An educational programme in neonatal intensive care units (SEPREVEN): a stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: Patients in neonatal intensive care units (NICUs) are at high risk of adverse events. The effects of medical and paramedical education programmes to reduce these have not yet been assessed. METHODS: In this multicentre, stepped-wedge, cluster-randomised controlled trial done in France, we randomly assigned 12 NICUs to three clusters of four units. Eligible neonates were inpatients in a participating unit for at least 2 days, with a postmenstrual age of 42 weeks or less on admission. Each cluster followed a 4-month multifaceted programme including education about root-cause analysis and care bundles. The primary outcome was the rate of adverse events per 1000 patient-days, measured with a retrospective trigger-tool based chart review masked to allocation of randomly selected files. Analyses used mixed-effects Poisson modelling that adjusted for time. This trial is registered with ClinicalTrials.gov, NCT02598609. FINDINGS: Between Nov 23, 2015, and Nov 2, 2017, event rates were analysed for 3454 patients of these 12 NICUs for 65 830 patient-days. The event rate per 1000 patient-days reduced significantly from the control to the intervention period (33·9 vs 22·6; incidence rate ratio 0·67; 95% CI 0·50-0·88; p=0·0048). INTERPRETATION: A multiprofessional safety-promoting programme in NICUs reduced the rate of adverse events and severe and preventable adverse events in highly vulnerable patients. This programme could significantly improve care offered to critically ill neonates. FUNDING: Solidarity and Health Ministry, France.

Usefulness of routine early œsophagogram after primary repair of œsophageal atresia: a multicenter study.

BACKGROUND: Advances in surgical and neonatal care have led to improved survival of patients with œsophageal atresia (OA) over time. Morbidity remains significant, with one-third of patients being affected by a postoperative complication. Several aspects of management are not consensual, such as the use of œsophagogram before starting oral feeding. METHODS: We conducted a multicenter retrospective study, including all children with OA that underwent a primary anastomosis in the first days of life, between 2012 and 2018 in five French centers, to determine the usefulness of postoperative œsophagogram during the 10 days after early primary repair of OA to diagnose the anastomotic leak and congenital œsophageal stenosis. RESULTS: Among 225 included children, 90 (40%) had a routine œsophagogram and 25 (11%) had an anastomotic leak, clinically diagnosed before the scheduled œsophagogram in 24/25 (96%) children at median postoperative day 4. Ten patients had associated congenital œsophageal stenosis diagnosed on the œsophagogram in only 30% of cases. CONCLUSION: Early œsophagogram is rarely useful in the diagnosis of an anastomotic leak, which is clinically diagnosed before performing an œsophagogram in the majority of cases. The need for a postoperative œsophagogram should be evaluated on a case-by-case basis. IMPACT: Early œsophagogram is not helpful in the diagnosis of an anastomotic leak in the majority of cases. An anastomotic leak is most often diagnosed clinically before performing an œsophagogram. Early postoperative œsophagogram could be helpful for the diagnosis of congenital œsophageal stenosis. However, dysphagia occurs later and early diagnosis of congenital œsophageal stenosis has no impact on the management and outcome of asymptomatic children. Indication of postoperative œsophagogram has to be evaluated on a case-by-case basis.

Exome sequencing of extreme phenotypes in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants with growing evidence that genetic factors contribute largely to moderate and severe cases. We assessed by exome sequencing if rare genetic variants could account for extremely severe phenotypes. We selected 6 infants born very preterm with severe bronchopulmonary dysplasia and 8 very preterm born controls for exome sequencing. We filtered whole exome sequencing results to include only rare variants and selected variants and/or genes with variants that were present in at least 2 cases and absent in controls. We selected variants, all heterozygous, in 9 candidate genes, 7 with a putative role in lung development and 2 that displayed 3 variations in 3 different cases, independently of their potential role in lung development. Sequencing of 5 other severe cases for these variants did not replicate our results.Conclusion: In selected preterm born infants with severe bronchopulmonary dysplasia and controls, we failed to find any rare variant shared by several infants with an extremely severe phenotype. Our results are not consistent with the role of rare causative variants in bronchopulmonary dysplasia's development and argue for the highly polygenic nature of susceptibility of this disorder.What is Known:• Bronchopulmonary dysplasia is a multifactorial disease resulting from complex environmental and genetic interactions occurring in an immature lung.• It is not known whether rare genetic variants in coding regions could account for extreme phenotypes of the disease.What is New:• In a group of infants with an extreme phenotype of bronchopulmonary dysplasia and in comparison to controls, no common genetic variants were found, nor did variants that were select in other exome studies in this setting.• These results argue for the highly polygenic nature of susceptibility of bronchopulmonary dysplasia.

Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial.

OBJECTIVES: Most studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO. METHODS: A 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life. RESULTS: A total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes. CONCLUSIONS: iNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.

Melatonin Levels in Preterm and Term Infants and Their Mothers.

The prevention of perinatal brain damage following preterm birth remains a public health priority. Melatonin has been shown to be a promising neuroprotectant in neonatal preclinical models of brain damage, but few studies have investigated melatonin secretion in newborns. We hypothesized that melatonin circulating levels would be lower in preterm compared to term infants. We conducted a prospective, longitudinal, multicenter study to assess melatonin, and 6-sulfatoxy-melatonin (aMT6s) concentrations, measured by radioimmunoassay. Among 209 neonates recruited, 110 were born before 34 gestational weeks (GW) and 99 born after 34 GW. Plasma melatonin concentrations, measured at birth and on Day 3 were below detectable levels (≤7 pg/mL) in 78% and 81%, respectively, of infants born before 34 GW compared to 57% and 34%, respectively, of infants born after 34 GW. The distribution of plasma melatonin concentrations was found to be correlated with gestational age at both time-points (p < 0.001). Median urine aMT6s concentrations were significantly lower in infants born before 34 GW, both on Day 1 (230 ng/L vs. 533 ng/L, p < 0.0001) and on Day 3 (197 ng/L vs. 359 ng/L, p < 0.0001). In conclusion, melatonin secretion appears very low in preterm infants, providing the rationale for testing supplemental melatonin as a neuroprotectant in clinical trials.

Is melatonin ready to be used in preterm infants as a neuroprotectant?

The prevention of neurological disabilities following preterm birth remains a major public health challenge and efforts are still needed to test the neuroprotective properties of candidate molecules. Melatonin serves as a neuroprotectant in adult models of cerebral ischemia through its potent antioxidant and anti-inflammatory effects. An increasing number of preclinical studies have consistently demonstrated that melatonin protects the damaged developing brain by preventing abnormal myelination and an inflammatory glial reaction, a major cause of white matter injury. The main questions asked in this review are whether preclinical data on the neuroprotective properties of melatonin are sufficient to translate this concept into the clinical setting, and whether melatonin can reduce white matter damage in preterm infants. This review provides support for our view that melatonin is now ready to be tested in human preterm neonates, and discusses ongoing and planned clinical trials.

Premedication for neonatal endotracheal intubation: results from the epidemiology of procedural pain in neonates study.

OBJECTIVES: To describe the frequency and nature of premedications used prior to neonatal endotracheal intubation; to confront observed practice with current recommendations; and to identify risk factors for the absence of premedication. DESIGN, SETTING, AND PATIENTS: Data concerning intubations were collected prospectively at the bedside as part of an observational study collecting around-the-clock data on all painful or stressful procedures performed in neonates during the first 14 days of their admission to 13 tertiary care units in the region of Paris, France, between 2005 and 2006. INTERVENTION: Observational study. MEASUREMENTS AND MAIN RESULTS: Specific premedication prior to endotracheal intubation was assessed. Ninety one intubations carried out on the same number of patients were analyzed. The specific premedication rate was 56% and included mostly opioids (67%) and midazolam (53%). Compared with recent guidance from the American Academy of Pediatrics, used premedications could be classified as "preferred" (12%), "acceptable" (18%), "not recommended" (27%), and "not described" (43%). In univariate analysis, infants without a specific premedication compared with others were younger at the time of intubation (median age: 0.7 vs. 2.0 days), displayed significantly more frequent spontaneous breathing at the time of intubation (31% vs. 12%) and a higher percentage of analgesia for all other painful procedures (median values: 16% vs. 6%). In multivariate analysis, no factor remained statistically significant. CONCLUSIONS: Premedication use prior to neonatal intubation was not systematically used and when used it was most frequently inconsistent with recent recommendations. No patient- or center-related independent risk factor for the absence of premedication was identified in this study.

Humidity during high-frequency oscillatory ventilation compared to intermittent positive pressure ventilation in extremely preterm neonates: An in vitro and in vivo observational study.

BACKGROUND: Inappropriate humidification of inspired gas during mechanical ventilation can impair lung development in extremely low birthweight (ELBW) infants. Humidification depends on multiple factors, such as the heater-humidifier device used, type of ventilation, and environmental factors. Few studies have examined inspired gas humidification in these infants, especially during high-frequency oscillatory ventilation (HFOV). Our objective was to compare humidity during HFOV and intermittent positive pressure ventilation (IPPV), in vitro and in vivo. METHODS: In vitro and in vivo studies used the same ventilator during both HFOV and IPPV. The bench study used a neonatal test lung and two heater-humidifiers with their specific circuits; the in vivo study prospectively included preterm infants born before 28 weeks of gestation. RESULTS: On bench testing, mean absolute (AH) and relative (RH) humidity values were significantly lower during HFOV than IPPV (RH = 79.4 ± 8.1% vs. 89.0 ± 6.2%, p < 0.001). Regardless of the ventilatory mode, mean RH significantly differed between the two heater-humidifiers (89.6 ± 6.7% vs 78.7 ± 6.8%, p = 0.003). The in vivo study included 10 neonates (mean ± SD gestational age: 25.7 ± 0.9 weeks and birthweight: 624.4 ± 96.1 g). Mean RH during HFOV was significantly lower than during IPPV (74.6 ± 5.7% vs. 83.0 ± 6.7%, p = 0.004). CONCLUSION: RH was significantly lower during HFOV than IPPV, both in vitro and in vivo. The type of heater-humidifier also influenced humidification. More systematic measurements of humidity of inspired gas, especially during HFOV, should be considered to optimize humidification and consequently lung protection in ELBW infants.

Instrumental dead space: A glass ceiling for extremely low birth weight preterm infants? A dead space washout bench study.

BACKGROUND: When ventilating extremely low birth weight infants, clinicians face the problem of instrumental dead space, which is often larger than tidal volume. Hence, aggressive ventilation is necessary to achieve CO2 removal. Continuous tracheal gas insufflation can wash out CO2 from dead space and might also have an impact on O2 and water vapor transport. The objective of this bench study is to test the impact of instrumental dead space on the transport of CO2 , O2 , and water vapor and the ability of continuous tracheal gas insufflation to remedy this problem during small tidal volume ventilation. METHODS: A test-lung located in an incubator at 37°C was ventilated with pressure levels needed to reach different tidal volumes from 1.5 to 5 mL. End-tidal CO2 at the test-lung exit, O2 concentration, and relative humidity in the test-lung were measured for each tidal volume with and without a 0.2 L/min continuous tracheal gas insufflation flow. RESULTS: CO2 clearance was improved by continuous tracheal gas insufflation allowing a 28%-44% of tidal volume reduction. With continuous tracheal gas insufflation, time to reach desired O2 concentration was reduced from 20% to 80% and relative humidity was restored. These results are inversely related to tidal volume and are particularly critical below 3 mL. CONCLUSION: For the smallest tidal volumes, reduction of instrumental dead space seems mandatory for CO2 , O2 , and water vapor transfer. Continuous tracheal gas insufflation improved CO2 clearance, time to reach desired O2 concentration and humidification of airways and, thus, may be an option to protect lung development.

Determinants of morbidity and mortality related to health care-associated primary bloodstream infections in neonatal intensive care units: a prospective cohort study from the SEPREVEN trial.

Background: Health care-associated primary bloodstream infections (BSIs), defined as not secondary to an infection at another body site, including central line-associated BSI, are a leading cause of morbidity and mortality in patients in neonatal intensive care units (NICUs). Our objective was to identify factors associated with severe morbidity and mortality after these infections in neonates in NICUs. Methods: This ancillary study of the SEPREVEN trial included neonates hospitalized ≥2 days in one of 12 French NICUs and with ≥ 1 BSI during the 20-month study period. BSIs (all primary and health care-associated) were diagnosed in infants with symptoms suggestive of infection and classified prospectively as possible (one coagulase-negative staphylococci (CoNS)-growing blood culture) or proven (two same CoNS, or ≥1 recognized pathogen-growing blood culture). BSI consequences were collected prospectively as moderate morbidity (antibiotic treatment alone) or severe morbidity/mortality (life-saving procedure, permanent damage, prolonged hospitalization, and/or death). Results: Of 557 BSIs identified in 494 patients, CoNS accounted for 378/557 (67.8%) and recognized bacterial or fungal pathogens for 179/557 (32.1%). Severe morbidity/mortality was reported in 148/557 (26.6%) BSIs. Independent factors associated with severe morbidity/mortality were corrected gestational age <28 weeks (CGA) at infection (P < .01), fetal growth restriction (FGR) (P = .04), and proven pathogen-related BSI vs. CoNS-related BSI (P < .01). There were no differences in severe morbidity and mortality between proven and possible CoNS BSIs. In possible BSI, S. epidermidis was associated with a lower risk of severe morbidity than other CoNS (P < .01), notably S. capitis and S. haemolyticus. Conclusions: In BSIs in the NICU, severe morbidity/mortality was associated with low CGA at infection, FGR, and proven pathogen-related BSIs. When only one blood culture was positive, severe morbidity/mortality were less frequent if it grew with S. epidermidis compared to other CoNS. Further studies to help distinguish real CoNS BSIs from contaminations are needed. Study registration: ClinicalTrials.gov (NCT02598609).

Perinatal risk factors for bronchopulmonary dysplasia in extremely low gestational age infants: a pregnancy disorder-based approach.

OBJECTIVE: To analyze risk factors for bronchopulmonary dysplasia (BPD) or death according to the condition leading to extremely preterm birth, preterm labor, or vascular disorders. STUDY DESIGN: Retrospective study of all premature births before 28 weeks of gestation in a single Level III institution. Mother/infants were attributed to the "preterm labor" or "vascular disorder" group according to the condition leading to delivery. Characteristics and outcomes were compared between groups. Independent risk factors for BPD or the composite outcome "BPD or death" were identified within each group. RESULTS: Three hundred ninety-six infants from 349 pregnancies were characterized for perinatal characteristics. BPD was significantly more frequent in the vascular disease group than in the preterm labor group (29% vs 11%, P < .01). Independent risk factors of BPD were a low gestational age in the preterm labor group and severe growth restriction in the vascular disease group. CONCLUSION: Classification of preterm birth according to the condition leading to delivery might help to reduce confounding of risk factors for BPD. Intrauterine vascular disorders are significantly associated with BPD.

Patient-Ventilator Synchrony in Extremely Premature Neonates during Non-Invasive Neurally Adjusted Ventilatory Assist or Synchronized Intermittent Positive Airway Pressure: A Randomized Crossover Pilot Trial.

INTRODUCTION: Synchronization of non-invasive ventilation is challenging in extremely premature infants. We compared patient-ventilator synchrony between non-invasive neurally adjusted ventilatory assist (NIV-NAVA) using transdiaphragmatic (Edi) catheter and synchronized intermittent positive airway pressure (SiPAP) using an abdominal trigger. METHODS: This study was a monocentric, randomized, crossover trial in premature infants born before 28 weeks of gestation, aged 3 days or more, and below 32 weeks postmenstrual age. NIV-NAVA and SiPAP were applied in a random order for 2 h with analysis of data from the second hour. The primary outcome was the asynchrony index. RESULTS: Fourteen patients were included (median [IQR] gestational age at birth 25.6 (25.3-26.4) weeks, median [IQR] birth weight 755 [680-824] g, median [IQR] postnatal age 26.5 [19.8-33.8] days). The median (IQR) asynchrony index was significantly lower in NIV-NAVA versus SiPAP (49.9% [44.1-52.6] vs. 85.8% [74.2-90.9], p < 0.001). Ineffective efforts and auto-triggering were significantly less frequent in NIV-NAVA versus SiPAP (3.0% vs. 32.0% p < 0.001 and 10.0% vs. 26.6%, p = 0.004, respectively). Double triggering was significantly less frequent in SiPAP versus NIV-NAVA (0.0% vs. 9.0%, p < 0.001). No significant difference was observed for premature cycling and late cycling. Peak Edi and swing Edi were significantly lower in NIV-NAVA as compared to SiPAP (7.7 [6.1-9.9] vs. 11.0 [6.7-14.5] µV, p = 0.006; 5.4 [4.2-7.6] vs. 7.6 [4.3-10.8] µV, p = 0.007, respectively). No significant difference was observed between NIV-NAVA and SiPAP for heart rate, respiratory rate, COMFORTneo scores, apnoea, desaturations, or bradycardias. DISCUSSION/CONCLUSION: NIV-NAVA markedly improves patient-ventilator synchrony as compared to SiPAP in extremely premature infants.

Continuous intravenous to oral morphine switch in very premature ventilated infants: A retrospective study on efficacy, efficiency, and tolerability.

Background: Continuous intravenous (IV) morphine is commonly used in ventilated neonates. Oral route is theoretically feasible but data on oral morphine in ventilated premature infants are lacking. Objective: To assess the efficacy, efficiency, and tolerability of a continuous intravenous to oral morphine switch protocol. Design: Retrospective study. Setting: Single level III center's neonatal intensive care unit. Patients: Ventilated premature infants hospitalized in the NICU in 2016 and 2017, receiving continuous IV morphine with an expected ventilation course of at least 72 more hours. We excluded patients treated for withdrawal syndrome or palliative care. Interventions: Continuous IV to oral morphine switch with the same initial cumulated daily dose. Main outcome measures: Pain scores (ComfortNeo scale) and morphine doses were analyzed over time using Friedman's test in the 24 hours preceding and the 48 hours following the oral switch. Adverse effects attributable to opioids were collected. Results: Seventeen infants were included with a median [IQR] gestational age at birth of 25.9 [24.6-26.9] weeks and a median postnatal age at oral switch of 30 [22-36] days. One patient's intravenous treatment had to be resumed because of a high ComfortNeo score. All others remained on oral morphine. No significant change over time was observed for ComfortNeo scores (P = .15). Median [IQR] doses were 13.5 [10-20] µg/kg/h in the IV period and significantly increased to 15 [10-25] µg/kg/h in the oral period (P = .009). No short-term respiratory, digestive, or urinary adverse event was observed. After a median [IQR] duration of 13 [4-20] days of oral morphine treatment, 11 (65%) patients showed signs of withdrawal. Upon hospital discharge, 16 infants (94%) had bronchopulmonary dysplasia and none had severe cerebral abnormality on brain imaging. Conclusion: Oral morphine might be useful in ventilated neonates in the NICU but deserves further studies and additional safety assessment.

Reduced Sufentanil Doses are Effective for Postoperative Analgesia After Ductal Closure in Extremely Premature Infants: A 10 Years Retrospective Cohort Study.

OBJECTIVES: The objective of the study was to assess the efficacy of reduced sufentanil doses for postoperative analgesia following surgical ductal closure in extremely premature infants. METHODS: This was a retrospective, single-center, cohort study comparing 2 sufentanil dosing regimens used between 2001 and 2010 and included all infants born at <28 weeks of gestation with surgical ductal closure. Sufentanil doses were reduced in 2007 as a standard of care. Time was divided into 3 epochs to distinguish the effects of practice changes over time from the effects of sufentanil dose change: epoch 1 (2001 to 2004), epoch 2 (May 2005 to 2007), and epoch 3 (June 2007 to 2010). RESULTS: A total of 109 of 114 eligible infants were analyzed (mean [±SD], gestational age: 25.1 [±1.1] wk; mean [±SD], birth weight: 756 [±144] g). Median sufentanil doses were significantly higher during epochs 1 and 2 (0.1 to 0.2 µg/kg/h) than during epoch 3 (0.03 to 0.04 µg/kg/h) (P<0.0001). EDIN (Echelle de Douleur et d'Inconfort du Nouveau-né) pain scores were mostly ≤4 throughout the study period and their changes over time were not contemporaneous with the reduction in sufentanil doses; they were lower during epoch 1 versus epochs 2 and 3 (P<0.0001) and comparable between epochs 2 and 3. Midazolam doses and paracetamol use were not higher during epoch 3 as compared with epochs 1 and 2. No difference in opioid-related adverse events was observed between the 3 epochs. CONCLUSION: Our study supports the use of low continuous intravenous sufentanil doses, consistent with morphine doses currently recommended in this population.

Are cytochrome P450 CYP2C8 and CYP2C9 polymorphisms associated with ibuprofen response in very preterm infants?

BACKGROUND: Patent ductus arteriosus (PDA) in extremely preterm infants remains a challenging condition with conflicting treatment strategies. Ibuprofen is currently used to treat PDA with ductal closure failure rate up to 40%. We test the hypothesis that cytochrome P450 CYP2C8/2C9 polymorphisms may predict ibuprofen response. METHODOLOGY/PRINCIPAL FINDINGS: We studied extremely preterm neonates with haemodynamically significant PDA and treated with ibuprofen. One or two variant CYP2C8 and/or 2C9 alleles were found in 17% of the population, most of them were from Caucasian ethnicity (67-74%). Response to ibuprofen and clinical course of infants carrying variants CYP2C8 and CYP2C9 were similar. Comparing infants with wild type or variant CYP2C8 and CYP2C9 genotypes, response rate to ibuprofen was significantly higher in wild type than in mutated carriers in univariate analysis (73% versus 52%, p = 0.04). Comparing responders (ductus closure; n = 75) and non-responders (surgical ligation; n = 36), the only two factors significantly associated with the response to ibuprofen using multivariate analysis were higher gestational age and non Caucasian ethnicity but not CYP2C polymorphism. CONCLUSIONS: CYP2C polymorphism was not associated with PDA response to ibuprofen and this factor appears not appropriate to optimize the ductal closure rate by modulating ibuprofen dosing strategy. This study points out the role for ethnicity in the interindividual variability of response to ibuprofen in extremely preterm infants.

A randomized trial of delayed extubation for the reduction of reintubation in extremely preterm infants.

OBJECTIVE: To compare immediate extubation versus delayed extubation after 36 hr in extremely low-birth weight infants receiving gentle mechanical ventilation and perinatal lung protective interventions. Our hypothesis was that a delayed extubation in this setting would decrease the rate of reintubation. STUDY DESIGN/METHODOLOGY: A prospective, unmasked, randomized, controlled trial to compare immediate extubation and delayed extubation after 36 hr. Optimized ventilation in both groups included continuous tracheal gas insufflation (CTGI), prophylactic surfactant administration, low oxygen saturation target and moderate permissive hypercapnia. Successful extubation for at least 7 days was the primary criterion and ventilatory support requirements until 36 weeks gestational age the main secondary criteria. PATIENT SELECTION: Eighty-six infants under 28 weeks gestational age in a single neonatal intensive tertiary care unit. RESULTS: Delayed extubation (1.9 +/- 0.8 days vs. 0.5 +/- 0.7 days) did not improve the rate of successful extubation but had no long-term adverse effects. CTGI and the lung protective strategy we describe resulted in a very gentle ventilation. The rate of survival without bronchopulmonary dysplasia (BPD, defined as any respiratory support at 36 weeks gestational age) was similar in the two groups and remarkably high for the global population (78%) and for the subgroup of infants <1,000 g at birth (75%). CONCLUSIONS: Adding 36 hr of optimized mechanical ventilation before first extubation does not improve the rate of successful extubation but has no adverse effects.

Matrix metalloproteinase gene polymorphisms and bronchopulmonary dysplasia: identification of MMP16 as a new player in lung development.

BACKGROUND: Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD). METHODS AND FINDINGS: Two hundred and eighty-four consecutive neonates with a gestational age of <28 weeks were included in this prospective study. Forty-five neonates developed BPD. Nine single-nucleotide polymorphisms (SNPs) were sought in the MMP2, MMP14 and MMP16 genes. After adjustment for birth weight and ethnic origin, the TT genotype of MMP16 C/T (rs2664352) and the GG genotype of MMP16 A/G (rs2664349) were found to protect from BPD. These genotypes were also associated with a smaller active fraction of MMP2 and with a 3-fold-lower MMP16 protein level in tracheal aspirates collected within 3 days after birth. Further evaluation of MMP16 expression during the course of normal human and rat lung development showed relatively low expression during the canalicular and saccular stages and a clear increase in both mRNA and protein levels during the alveolar stage. In two newborn rat models of arrested alveolarization the lung MMP16 mRNA level was less than 50% of normal. CONCLUSIONS: MMP16 may be involved in the development of lung alveoli. MMP16 polymorphisms appear to influence not only the pulmonary expression and function of MMP16 but also the risk of BPD in premature infants.

Unexplained mental retardation: is brain MRI useful?

BACKGROUND: Mental retardation (MR), defined as an IQ below 70, is a frequent cause of consultation in paediatrics. OBJECTIVE: To evaluate the yield of brain MRI in the diagnostic work-up of unexplained MR in children. PATIENTS AND METHODS: The MRI features and clinical data of 100 patients (age 1-18 years) affected with non-progressive MR of unknown origin were compared to an age-matched control group (n=100). Two radiologists conducted an independent review of the MRI scans. RESULTS: Univariate and multivariate analyses showed a higher incidence of brain anomalies in the MR group than in the control group (53 vs 17, OR=5.7 [2.9-11.1]), for signal abnormalities within the periventricular white matter (OR=20.3 [2.6-155.3]), lateral ventricular dilatation (OR=15.6 [2.0-124]), mild corpus callosum abnormalities (shortness, atrophy) (OR=6.8 [1.8-25.6]) and subtle cerebellar abnormalities, including fissure enlargement (OR=5.2 [1.1-26.2]). The diagnostic value of MRI abnormalities was considered good in 5% of patients (Alexander disease n=1, diffuse cortical malformation n=1, leukomalacia n=1, vermian agenesis n=1, commissural agenesis n=1), and weak in 48% of patients, in whom non-specific abnormalities did not lead to a diagnosis. Some clinical features resulted in a significantly higher percentage of abnormal MRI scans: abnormal neurological examination (82% vs 47%, P=0.008), abnormal skull circumference (66% vs 49%, P=0.04). Motor delay was associated with cerebellar abnormalities (P=0.01). CONCLUSIONS: This study confirms the weak diagnostic yield of MRI in mentally retarded children. The use of a control group has enabled us to identify the neuroimaging markers frequently associated with MR. Subgrouping patients according to neuroimaging markers and clinical signs should help identify those who would benefit from molecular studies.