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.