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.

Early treatment of neonatal diabetes with oral glibenclamide in an extremely preterm infant.

Early treatment of neonatal diabetes with sulfonylureas has been proven to produce marked improvements of neurodevelopment, beside the demonstrated efficacy on glycemic control. Several barriers still prevent an early treatment in preterm babies including the limited availability of suitable galenic form of glibenclamide. We adopted oral glibenclamide suspension (Amglidia) for the early treatment of neonatal diabetes due to an homozygous variant of KCNJ11 gene c.10C>T [p.Arg4Cys] in an extremely preterm infant born at 26 + 2 weeks' of gestational age. After ~6 weeks of insulin treatment with a low glucose intake (4.5 g/kg/day), the infant was switched to Amglidia 6 mg/ml diluted in maternal milk, via nasogastric tube (0.2 mg/kg/day) progressively reduced to 0.01 mg/kg/day (after ~3 months). While on glibenclamide, the patient exhibited a mean daily growth of 11 g/kg/day. The treatment was suspended at month 6 of birth (weight 4.9 kg [5th-10th centile], M3 of c.a.) for normalization of glucose profile. During the treatment, the patient exhibited a stable glucose profile within the range of 4-8 mmol/L in the absence of hypo or hyperglycemic episodes with 2-3 blood glucose tests per day. The patient was diagnosed with retinopathy of prematurity Stade II in Zone II without plus disease at 32 weeks, with progressive regression and complete retinal vascularization at 6 months of birth. Amglidia could be regarded as the specific treatment for neonatal diabetes even in preterm babies due to its beneficial effect on the metabolic and neurodevelopmental side.

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.

Association of serum angiogenic factors with bronchopulmonary dysplasia. The ANGIODYS cohort study.

OBJECTIVES: Angiogenic factors may be involved in lung development. To evaluate the relations between maternal and cord blood angiogenic factors (sFlt-1, placental growth factor [PlGF], soluble endogline [sEng], transforming growth factor ß [TGF-beta]) and their association with moderate and severe bronchopulmonary dysplasia (BPD) in very preterm growth-restricted infants. STUDY DESIGN: Prospective monocentric cohort study. Twenty-four mother-child dyads featuring antepartum preeclampsia, intra-uterine growth restriction (IUGR) and birth before 30 weeks' gestation were included. This ensured a 80% power to test whether sFlt-1 maternal levels would be twice as high in cases of BPD as in the absence of BPD. MAIN OUTCOME MEASURES: Four pro/anti-angiogenic factors from two pathways (sFlt-1, PlGF and sEng, TGF-beta) were measured in maternal serum before delivery (at the time of hospitalization or the day of birth) and in neonates' cord blood. Neonatal outcome was moderate to severe BPD, defined as oxygen requirement for at least 28 days and persistent need for oxygen or ventilatory support at 36 weeks' postmenstrual age. RESULTS: sFlt-1 levels were positively correlated in maternal serum and cord blood (rs = 0.83, p < .001) but levels of PlGF and TGF-beta and its receptor sEng were not. Among all the factors studied in cord and maternal blood, none was associated with BPD. CONCLUSIONS: In IUGR preterm babies born before 30 weeks' gestation from preeclamptic mothers, serum sFlt-1, PlGF and sEng, TGF-ß levels were not correlated with BPD. The increased BPD risk in preterm neonates born from preeclamptic mothers cannot be related to high sFlt-1 levels.

Effectiveness and efficiency of tele-expertise for improving access to retinopathy screening among 351 neonates in a secondary care center: An observational, controlled before-after study.

In France, secondary care hospitals encounter difficulties to adhere to retinopathy of prematurity (ROP) screening guidelines. Our objective was to assess the effectiveness and efficacy of a tele-expertise program for ROP screening in neonatal intensive care units without on-site ophthalmologists. We evaluated the impact of a tele-expertise program funded by the Paris Region Health Authority in a secondary care center general hospital of the Paris Region (CHSF), where there was previously no on-site ophthalmologist. We performed an observational, controlled before-after study, with a university tertiary care center with on-site ophthalmologists (Port-Royal) as the control group. Recruitment and data collection for both periods took place from 1 January 2012 to 31 December 31 2012, and from 1 January 2014 to 31 March 2015. The primary endpoint was the percentage of compliance with screening guidelines, secondary endpoints included pain scores and costs. Over the two periods, at total of 351 infants were recruited in the CHSF. Implementation of the tele-expertise resulted in an absolute +57.3% increase in the proportion of examinations realized in accordance with guidelines (3.8% during the "before" period and 61.1% during the "after" period, p<0.001). As compared with the control group, the proportion of infants appropriately screened improved (57.5% versus 43.1%, p = 0.002); median pain score on the acute pain rating scale for neonates during examination was significantly higher (median score 5.5/10, range [2.5-5.7] versus 2.0/10, range [1.0-3.1], p = 0.002). Screening rates in the control group remained unchanged. The average cost per examination increased from €337 in the "before" period to €353 in the "after period" in the tele-expertise group. The implementation of tele-expertise for ROP screening in the CHSF medical center resulted in a major improvement of access to care with a small cost increase. The issue of pain control during examination with tele-expertise should be further addressed.

Bronchopulmonary dysplasia in neonates born to mothers with preeclampsia: Impact of small for gestational age.

BACKGROUND AND OBJECTIVES: Small for gestational age and preeclampsia have both been described as risk factors for bronchopulmonary dysplasia in preterm neonates, but their respective role in the occurrence of bronchopulmonary dysplasia is debated. We evaluated the relation between small for gestational age and bronchopulmonary dysplasia in neonates born to mothers with preeclampsia. We hypothesized that low birth weight is still associated with bronchopulmonary dysplasia in this homogeneous population. METHODS: Retrospective single-center cohort study including 141 neonates born between 24 and 30 weeks' gestation to mothers with preeclampsia. The main outcome measure was moderate to severe bronchopulmonary dysplasia at 36 weeks' postmenstrual age. Neonates born small for gestational age (birthweight < 10th percentile on the AUDIPOG curves) were compared to those with appropriate birthweight for gestational age by bivariable analyses and logistic regression models, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Bronchopulmonary dysplasia rates were 61.5% (32/52) and 27.4% (20/73) for small for gestational age and appropriate birthweight for gestational age neonates (p < .001). On adjustment for gestational age and other confounding factors, the risk of moderate to severe bronchopulmonary dysplasia was greater for small for gestational age than appropriate birthweight for gestational age neonates (adjusted OR = 5.9, 95% CI [2.2-15.4]), as was the composite outcome death or moderate to severe bronchopulmonary dysplasia (adjusted OR = 4.7, 95% CI [1.9-11.3]). CONCLUSIONS: Small for gestational age was associated with bronchopulmonary dysplasia in very preterm neonates born to mothers with preeclampsia. REGISTRATION NUMBER: CNIL no. 1747084.

Efficacy of a first course of Ibuprofen for patent ductus arteriosus closure in extremely preterm newborns according to their gestational age-specific Z-score for birth weight.

OBJECTIVE: Therapeutic strategies for patent ductus arteriosus (PDA) in very preterm infants remain controversial. To identify infants likely to benefit from treatment, we analysed the efficacy of a first course of ibuprofen in small-for-gestational age (SGA) newborns. STUDY DESIGN: This single-centre retrospective study included 185 infants born at 24+0-27+6 weeks of gestation with haemodynamically significant PDA, who were treated by intravenous ibuprofen (Pedea): 10 mg/kg on day one and 5 mg/kg on days two and three. Birth weight and gestational age (GA) were analysed with reference to the standard deviations from the Olsen growth curve to define GA-specific Z-scores for birth weights. The efficacy of treatment was evaluated by echocardiography 48 hours after the last dose of ibuprofen. The primary outcome was failure of the first course of ibuprofen associated in a composite criterion with the most severe outcomes. RESULTS: The risk of treatment failure increased according to a continuous gradient in SGA neonates. A higher risk was observed on multiple regression analysis (crude OR: 3.8; 95% CI [1.2-12.3] p = 0.02; adjusted OR: 12.8; 95% CI [2.3-70.5] p=0.003). CONCLUSION: There is a linear relationship between infant birth weight and PDA treatment: the failure rate of a first course of ibuprofen increases with increasing degree of growth restriction.

Conservative management of an advanced abdominal pregnancy at 22 weeks.

Objective We report an uneventful conservative approach of an advanced abdominal pregnancy discovered at 22 weeks of gestation. Study Design This study is a case report. Results Attempting to extend gestation of an advanced abdominal pregnancy is not a common strategy and is widely questioned. According to the couple's request, the management consisted in continuous hospitalization, regular ultrasound scan, and antenatal corticosteroids. While the woman remained asymptomatic, surgery was planned at 32 weeks, leading to the birth of a preterm child without any long-term complications. Placenta was left in situ with a prophylactic embolization, and its resorption was monitored. Conclusion Depending on multidisciplinary cares and agreement of the parents, when late discovered, prolonging advanced abdominal pregnancy appears to be a reasonable option.

A risk-adapted study of cisplatin and etoposide, with or without ifosfamide, in patients with metastatic seminoma: results of the GETUG S99 multicenter prospective study.

BACKGROUND: Whether patients with good prognosis and intermediate/poor prognosis advanced seminoma should be treated differently has not been defined. OBJECTIVE: To assess a risk-adapted chemotherapy regimen in patients with advanced seminoma. DESIGN, SETTING, AND PARTICIPANTS: A total of 132 patients were included in this prospective study. Patients with a good prognosis according to the International Germ Cell Cancer Collaboration Group (IGGCCG) were treated with four cycles of cisplatin-etoposide (EP). Patients with an intermediate prognosis according to the IGCCCG (or a poor prognosis according to the Medical Research Council classification) were treated with four cycles of VIP (EP and ifosfamide) and granulocyte colony-stimulating factor (G-CSF). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Survival curves were estimated using the Kaplan-Meier method. RESULTS AND LIMITATIONS: The median follow-up was 4.5 yr (range: 0.4-11.6 yr). Among 108 patients (82%) with a good prognosis who received EP, grade 3-4 toxicity included neutropenia (47%) and neutropenic fever (12%). Among the 24 patients (18%) with an intermediate/poor prognosis who received VIP plus G-CSF, toxicity included grade 3-4 neutropenia (36%), neutropenic fever (23%), thrombocytopenia (23%), anemia (23%), and a toxicity-related death (n=1; 4%). The 3-yr progression-free survival (PFS) rate was 93% (range: 85-97%) in the good prognosis group and 83% (range: 63-93%) in the intermediate/poor prognosis group (p=0.03 for PFS). The 3-yr overall survival (OS) rate was 99% (range: 92-100%) and 87% (range: 67-95%), respectively (p<0.005 for OS). Only four patients died of seminoma or its treatment. CONCLUSIONS: A risk-adapted chemotherapy policy for advanced seminoma yielded an excellent outcome with a 3-yr OS rate of 96%.

Metastatic Medulloblastoma in Childhood: Chang's Classification Revisited.

Purpose. To correlate the radiological aspects of metastases, the response to chemotherapy, and patient outcome in disseminated childhood medulloblastoma. Patients and Methods. This population-based study concerned 117 newly diagnosed children with disseminated medulloblastoma treated at the Institute Gustave Roussy between 1988 and 2008. Metastatic disease was assessed using the Chang staging system, their form (positive cerebrospinal fluid (CSF), nodular or laminar), and their extension (positive cerebrospinal fluid, local, extensive). All patients received preirradiation chemotherapy. Results. The overall survival did not differ according to Chang M-stage. The 5-year overall survival was 59% in patients with nodular metastases compared to 35% in those with laminar metastases. The 5-year overall survival was 76% in patients without disease at the end of pre-irradiation chemotherapy compared to 34% in those without a complete response (P = 0.0008). Conclusions. Radiological characteristics of metastases correlated with survival in patients with medulloblastoma. Complete response to sandwich chemotherapy was a strong predictor of survival.