Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.

Background Adequate enteral nutrition may be difficult to achieve early in neonates after cardiac surgery, but it is essential for growth, wound healing, and immune function. Objective To assess caloric intake in neonates receiving enteral nutrition after surgery. Methods A retrospective chart review was conducted of daily enteral caloric intake in the cardiac intensive care unit of a tertiary children's hospital. Data on the institution of enteral feeding and the discontinuation of parenteral nutrition were assessed for full-term neonates who had undergone cardiac surgery. Results Caloric intake was assessed in 100 patients, 52 with biventricular cardiac defects and 48 with a functional single ventricle. The median duration of stay in the cardiac intensive care unit was 13 days (range, 4-69), and patients received enteral feeding exclusively for a median of 5 days (range, 1-43). In total, 705 patient days were evaluated. The median caloric intake per day was 93 kcal/kg (range, 43-142). A goal of 100 kcal/kg was achieved for 48.4% of patient days and 120 kcal/kg for only 19.7% of patient days. Median weight change for the period of enteral feeding was -20 g (range, -775 to 1485 g). Conclusions Enteral feeding alone is often suboptimal after neonatal cardiac surgery. New strategies to improve caloric intake may enhance postoperative recovery.

In the current era, continuous electroencephalographic monitoring demonstrates early postoperative seizures in 11.2% of a heterogeneous cohort of neonates and infants with complex congenital heart defects. Increasing duration of DHCA was identified as a predictor of seizures. However, the incidence of seizures in children with limited duration of DHCA was similar to that in infants undergoing continuous cardiopulmonary bypass alone.

OBJECTIVE-The goal was to evaluate polymorphisms of the APOE gene as modifiers of neurobehavioral outcomes for preschool-aged children with congenital heart defects, after cardiac surgery.METHODS-A prospective observational study with neurodevelopmental evaluation between the fourth and fifth birthdays was performed. Attention and behavioral skills were assessed through parental report. RESULTS-Parents of 380 children completed the neurobehavioral measures. Child BehaviorChecklist scores for the pervasive developmental problem scale were in the at-risk or clinically significant range for 15% of the cohort, compared with 9% for the normative data (P < .00001). Attention problem scores were in the at-risk or clinically significant range for 12% of the cohort, compared with 7% for the normative data (P = .0002). The Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Preschool Version, was completed for 378 children; 30% scored in the clinically Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml NIH Public Access Author ManuscriptPediatrics. Author manuscript; available in PMC 2010 July 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript significant range for inattention and 22% for impulsivity. After adjustment for covariates, the APOE ε2 allele was significantly associated with higher scores (worse problems) for multiple Child Behavior Checklist indices, including somatic complaints (P = .009), pervasive developmental problems (P = .032), and internalizing problems (P=.009). In each case, the ε4 allele was associated with a better outcome. APOE ε2 carriers had impaired social skills, compared with ε4 carriers (P = . 009).CONCLUSIONS-For preschool-aged children with congenital heart defects requiring surgery, parental rating scales showed an increased prevalence of restricted behavior patterns, inattention, and impaired social interactions. The APOE ε2 allele was associated with increased behavior problems, impaired social interactions, and restricted behavior patterns. Keywordscongenital heart defects; genetic predisposition to disease; apolipoprotein E; behavioral symptoms; attention-deficit/hyperactivity disorder; impulsive behavior; autistic disorderCongenital heart defects (CHDs) are the most common birth defects in humans, affecting 8 per 1000 live births (~30 000-40 000 children each year in the United States), with one third of affected children requiring intervention in early infancy. Neurodevelopmental dysfunction is the most common and potentially most disabling outcome of CHDs and their treatment. Improved survival rates, combined with expectations for independence and behavioral selfregulation as the children mature, have led to increasing recognition of neurobehavioral symptoms and impaired functional outcomes for some survivors. Recent reports identified a high prevalence of inattention and hyperactivity/impulsivity behaviors, consistent with the behavioral phenotype of attention-deficit/hyperactivit...

This article is a summary of good adaptive practices for the planning and implementation of adaptive designs compiled from experiences gained in the pharmaceutical industry. The target audience is anyone involved in the planning and execution of clinical trials. The first step prior to planning an adaptive design is to assess the appropriateness of its use. Hence, strategic points to consider when assessing if an adaptive design is the right choice for a trial are discussed. In addition, strategic points for consideration at the design and implementation stage are included from operational, regulatory, clinical, and statistical perspectives. Good practices for trial simulation, trial documentation, and data monitoring committees are provided.

Objectives Copy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and over-represented in children with congenital heart disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD and evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival. Methods These cases are derived from a prospective cohort of non-syndromic CHD patients (n=422) ascertained prior to their first surgery. Healthy pediatric controls (n=500) were obtained from the electronic Medical Records and Genetic Epidemiology (eMERGE) Network and CNV frequency was contrasted for CHD cases and controls. CNVs were algorithmically determined, subsequently screened for >95% overlap between two methods, size (>300kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs), and separately validated with quantitative-PCR. Survival likelihoods were calculated for cases using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival. Results Children with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared to pediatric controls (12.1% vs. 5.0%, P=0.00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (HR=3.42, 95% CI: 1.66-7.09, P=0.00090) with confounder adjustment. Conclusions We confirm that children with isolated CHD have a greater burden of rare/large CNVs. We report a novel finding that these CNVs are associated with an adjusted 2.55-fold increased risk of death or transplant. These data suggest that CNV burden is an important modifier of survival after surgery for CHD.

Objectives Despite improved survival in children with hypoplastic left heart syndrome (HLHS), significant concern persists regarding their neurodevelopmental (ND) outcomes. Previous studies have identified patient factors, such as prematurity and genetic syndromes, to be associated with worse ND outcomes. However, no consistent relationships have been identified among modifiable management factors, including cardiopulmonary bypass strategies, and ND outcomes after cardiac surgery in infancy. Studies in immature animals, including primates, have demonstrated neurodegeneration and apoptosis in the brain after certain levels and extended durations of anesthetic exposure. Retrospective human studies have also suggested relationships between adverse ND effects and anesthetic exposure. Methods Cumulative minimum alveolar concentration hours (MAC-hrs) of exposure to volatile anesthetic agents (VAA) (desflurane, halothane, isoflurane and sevoflurane) were collected from an anesthetic database and medical record review for 96 patients with HLHS or variants. ND testing was performed between ages 4 and 5 years including full-scale IQ, verbal IQ, performance IQ and processing speed. Four generalized linear modes were hypothesized a priori and tested using a Gaussian (normal) distribution with an identity link. Results Cumulative VAA exposure ranged from 0 to 35.3 MAC-hrs (median 7.5 hrs). Using specified covariates identified previously as significant predictors of ND outcomes, statistically significant relationships were identified between total MAC-hrs exposure and worse full-scale IQ and verbal IQ scores (p’s < 0.05) alone and after adjusting for relevant covariates. Conclusion Increased cumulative MAC-hrs exposure to VAA is associated with worse ND outcomes in certain domains in children with HLHS and variants.

The occurrence of a seizure after cardiac operation is a marker of central nervous system injury. However, in this cohort of neonates and infants with complex congenital heart defects, the occurrence of a seizure was not predictive of a worse developmental outcome at 1 year of age as assessed by the Bayley Scales of Infant Development II.