-up period. Thirty-one patients were successfully extubated while receiving the dexmedetomidine infusion. Only one patient remained intubated due to oversedation during the infusion. While receiving dexmedetomidine, there was a decrease in heart rate compared with baseline, 132 versus 161 bpm, but there was an increase in heart rate compared with postinfusion values, 132 versus 128 bpm. There was no statistically or clinically significant change in mean arterial blood pressure. Conclusions Dexmedetomidine administration in infants following open heart surgery can provide improved sedation with reduction in supplemental medication requirements, leading to successful extubation while receiving a continuous infusion. The postoperative hemodynamic changes that occur in infants postoperative from open heart surgery are multifactorial. Although dexmedetomidine may play a role in decreasing heart rate immediately postoperative, the changes were not clinically significant and did not fall below postinfusion heart rates.

Existing studies of patients palliated with the Fontan operation are limited by heterogeneous patient populations and incomplete follow-up. This study aimed to describe long-term post-Fontan survival in a modern patient cohort.All 773 patients who underwent a first Fontan operation at our institution between 1992 and 2009 were reviewed. The primary outcome was the composite endpoint of Fontan takedown, heart transplantation, or death before 2013.Follow-up rate was 99.2%. Survival with intact Fontan circulation was 94% at 1 year (95% confidence interval [95% CI], 92%-95%), 90% at 10 years (95% CI, 88%-92%), 85% at 15 years (95% CI, 82%-88%), and 74% at 20 years (95% CI, 67%-80%). Distinct risk factors were identified for early (≤1 year) and late composite outcomes. Independent risk factors for early outcome included prolonged pleural drainage (hazard ratio [HR], 4.4; P .001), intensive care unit stay 1 week (HR, 2.4; P .001), Fontan before 1997 (HR, 3.3; P .001), preoperative atrioventricular valve regurgitation (HR, 2.0; P .001), and longer crossclamp time (HR, 1.3 per 10 minutes; P .001). Late outcome was predicted by atrioventricular valve regurgitation prior to Fontan (HR, 2.0; P ≤ .001), and post-Fontan ICU stay 1 week (HR, 2.4; P .001).Long-term mortality after Fontan operation remains substantial. Risk factors for death or loss of Fontan circulation differ between the early and late postoperative periods. Long-term survival has not improved appreciably over the last decade, suggesting that alternatives to the Fontan are warranted.

Background: Patients with a single ventricle experience a high rate of brain injury and adverse neurodevelopmental outcome; however, the incidence of brain abnormalities throughout surgical reconstruction and their relationship with cerebral blood flow, oxygen delivery, and carbon dioxide reactivity remain unknown. Methods: Patients with a single ventricle were studied with magnetic resonance imaging scans immediately prior to bidirectional Glenn (pre-BDG), before Fontan (BDG), and then 3 to 9 months after Fontan reconstruction. Results: One hundred sixty-eight consecutive subjects recruited into the project underwent 235 scans: 63 pre-BDG (mean age, 4.8±1.7 months), 118 BDG (2.9±1.4 years), and 54 after Fontan (2.4±1.0 years). Nonacute ischemic white matter changes on T2-weighted imaging, focal tissue loss, and ventriculomegaly were all more commonly detected in BDG and Fontan compared with pre-BDG patients ( P P Conclusions: Significant brain abnormalities are commonly present in patients with a single ventricle, and detection of these lesions increases as children progress through staged surgical reconstruction, with multiple coexisting lesions more common earlier than later. In addition, this study demonstrated that BDG patients had greater cerebral blood flow than did Fontan patients and that an inverse association exists of various indexes of cerebral blood flow with these brain lesions. However, CO 2 reactivity and oxygen delivery (with 1 exception) were not associated with brain lesion development. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02135081.

Background Collaborative learning is a technique through which individuals or teams learn together by capitalizing on one another's knowledge, skills, resources, experience, and ideas. Clinicians providing congenital cardiac care may benefit from collaborative learning given the complexity of the patient population and team approach to patient care. Rationale and development Industrial system engineers first performed broad-based time-motion and process analyses of congenital cardiac care programs at 5 Pediatric Heart Network core centers. Rotating multidisciplinary team site visits to each center were completed to facilitate deep learning and information exchange. Through monthly conference calls and an in-person meeting, we determined that duration of mechanical ventilation following infant cardiac surgery was one key variation that could impact a number of clinical outcomes. This was underscored by one participating center's practice of early extubation in the majority of its patients. A consensus clinical practice guideline using collaborative learning was developed and implemented by multidisciplinary teams from the same 5 centers. The 1-year prospective initiative was completed in May 2015, and data analysis is under way. Conclusion Collaborative learning that uses multidisciplinary team site visits and information sharing allows for rapid structured fact-finding and dissemination of expertise among institutions. System modeling and machine learning approaches objectively identify and prioritize focused areas for guideline development. The collaborative learning framework can potentially be applied to other components of congenital cardiac care and provide a complement to randomized clinical trials as a method to rapidly inform and improve the care of children with congenital heart disease.

We quantified the effect of anesthesia on cerebral oxygen saturation and blood flow in infants with congenital heart disease. We find that both ScO2 and CBF decrease after induction of anesthesia independent of cardiac diagnosis.

Objectives The aim of this study was to evaluate Fontan peri-operative outcomes for 771 consecutive patients. Background Since the initial description by Fontan, mortality associated with the Fontan operation has declined substantially. However, postoperative effusions remain a significant challenge. Effusions are a key determinant of postoperative length-of-stay and have been shown to be associated with the development of protein-losing enteropathy and with decreased survival. Methods This study was a single-center, retrospective review of 771 patients who underwent Fontan palliation from 1992 to 2009. Results Patients were divided into 3 eras dictated by shift in clinical practice. Overall mortality was 3.5%, 1% since 1996. Importantly, age at Stage II palliation decreased from Era 1 to Era 3 (7.1 vs. 5.9 months; p = 0.0001), whereas age at Fontan increased (1.7 vs. 2.8 years; p = 0.0001). The proportion of patients with prolonged hospital stay (46.7% vs. 8.2% vs. 19.5%, p Conclusions Mortality in the modern era is rare, whereas postoperative pleural drainage remains the dominant morbidity. Elevated pulmonary artery pressure seems to be a marker of unfavorable outcome. Continued investigation is warranted to determine whether medical interventions or alterations to operative strategy can alter peri-operative results and improve long-term outcomes.

Objective Evaluate the impact of near-term delivery on neurodevelopmental (ND) outcomes in children with congenital heart disease (CHD). Methods Secondary analysis of data from a study of genetic polymorphisms and ND outcomes after cardiac surgery in infants. The effect of gestational age (GA) as a continuous variable on ND outcomes was evaluated using general linear regression models. GA was also evaluated as a categorical variable to seek a threshold for better outcomes. ND domains tested at 4 years of age included cognition, language skills, attention, impulsivity, memory, executive function, social competence, visual-motor, and fine-motor skills. Results ND outcomes and GA were available for 378 infants. Median GA was 39 weeks (range, 28-42 weeks) with 351 born at 36 weeks or more (near-term/term). In univariate analysis of the near-term/term subgroup, older GA predicted better performance for cognition, visual-motor, and fine-motor skills. After covariate adjustment, older GA predicted better performance for fine-motor skills ( P = .018). Performance for cognition, language, executive function, social skills, visual-motor, and fine-motor skills was better for those born at 39 to 40 weeks of GA or more versus those born at less than 39 weeks (all P Conclusions These findings are consistent with the hypothesis that delivery before 39 to 40 weeks of GA is associated with worse outcomes in patients with CHD. Early delivery of a child with CHD is often indicated because of maternal or fetal health issues. In the absence of these concerns, these data suggest that elective (or spontaneous) delivery at 39 to 40 weeks of GA is associated with better ND outcomes.

Patients on circulatory support can be the source of multiple challenges including optimizing the circuit for specific congenital heart lesions, troubleshooting circuit failures, transporting patients on the circuit, anticoagulation and bleeding, transitioning to more mobile ventricular assist device, listing for thoracic organ transplantation, weaning from the circuit, and educating the patient and family about mechanical support. These challenges ideally require a specialized multidisciplinary team, which includes anesthesiologists, child life specialists, extracorporeal membrane oxygenation (ECMO) specialists, intensivists, nurses, nutritionists, perfusionists, pharmacists, respiratory therapists, social workers, and surgeons.