Merle G. Paule

A pilot study of preemptive morphine analgesia in preterm neonates: Effects on head circumference, social behavior, and response latencies in early childhood

Use of preemptive analgesia in Neonatal Intensive Care Units is recommended for severe and/or invasive procedures. However, the potential long-term consequences of such analgesia, which may be prolonged, are only beginning to be studied. In this pilot study, a subset of subjects previously enrolled in the Neurological Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial was assessed at early childhood. These ex-preterm infants (born at 23-32 weeks of gestational age) required intubation within 72 h postpartum and were randomized to receive either preemptive morphine analgesia (maximum of 14 days) or placebo within 8h post-intubation. At 5-7 years of age, neuropsychological outcomes, morphometrics, adaptive behavior, parent-rated behavior, motivation, and short-term memory were measured. Although overall IQ and academic achievement did not differ between the morphine treated (n=14) and placebo (n=5) groups, preemptive morphine analgesia was associated with distinct differences in other outcome variables. Head circumference of morphine treated children was approximately 7% smaller (Cohensd: 2.83, effect size large) and body weight was approximately 4% less (Cohensd: 0.81, effect size large); however, height did not differ. In the short-term memory task (delayed matching to sample), morphine treated children exhibited significantly longer choice response latencies than placebo children (3.86±0.33 and 2.71±0.24 s, respectively) (p<0.03) and completed approximately 27% less of the task than placebo children (Cohensd: 0.96, effect size large). Parents described morphine treated children as having more social problems, an effect specific to creating and maintaining friendships (Cohensd: -0.83, effect size large). Despite the small sample size and the preliminary nature of this study, these results are strongly suggestive of long-lasting effects of preemptive morphine analgesia. A larger investigation with more comprehensive assessments of some of these key features will enable a more complete understanding of the relationship between preemptive morphine treatment and long-term neurocognitive, behavioral, and adaptive outcomes.

Effects of chronic in utero exposure to cocaine on behavioral adaptability in rhesus monkey offspring when examined in adulthood.

MERLE G. PAULE,a,b,d MICHAEL P. GILLAM,a RICHARD R. ALLEN,c AND JOHN J. CHELONISb aBehavioral Toxicology Laboratory, Division of Neurotoxicology, HFT-132, National Center for Toxicological Research/FDA, 3900 NCTR Road, Jefferson, Arkansas, 72079-9502, USA bComplex Brain Function Laboratory, Center for Applied Research and Evaluation, Arkansas Children’s Hospital, 800 Marshall Street, Little Rock, Arkansas, 72202-3591, USA cPeak Statistical Services, 5691 Northwood Drive, Evergreen, Colorado 80439-5520, USA

Approaches to Utilizing Aspects of Cognitive Function as Indicators of Neurotoxicity

Publisher Summary This chapter proposes research approaches that utilize complex brain functions, modeled by specific behaviors, as biomarkers of neurotoxicity. The focus in this chapter is on efforts to increase the use of laboratory animals, instead of humans, as sources of experimental data. The need to use animal models for predicting the effects of neuroactive agents on complex brain functions in humans is absolute and has led to the development of automated systems for administering identical behavioral tasks to both laboratory animals and humans. The maintenance of task continuity across species allows for the quantitative determination of interspecies similarities and differences in complex brain function and assists in the extrapolation of data from laboratory animals to humans. Efforts to develop behaviors for modeling additional complex brain functions in animals will increase the number of functional domains amenable to the risk assessment process. This chapter elaborates similarities between human and monkey performance of complex behavioral tasks. The chapter also describes in detail the test battery approach for interspecies comparisons.

Evaluation of Dopamine Receptor Integrity after Sevofl urane Exposure in Neonatal Rat Brain Using Positron Emission Tomography

Aims: The volatile general anesthetic sevofl urane is commonly used across all ages in the clinic. nSevofl urane-induced neurotoxic effects on the developing dopaminergic system are still unclear. The aim nof this study was to evaluate the integrity of the D2/D3 receptor in developing rat brain utilizing molecular nimaging techniques.

MicroPET/CT Assessment of Minocycline Effects on Anesthetic-Induced Neuronal Injury in Developing Rats

Ketamine is a dissociative anesthetic that is frequently used for the induction and maintenance of general anesthesia in children. It has been reported that blockade of NMDA receptors by ketamine may cause neurotoxicity in neonatal rats when given over a 12 hour period during the brain growth spurt.