Every year millions of fetuses and newborn humans are exposed, directly or indirectly, to general anesthetics/analgesics /sedatives for pain relief and surgical stress. The main concerns in this area come from the perception of increased risk of morbidity and potential neurodevelopmental effects induced by anesthesia/analgesia/sedation (A/A/S) used during immaturity specially of the central nervous system. The effects of A/A/S, administered to young infants, particularly neonates with higher risk surgical pathology, are not yet sufficiently studied. The main objective of this thesis was to contribute to the scientific knowledge in this field, by conducting a series of studies of experimental (Study A) and clinical (Studies B to D) nature. Our experimental study (Study A) raises important questions about the impact on the neurodevelopment of immature beings exposed to midazolam or fentanyl , drugs widely used in the clinical setting further studied in this context (neonates hospitalized in pediatric intensive care units undergoing surgery under anesthesia). Using a murine model of neonatal postoperative pain, pups were divided into four groups: (1) fentanyl, (2) midazolam, (3) sham and (4) non-operated, whose physical development and behavior were evaluated over the study period after repeated administration of the test drug. At the end of the experiment, histopathological and histomorphometric study of areas of peri-rhinal cortex, dentate gyrus of the hippocampus and cerebellum was also conducted. Our results suggest that repeated administration of fentanyl or midazolam to rats subjected to surgical stress during brain immaturity altered the normal growth and development, with variable impact, either positive or negative, on the different parameters studied, with emphasis on globally positive findings for fentanyl, with improved acquisition of cognitive skills (memory) and unfavorable findings for midazolam which negatively affected memory and anxious behavior. Studies B and C, respectively , aimed (Study B) to analyze the results and conclusions of epidemiological studies published in literature on persistent neurodevelopmental disorders following exposure of children during brain immaturity to anesthetics and (Study C) to analyze the epidemiological profile of morbidity and mortality related to anesthesia and surgery in the first year of age and particularly in the neonatal period (first month of age), through a systematic review of the literature. In Study B , analysis of publications revealed studies with conflicting conclusions and numerous limitations that make the information reported still deemed insufficient to change current clinical practice and, in Study C, a great variability was observed in rates of mortality and morbidity in the age in analysis , as well as in its subgroups . However, despite the obvious methodological heterogeneity and absence of specific studies, epidemiological profiles of morbidity and mortality related to anesthesia in children in the first year of age showed higher frequency in this age group, with the highest peaks of incidence for neonates. Study D aimed to analyze the morbidity and mortality in a large cohort of infants undergoing neonatal surgery under general anesthesia in a regional center of reference in Portugal, in the context of optimal health care for this population. The use of statistical analysis using the logistic regression method allowed the determination of independent risk factors for mortality and for severe postoperative complications (grades III to V in the Clavien - Dindo classification) in the first 30 days after neonatal surgery. Among the relevant results, a 6.4 % rate of in-hospital mortality was found, which is within the prevalence reported by developed countries. Mortality and severe postoperative complications in the first 30 days after neonatal surgeries under general anesthesia were respectively 5% and 23%. Variables ASA physical status 3 or higher and necrotizing enterocolitis/gastrointestinal perforation were identified as independent risk factors for early neonatal postoperative mortality and variables more than one intervention, surgical repair of congenital diaphragmatic hernia, prematurity under 32 weeks gestational age and abdominal surgery were identified as independent risk factors for severe complications after neonatal anesthesia/surgery . Our personal contribution of experimental nature can help support the neonatal use of fentanyl, when indicated, in post-surgical settings, including in premature neonates. With regard to midazolam, its use should be restricted to the lowest exposure possible until its effects on human brain development are better clarified. However, extrapolation of our data to the clinical context should be done with caution as in any animal study. The contribution provided by the clinical studies, by systematizing the available information and establishing independent risk factors can help health professionals to improve results and to better define the postoperative outcome in neonates with surgical pathology.
|Translated title of the contribution
|Anesthesia, analgesia and sedation effects in the immature being experimental and clinical study
|Doctor of Philosophy
|14 Oct 2014
|Published - 14 Oct 2014