Systematic culture of central catheters and infections related to catheters in a neonatal intensive care unit: an observational study.

Systematic culture of the tip of central lines is performed in many neonatal intensive care units (NICUs) to guide any subsequent antibiotic therapy. The clinical relevance of this procedure is debated, given the significant bacterial contamination during its removal. We aimed to describe infections related to catheters and assess the usefulness of central catheter systematic cultures for probabilistic antibiotic therapy in cases of suspicion of catheter-related infections in a NICU. A retrospective study in a NICU included all newborn patients hospitalized with a central catheter, between January 2018, and June 2019. The main outcome measures were bacterial catheter colonization, catheter-related infection rate, and simulation-based approach to antibiotic prescription. Three hundred and seventy-five newborns, with 634 central catheters were included. There were 273 (43%) catheters that were colonized by at least one microorganism. There were 183 cases of suspected sepsis, with 31 infections definitively related to the catheter. In our simulation antibiotic prescription approach, there was no significant difference in terms of the efficacy toward the microorganism(s) involved between the probabilistic antibiotic therapies proposed by the experts and those ultimately prescribed. Performing a catheter culture only if catheter-related infection is suspected could be an alternative to routine screening.

[Neurodevelopment and neuroprotection in young children]. / Le neurodéveloppement et la neuroprotection du jeune enfant.

In France, the most pessimistic estimates put the prevalence of neurodevelopmental disorders (NDD) at 15 % of births. The two largest populations of newborns at highest risk of NDD are premature babies and babies born into siblings with one or more infants who already have an autism spectrum disorder or another NDD. The high prevalence of these disorders justifies a health promotion policy, centred on the child and his or her family. Prevention is based on the early identification of high-risk factors, by informing families and training pregnancy and early childhood professionals, and implementing perinatal prevention protocols for high-risk newborns (antenatal corticosteroid therapy and magnesium sulfate for women at risk of preterm delivery before 32 weeks, developmental care, therapeutic hypothermia for full-term infants with early neonatal encephalopathy presumed to be anoxic). Preventing the severity of NDD depends on their early identification, as early as possible in the highest plastic "1000 days" developmental window, a smooth flow of diagnosis and care for mothers and children, and the establishment of an ecosystem that includes multi-modal early intervention, at the best in multi-disciplinary teams such as the early medical and social action centres, support for families through guidance programs and inclusion in the community, first in day-care centers and then in nursery schools.

Creation of a rating scale to teach Less Invasive Surfactant Administration (LISA) in simulation.

BACKGROUND: Simulation-based training is gaining increasing prominence in neonatology training. The Less Invasive Surfactant Administration (LISA) method is starting to be taught in simulation. The aim of this educational study was to develop and validate a rating scale for teaching the LISA method in simulation. METHODS: The Downing framework was used to create this performance-rating scale. A first version of the scale was submitted to 12 French and Belgian experts to obtain their opinions. Consensus was reached using a modified Delphi method. The performance of 40 pediatricians was then evaluated with this scale on a preterm neonate manikin simulating a neonatal respiratory distress syndrome. Each run was evaluated using the scale by two independent observers based on video recordings. RESULTS: The Cronbach alpha score of the rating scale was 0.72. The intraclass correlation coefficient (ICC) was 0.91 and the scores between raters were not significantly different. Finally, this rating scale correctly distinguished the experienced from the inexperienced learners (p < 0.01). CONCLUSIONS: This rating scale is one of the first rating scales for the evaluation and teaching of the LISA method in simulation. This tool has ample potential for use in clinical practice to evaluate the performance of surfactant administration in preterm neonates.

Low-Dose Remifentanil in Preterm Cesarean Section with General Anesthesia: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVE: The conventional technique of general anesthesia induction during a Cesarean section involves the use of opioids only after cord clamping. We hypothesized that the use of remifentanil before cord clamping might reduce the use of maternal supplemental anesthetic agents and improve the maternal hemodynamics status and neonatal adaptation of the preterm neonate. METHODS: A phase III, double-blind, randomized, placebo-controlled, hospital-based trial enrolled parturients undergoing a Cesarean section under general anesthesia before 37 weeks of gestation. Block randomization allocated pregnant women to remifentanil or placebo. The primary outcome was the rate of newborns with Apgar scores < 7 at 5 min. Secondary outcomes were maternal hemodynamic parameters, complications of anesthetic induction, use of adjuvant anesthetic agents, neonatal respiratory distress, umbilical cord pH, and lactate levels. RESULTS: A total of 52/55 participants were analyzed, comprising 27 women in the remifentanil group and 25 in the placebo group. Nine of 27 (33.3%) neonates had an Apgar score < 7 at 5 min in the remifentanil group versus 11/25 (44.0%) in the placebo group (p = 0.45, odds ratio = 0.66, 95 confidence interval 0.20-2.18). The blood cord gases, cognitive, behavior, sensory, sleeping, and feeding scores at 1 and 2 years of corrected age were not different. For the mothers, hemodynamic parameters, anesthesia duration, and the cumulative treatment dose until cord clamping did not differ between the groups. CONCLUSIONS: The use of a low dose of remifentanil before cord clamping for a Cesarean section appears to be safe both for the mother and the preterm newborn, but it does not improve maternal or neonatal outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02029898.

Fetal, Preterm, and Term Neonate Exposure to Remifentanil: A Systematic Review of Efficacy and Safety.

BACKGROUND: Owing to its pharmacodynamic properties, especially the rapid onset and short duration of its action, the use of remifentanil in obstetric anesthesia, as well as in neonatology, might be increasingly used. OBJECTIVE: We conducted a systematic review to assess the efficacy and safety of remifentanil in preterm and term neonates. Outcomes of interest were neonatal adaptation after fetal exposure; neonatal pain, distress, and discomfort control during invasive procedures; and the occurrence of hemodynamic effects or respiratory depression induced by remifentanil infusion. METHODS: Given the different contexts of use, we have organized this work into three parts: (A) use of remifentanil for labor or cesarean section, with exposure of the fetus before birth, (B) brief use for neonatal procedural analgesia, and (C) prolonged use for sedation/analgesia of neonates. The bibliographic search was conducted based on keywords using electronic medical databases (DATABASE, Cochrane Library, PubMed, and EMBASE) from 1 January 2000 until 31 December 2022. RESULTS: Twenty-two articles were included (10 in part A, 5 in part B and 7 in part C). Prospective, controlled, randomized, blinded, and intention-to-treat trials were retained. Neonates were well adapted after exposure to remifentanil in the fetal period. Pain, stress, and discomfort were controlled during a brief or prolonged invasive procedure when remifentanil was used for sedation/analgesia. The physiological parameters were stable and the procedures were straightforward. Chest wall rigidity appeared to be a common side effect, but this can be managed by slow and continuous infusion and by using the minimum effective dose. CONCLUSIONS: Remifentanil appears to be effective and safe in the short term in preterm and full-term neonates. However, its safety is compromised by the risk of chest wall rigidity. It should be used in appropriate neonatal units and in the presence of physicians able to monitor its side effects. Long-term outcomes have not been evaluated, to our knowledge.

Premedication before laryngoscopy in neonates: Evidence-based statement from the French society of neonatology (SFN).

Context: Laryngoscopy is frequently required in neonatal intensive care. Awake laryngoscopy has deleterious effects but practice remains heterogeneous regarding premedication use. The goal of this statement was to provide evidence-based good practice guidance for clinicians regarding premedication before tracheal intubation, less invasive surfactant administration (LISA) and laryngeal mask insertion in neonates. Methods: A group of experts brought together by the French Society of Neonatology (SFN) addressed 4 fields related to premedication before upper airway access in neonates: (1) tracheal intubation; (2) less invasive surfactant administration; (3) laryngeal mask insertion; (4) use of atropine for the 3 previous procedures. Evidence was gathered and assessed on predefined questions related to these fields. Consensual statements were issued using the GRADE methodology. Results: Among the 15 formalized good practice statements, 2 were strong recommendations to do (Grade 1+) or not to do (Grade 1-), and 4 were discretionary recommendations to do (Grade 2+). For 9 good practice statements, the GRADE method could not be applied, resulting in an expert opinion. For tracheal intubation premedication was considered mandatory except for life-threatening situations (Grade 1+). Recommended premedications were a combination of opioid + muscle blocker (Grade 2+) or propofol in the absence of hemodynamic compromise or hypotension (Grade 2+) while the use of a sole opioid was discouraged (Grade 1-). Statements regarding other molecules before tracheal intubation were expert opinions. For LISA premedication was recommended (Grade 2+) with the use of propofol (Grade 2+). Statements regarding other molecules before LISA were expert opinions. For laryngeal mask insertion and atropine use, no specific data was found and expert opinions were provided. Conclusion: This statement should help clinical decision regarding premedication before neonatal upper airway access and favor standardization of practices.

Cerebral Palsy in Very Preterm Infants: A Nine-Year Prospective Study in a French Population-Based Tertiary Center.

OBJECTIVES: To describe the prevalence of cerebral palsy (CP) at age 2 years in infants born before 33 weeks of gestation and to analyze the fetal neuroprotective effect of the antenatal administration of magnesium sulfate (MgSO4) treatment on CP. STUDY DESIGN: Preterm infants born before 33 weeks of gestation and discharged from the Rouen University Hospital's Neonatal Intensive Care Unit between 2007 and 2015 were included. At age 2 years, pediatricians of the perinatal network of Eure and Seine-Maritime counties administered standardized questionnaires analyzing motor, cognitive, and behavioral items, derived from the Denver and Amiel-Tison scales. A routine protocol based on MgSO4 infusion was introduced in 2010. The primary outcome measure was the occurrence of CP according to the Surveillance of Cerebral Palsy in Europe network definition. RESULTS: A total of 1759 very preterm infants were included, among whom 138 (7.8%) died and 148 (9.1%) were lost to follow-up. Assuming that those lost to follow-up had no CP, at 2 years, 55 of 1621 infants (3.4%; 95% CI, 2.6%-4.4%) had CP. After statistical adjustment for birth term and antenatal corticosteroid use, a significant decrease in CP was observed after implementation of a protocol of MgSO4 administration in mothers before imminent preterm birth at <33 weeks of gestation (aOR, 0.53; 95% CI, 0.29-0.98; P = .04). CONCLUSIONS: The prevalence of CP at 2 years after very preterm birth was low. The implementation of a neuroprotective protocol with MgSO4 was associated with reduced CP occurrence; however, several relevant limitations must be considered for interpretation.

The cause of birth is associated with neonatal prognosis in late preterm singletons.

INTRODUCTION: Recent studies have shown that the cause of very preterm births may be related to neonatal morbidity and mortality. Even though these risks are lower among late preterm births, this group accounts for the vast majority of all preterm births. The objective of this study was to evaluate the relation of neonatal morbidity and mortality to the cause of late preterm birth. MATERIALS AND METHODS: This retrospective observational cohort study included all women who gave birth to liveborn singletons from 34 to 36 weeks+6 days of gestation in a French level III maternity hospital in the 5-year period 2013-2017. The causes of preterm delivery were divided into 6 mutually exclusive groups. The main outcome was a composite neonatal morbidity criterion, defined by at least one among the following criteria: neonatal respiratory distress, neurological complications, neonatal sepsis, severe necrotizing enterocolitis, and neonatal hypoglycemia. We analyzed the association between cause of preterm delivery and neonatal morbidity after adjustment for gestational age and antenatal corticosteroid therapy. The reference group was preterm labor, defined by spontaneous preterm labor with intact membranes. RESULTS: During the study period, there were a total of 27 110 births, including 1114 singleton births at 34 to 36 weeks of gestation + 6 days (4.1%). Among the 968 late preterm births included, the risk of neonatal morbidity in the group with preterm premature rupture of membranes (PPROM) was similar to that in the preterm labor (reference) group: adjusted odds ratio (aOR) 1.2 (95% CI, 0.8-1.8). All the other causes of late preterm birth were associated with a higher risk of neonatal morbidity than the reference group: aOR 2.0 [95% CI, 1.1-3.5] for hypertensive disorders without suspected fetal growth restriction (FGR) (9.1% of cases), aOR 2.4 [95% CI, 1.4-4.2] for hypertensive disorders with suspected FGR (8.9%), aOR 4.2 [95% CI, 2.2-8.0] for suspected FGR without hypertensive disorders (5.8%), and aOR 4.4 [95% CI, 2.2-8.8] for vaginal bleeding related to abnormal placental insertion (4.7%). CONCLUSION: Among infants born from 34 to 36 weeks + 6 days of gestation, PPROM and preterm labor had similar risks of neonatal morbidity, while the other causes were associated with a risk of neonatal morbidity at least twice that with preterm labor.

Efficacy and Safety Aspects of Remifentanil Sedation for Intubation in Neonates: A Retrospective Study.

Objective: To evaluate the efficacy and safety of remifentanil as a premedication in neonates undergoing elective intubation. Study Design: This retrospective study focused on neonates admitted to the Neonatal Intensive Care Unit of Port-Royal, Paris Centre University Hospitals, France, between June 2016 and November 2017, who received remifentanil before an elective intubation. First, atropine (10 µg/kg) was administered intravenously as a bolus, followed by remifentanil, which was administrated continuously. The dose of remifentanil was reduced twice during the study period in order to administer the minimum effective dose and thus reduce possible adverse events. Results: Fifty-four neonates were exposed to remifentanil and atropine. The intubating conditions were excellent or good for 46 procedures (85%) and the median Acute Pain in Newborn Infants score was 2 (IQ 25-75: 0-5) before the sedation, 1 (0-2) during the laryngoscopy, and 0 (0-0) after the intubation. The intubation was successful at the first attempt for 18 patients (33%). Chest wall rigidity occurred in 6 procedures (11%), other respiratory problems in 5 (9%), and laryngospasm in 1 (2%). Some of the procedures were complicated by bradycardia (23%) or desaturation (37%). Conclusions: Remifentanil and atropine prior to intubation provided satisfactory intubating conditions in neonates. Nevertheless, severe adverse effects (such as chest wall rigidity) are a potential risk, possibly related to the total dose received. These data do not support the safety of using remifentanil alone prior to intubation in neonates.

Beneficial Effects of Remifentanil Against Excitotoxic Brain Damage in Newborn Mice.

Background: Remifentanil, a synthetic opioid used for analgesia during cesarean sections, has been shown in ex vivo experiments to exert anti-apoptotic activity on immature mice brains. The present study aimed to characterize the impact of remifentanil on brain lesions using an in vivo model of excitotoxic neonatal brain injury. Methods: Postnatal day 2 (P2) mice received three intraperitoneal injections of remifentanil (500 ng/g over a 10-min period) or saline just before an intracortical injection of ibotenate (10 µg). Cerebral reactive oxygen species (ROS) production, cell death, in situ labeling of cortical caspase activity, astrogliosis, inflammation mediators, and lesion size were determined at various time points after ibotenate injection. Finally, behavioral tests were performed until P18. Results: In the injured neonatal brain, remifentanil significantly decreased ROS production, cortical caspase activity, DNA fragmentation, interleukin-1ß levels, and reactive astrogliosis. At P7, the sizes of the ibotenate-induced lesions were significantly reduced by remifentanil treatment. Performance on negative geotaxis (P6-8) and grasping reflex (P10-12) tests was improved in the remifentanil group. At P18, a sex specificity was noticed; remifentanil-treated females spent more time in the open field center than did the controls, suggesting less anxiety in young female mice. Conclusions: In vivo exposure to remifentanil exerts a beneficial effect against excitotoxicity on the developing mouse brain, which is associated with a reduction in the size of ibotenate-induced brain lesion as well as prevention of some behavioral deficits in young mice. The long-term effect of neonatal exposure to remifentanil should be investigated.

Factors associated with neonatal hypoxic ischemic encephalopathy in infants with an umbilical artery pH less than 7.00.

OBJECTIVE: Our objective was to identify factors associated with hypoxic-ischemic encephalopathy (HIE) among newborns with an umbilical pH < 7.00. STUDY DESIGN: Case-control study during a four-year study period in a single academic tertiary-center, including all neonates ≥35 weeks with an umbilical pH < 7.00. Cases were neonates with HIE, regardless of Sarnat classification, and controls were neonates without signs of HIE. We used univariate and multivariate analysis to compare the maternal, obstetric, and neonatal characteristics of cases and controls. RESULTS: Among 21,211 births, 179 neonates≥35 weeks (0.84%) had an umbilical pH < 7.00. One hundred and forty-seven(82.1%) newborns had severe asphyxia without HIE, 32(17.9%) had HIE and 21(11.7%) needed therapeutic hypothermia. Neonates with HIE were significantly more likely to have 5-minute Apgar score<7(75% versus 15.7% P < 0.01), together with a lower mean umbilical arterial pH (6.84 versus 6.95, P < 0.01) and lower mean base deficits (-17.0 versus -12.7, P < 0.01). Factors significantly associated with HIE were the mother being overweight(28.1% for cases versus 14.3% for controls, adjusted OR=4.6[1.4-15.2]) or obese(25.0% versus 13.6%, aOR=15.5[1.1-12.5]), smoking(18.7% versus 5.4%, aOR=5.8[1.6-21.2]), a sentinel event as cord prolaps or placenta abruption (34.4% versus 13.6%, aOR=2.7[1.1-7.2]), and decreased fetal heart rate variability(68.7% versus 44.2%, aOR=2.8[1.1-6.9]). CONCLUSION: Among neonates with an umbilical cord pH < 7.00, those with HIE had a more severe metabolic acidosis. Maternal factors associated with HIE among newborns with an umbilical pH < 7.00, were being overweight or obese, and smoking, and the associated obstetric factors were a sentinel event and decreased fetal heart rate variability.

Protection of brain development by antenatal magnesium sulphate for infants born preterm.

Cerebral palsy (CP) remains the most significant neurological disorder associated with preterm birth. It disrupts quality of life and places huge cost burdens on society. Antenatal magnesium sulphate administration to females before 32 weeks' gestation has proven to be an effective intervention to reduce the rate of CP. In models of hypoxia, hypoxia-ischemia, inflammation, and excitotoxicity in various animal species, magnesium sulphate preconditioning decreased the resulting lesion sizes and inflammatory cytokine levels, prevented cell death, and improved long-term cognitive and motor behaviours. In humans, meta-analyses of five randomized controlled trials using magnesium sulphate as a neuroprotectant showed prevention of CP at 2 years. The benefit remained consistent regardless of gestational age, cause of preterm birth, and total dose received. Antenatal magnesium sulphate treatment is now recommended by the World Health Organization and by many obstetric societies. Its cost-effectiveness further justifies its widespread implementation. WHAT THIS PAPER ADDS: Neuroprotective effect of magnesium sulphate to reduce cerebral palsy in infants born preterm when administered to females at risk of imminent preterm birth. Neuroprotection regardless of gestational age, cause of preterm birth, and total dose. Antenatal magnesium sulphate treatment has good cost-effectiveness.

Magnesium sulfate and fetal neuroprotection: overview of clinical evidence.

Antenatal administration of magnesium sulfate is an important part of the neuroprotective strategy for preterm infants. Strong evidence from five randomized controlled trials and five meta-analyses has demonstrated that magnesium sulfate, when administered before preterm delivery, significantly reduces the risk of cerebral palsy at two years. Through secondary analyses of randomized controlled trials and other original clinical studies, this state-of-the-art review highlights the absence of serious adverse effects in both pregnant women and neonates, as well as the impact of maternal body mass index and preeclamptic status on the maternal and neonatal magnesium levels, which could influence the magnitude of the neuroprotective effect. Although antenatal magnesium sulfate is a cost-effective strategy, some practice surveys have demonstrated that the use of magnesium sulfate is not sufficient and that its use is heterogeneous, differing among different maternity wards. Since 2010, an increasing number of obstetrical societies have recommended its use to improve the neurological outcomes of preterm infants, especially the International Federation of Gynecology and Obstetrics and World Health Organization in 2015, and France in 2017. Considering the neuroprotective impact of magnesium sulfate when administered before delivery, postnatal administration should be considered, and its effects should be assessed using randomized controlled trials.

Fetal Neuroprotection by Magnesium Sulfate: From Translational Research to Clinical Application.

Despite improvements in perinatal care, preterm birth still occurs regularly and the associated brain injury and adverse neurological outcomes remain a persistent challenge. Antenatal magnesium sulfate administration is an intervention with demonstrated neuroprotective effects for preterm births before 32 weeks of gestation (WG). Owing to its biological properties, including its action as an N-methyl-d-aspartate receptor blocker and its anti-inflammatory effects, magnesium is a good candidate for neuroprotection. In hypoxia models, including hypoxia-ischemia, inflammation, and excitotoxicity in various species (mice, rats, pigs), magnesium sulfate preconditioning decreased the induced lesions' sizes and inflammatory cytokine levels, prevented cell death, and improved long-term behavior. In humans, some observational studies have demonstrated reduced risks of cerebral palsy after antenatal magnesium sulfate therapy. Meta-analyses of five randomized controlled trials using magnesium sulfate as a neuroprotectant showed amelioration of cerebral palsy at 2 years. A meta-analysis of individual participant data from these trials showed an equally strong decrease in cerebral palsy and the combined risk of fetal/infant death and cerebral palsy at 2 years. The benefit remained similar regardless of gestational age, cause of prematurity, and total dose received. These data support the use of a minimal dose (e.g., 4 g loading dose ± 1 g/h maintenance dose over 12 h) to avoid potential deleterious effects. Antenatal magnesium sulfate is now recommended by the World Health Organization and many pediatric and obstetrical societies, and it is requisite to maximize its administration among women at risk of preterm delivery before 32 WG.

Antenatal magnesium sulphate administration for fetal neuroprotection: a French national survey.

BACKGROUND: Magnesium sulphate (MgSO4) is the only treatment approved for fetal neuroprotection. No information on its use is available in the absence of a national registry of neonatal practices. The objective of our study was to evaluate the use of MgSO4 for fetal neuroprotection in French tertiary maternity hospitals (FTMH). METHODS: Online and phone survey of all FTMH between August 2014 and May 2015. A participation was expected from one senior obstetrician, one senior anaesthetist and one senior neonatologist from each FTMH. Information was obtained from 63/63 (100%) FTMH and 138/189 (73%) physicians. Use of MgSO4 for fetal neuroprotection, regimen and injection protocols, reasons for non-use were the main outcome measures. RESULTS: 60.3% of FTMH used MgSO4 for fetal neuroprotection. No significant difference was observed between university and non-university hospitals or according to the annual number of births. Protocols differed especially in terms of the maximum gestational age (3% <28 WG, 71% <33 WG, 18% <34 WG and 8% < 35 WG). Eighty seven percent of centers using MgSO4 prescribed retreatment when necessary, but according to non-consensual modalities in terms of number of treatments or between-treatment intervals. Injections and monitoring were mostly performed in the delivery room (97%) but also in the recovery room in one half of hospitals. Lack of experience (52%), absence of a written protocol (49%) and national guidelines (46%) were the reasons most commonly reported to explain non-use of MgSO4 as a neuroprotective agent. CONCLUSIONS: Sixty percent of FTMH used MgSO4 for fetal neuroprotection, but according to heterogeneous regimens. National guidelines could allow standardization of practices and better MgSO4 coverage.

Experimental and clinical evidence of differential effects of magnesium sulfate on neuroprotection and angiogenesis in the fetal brain.

Clinical studies showed beneficial effects of magnesium sulfate regarding the risk of cerebral palsy. However, regimen protocols fluctuate worldwide and risks of adverse effects impacting the vascular system have been reported for human neonates, keeping open the question of the optimal dosing. Using clinically relevant concentrations and doses of magnesium sulfate, experiments consisted of characterizing, respectively, ex vivo and in vivo, the effects of magnesium sulfate on the nervous and vascular systems of mouse neonates by targeting neuroprotection, angiogenesis, and hemodynamic factors and in measuring, in human fetuses, the impact of a 4-g neuroprotective loading dose of magnesium sulfate on brain hemodynamic parameters. Preclinical experiments using cultured cortical slices from mouse neonates showed that the lowest and highest tested concentrations of magnesium sulfate were equally potent to prevent excitotoxic-induced cell death, cell edema, cell burst, and intracellular calcium increase, whereas no side effects were found regarding apoptosis. In contrast, in vivo data revealed that magnesium sulfate exerted dose-dependent vascular effects on the fetal brain. In particular, it induced brain hypoperfusion, stabilization of Hif-1α, long-term upregulation of VEGF-R2 expression, impaired endothelial viability, and altered cortical angiogenesis. Clinically, in contrast to 6-g loading doses used in some protocols, a 4-g bolus of magnesium sulfate did not altered fetal brain hemodynamic parameters. In conclusion, these data provide the first mechanistic evidence of double-sword and dose-dependent actions of magnesium sulfate on nervous and vascular systems. They strongly support the clinical use of neuroprotection protocols validated for the lowest (4-g) loading dose of magnesium sulfate.

The antiapoptotic effect of remifentanil on the immature mouse brain: an ex vivo study.

BACKGROUND: The use of remifentanil in a context of potential prematurity led us to explore ex vivo the opioid effects on the immature mouse brain. Remifentanil enhances medullary glutamatergic N-methyl-D-aspartate (NMDA) receptor activity. Furthermore, in neonatal mouse cortex, NMDA was previously shown to exert either excitotoxic or antiapoptotic effects depending on the cortical layers. With the use of a model of acute cultured brain slices, we evaluated the potential necrotic and apoptotic effects of remifentanil, alone or associated with its glycine vehicle (commercial preparation of remifentanil, C.P. remifentanil), on the immature brain. METHODS: Cerebral slices from postnatal day 2 mice were treated up to 5 hours with the different compounds, incubated alone or in the presence of NMDA. The necrotic effect was studied by measuring lactate dehydrogenase activity and 7-Aminoactinomycin D labeling. Apoptotic death was evaluated by measurement of caspase-3 activity and cleaved caspase-3 protein levels, using Western blot and immunohistochemistry. Extrinsic and intrinsic apoptotic pathways were investigated by measuring caspase-8, caspase-9 activities, Bax protein levels, and mitochondrial integrity. RESULTS: C.P. remifentanil was ineffective on necrotic death, whereas it significantly reduced caspase-3 activity and cortical cleaved caspase-3 levels. C.P. remifentanil inhibited cortical Bax protein expression, caspase-9 activity, and preserved mitochondrial integrity, whereas it had no effect on caspase-8 activity. Its action targeted the neocortex superficial layers, and it was reversed by the opioid receptors antagonist naloxone and the NMDA antagonist MK801. Remifentanil and glycine acted synergistically to inhibit apoptotic death. In addition, C.P. remifentanil enhanced the antiapoptotic effect of NMDA, whereas it did not improve NMDA excitotoxicity in brain slices. CONCLUSION: The present data indicate that at a supraclinical concentration C.P. remifentanil had no pronecrotic effect but exerted ex vivo antiapoptotic action on the immature mouse brain, involving the opioid and NMDA receptors, and the mitochondrial-dependent apoptotic pathway. Assessment of the impact of the antiapoptotic effect of remifentanil in in vivo neonatal mouse models of brain injury will also be essential to measure its consequences on the developing brain.