Adverse events related to ibuprofen treatment for patent ductus arteriosus in premature neonates.

OBJECTIVE: Our study aimed to review adverse drug reactions (ADRs) associated with ibuprofen treatment of patent ductus arteriosus (PDA) in premature neonates. METHOD: We retrospectively evaluated electronic patient records from neonates treated with ibuprofen for PDA during 5 years in a French neonatal intensive care unit. Full chart review and targeted triggers were used to detect ADRs. The causality between suspected ADRs and medication was evaluated using the WHO causality assessment method by pharmacovigilance experts. Categorical variables were compared using chi-square tests or Fisher's test. Quantitative variables were compared using the Student t test. We explored the risk factors associated with ADR using univariate model analysis. RESULT: Of 227 infants with a mean gestational age (GA) of 27 weeks (24-33), 12 (5%) developed intestinal perforation and seven, necrotizing enterocolitis (3%). The perforation occurred less frequently in infants older than 27 weeks GA (OR=0.14; 95% CI=0.03-0.66, P=0.01). Other observed ADRs were acute renal failure (25 infants, 11%) and thrombocytopenia (five infants, 2%). CONCLUSION: Gastrointestinal complications observed in infants treated with ibuprofen for PDA including gastrointestinal perforations occur in less mature infants. Active chart review of the patient's medical file with a trigger tool should be evaluated for routine ADR monitoring.

Postsurgery analgesic and sedative drug use in a French neonatal intensive care unit: A single-center retrospective cohort study.

OBJECTIVE: To describe pain assessment, the pattern of analgesic and sedative drug use, and adverse drug reactions in a neonatal intensive care unit (NICU) during the postsurgery phase. METHOD: Demographic characteristics, pain scores, and drug use were extracted and analyzed from electronic patient medical files for infants after surgery, admitted consecutively between January 2012 and June 2013. RESULT: One hundred and sixty-eight infants were included. Acute (DAN score) and prolonged (EDIN score) pain assessment scores were used in 79% and 64% of infants, respectively, on the 1st day. This percentage decreased over the 7 days following surgery. The weekly average scores postsurgery were 2/15 (±2.2) for the EDIN score and 1.6/10 (±2.0) for the DAN score. The rates of pain control were 88% for the EDIN and 72% for the DAN. The most prescribed opiate drug was fentanyl (98 patients; 58%) with an average dose of 1.8 (±0.6) µg/kg/h. Midazolam was used in 95 patients (56%), with an average dose of 35 (±14) µg/kg/h. A bolus was administered in 7% (±7.4) of the total dose for fentanyl and 8% (±9.3) for midazolam. Similar doses were used in term and preterm neonates. Of 118 patients receiving fentanyl and/or midazolam, 40% presented urinary retention, 28% a weaning syndrome. Paracetamol (155 patients; 92%) and nalbuphine (55 patients; 33%) were the other medications most often prescribed. CONCLUSION: The off-label use of fentanyl and midazolam was necessary to treat pain after surgery. Pain assessment should be conducted for all neonates in order to optimize their treatment. Research on analgesic and sedative medicine in vulnerable neonates seems necessary to standardize practices and reduce adverse drug reactions.

[Nuclear magnetic resonance based metabolic phenotyping for patient evaluations in operating rooms and intensive care units]. / Phénotypage métabolique par résonance magnétique nucléaire pour l'évaluation périopératoire et en réanimation.

Metabolic phenotyping consists in the identification of subtle and coordinated metabolic variations associated with various pathophysiological stimuli. Different analytical methods, such as nuclear magnetic resonance, allow the simultaneous quantification of a large number of metabolites. Statistical analyses of these spectra thus lead to the discrimination between samples and the identification of a metabolic phenotype corresponding to the effect under study. This approach allows the extraction of candidate biomarkers and the recovery of perturbed metabolic networks, driving to the generation of biochemical hypotheses (pathophysiological mechanisms, diagnostic tests, therapeutic targets…). Metabolic phenotyping could be useful in anaesthesiology and intensive care medicine for the evaluation, monitoring or diagnosis of life-threatening situations, to optimise patient managements. This review introduces the physical and statistical fundamentals of NMR-based metabolic phenotyping, describes the work already achieved by this approach in anaesthesiology and intensive care medicine. Finally, potential areas of interest are discussed for the perioperative and intensive management of patients, from newborns to adults.

[Evolution of neonatal transfusion practices: current recommendations]. / Évolution des pratiques transfusionnelles en néonatalogie: recommandations actuelles.

Newborns and particularly preterm infants are a population at high risk of transfusion. The implementation of strategies to prevent transfusion by reducing blood loss, use of recombinant human erythropoietin, administration of iron and vitamins and delayed umbilical cord clamping have reduced the frequency of transfusions neonatal periods. The emergence of more stringent recommendations on indications for transfusion has been involved in this development. Various transformations and qualifications for red cell concentrates, platelet concentrates and fresh frozen plasma must be known to better adapt the blood products to newborn term and preterm according to their pathologies. Preparing pediatric units from a single donor for repeated transfusions reduces the allo-immune and infectious risks.

Pathophysiology of neonatal brain lesions: lessons from animal models of excitotoxicity.

AIM: The pathophysiology of perinatal brain lesions is probably complex and multifactorial. The development and characterization of distinct yet complementary animal models should help to unravel the cellular and molecular mechanisms underlying perinatal brain lesions. This paper reviews experimental data obtained in animal models of neonatal excitotoxic brain lesions that closely mimic some of the lesions found in human cerebral palsy. CONCLUSION: Available data point to a key role for brain macrophages and oligodendrocytes in neonatal rodent excitotoxic brain lesions and underline the impact of cytokines on these lesions.

Early microglial activation following neonatal excitotoxic brain damage in mice: a potential target for neuroprotection.

Previous studies in a mouse model of neonatal excitotoxic brain damage mimicking the brain lesions in human cerebral palsy showed microglial activation within 24 h after intracerebral injection of the glutamatergic analog ibotenate. Using this model, we studied the expression of CD-45 antigen, a marker of blood-derived cells, by these activated microglial cells labeled by Griffonia simplicifolia I isolectin B4. Immunohistochemistry performed during early development of excitotoxic lesions showed that most cells labeled with the isolectin B4 were CD-45-negative, suggesting that these early activated microglial cells were deriving chiefly from resident microglia and not from circulating monocytes. We also directly tested the hypothesis that activated resident microglia and/or blood-derived monocytes play a role in the pathophysiology of excitotoxic brain damage. Repeated i.p. administrations of chloroquine, chloroquine+colchicine, minocycline, or an anti-MAC1 antibody coupled to the toxin saporin before and/or after ibotenate injection induced a significant reduction in the density of isolectin B4-positive cells. This inhibition of resident microglial and/or blood-derived monocytes activation was accompanied by a significant reduction in the severity of ibotenate-induced brain lesions (up to 79% lesion size reduction with the highest minocycline dose) as well as of ibotenate-induced cortical caspase-3 activation (49% reduction).

Neuroprotective properties of tianeptine: interactions with cytokines.

Tianeptine is an antidepressant with proven clinical efficacy and effects on hippocampal plasticity. Hypoxia increased lactate dehydrogenase (LDH) release from cortical neuronal cultures, and tianeptine (1, 10 and 100 microM) inhibited LDH release as efficiently as the N-methyl-D-aspartate (NMDA) antagonist, MK-801. However, tianeptine did not block apoptosis in cultured cortical neurones caused by NMDA, but reduced apoptosis when interleukin-1beta (IL-1beta) was included with NMDA. In 5-day old mice, intracerebral injection of ibotenate induced reproducible lesions in cortex and white matter. Lesion size was markedly reduced by co-administration of MK-801 (1 mg/kg i.p.) but neither by tianeptine or its enantiomers administered acutely (1, 3 or 10 mg/kg i.p.) nor by tianeptine administered chronically (10 mg/kg i.p. for 5 days). Chronic administration of IL-1beta (10 ng/kg i.p. for 5 days) prior to ibotenate injection exacerbated lesion size in cortex and white matter, and this exacerbation was prevented by chronic pre-treatment with tianeptine (10 mg/kg i.p.) or by acute administration of tianeptine (10 mg/kg i.p.) concomitantly with ibotenate. Thus tianeptine has neuroprotective effects against hypoxia in tissue culture and against the deleterious effects of cytokines in cortex and white matter, but not against NMDA receptor-mediated excitotoxicity.