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.

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.

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.

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.

Study on preventing adverse events in neonates (SEPREVEN): A stepped-wedge randomised controlled trial to reduce adverse event rates in the NICU.

INTRODUCTION: Adverse events (AE) in care are recognized as a leading cause of mortality and injury in patients. Improving patients' safety is difficult to achieve. Therefore, innovative research strategies are needed to identify errors in subgroups of patients and related severity of outcomes as well as reliably measured efficiency of reproducible strategies to improve safety. This trial aims to evaluate the impact of a combined multiprofessional education program on the rate of AE in neonatal intensive care units (NICUs). METHODS AND ANALYSIS: This is a stepped-wedge cluster randomised controlled trial with 3 clusters each containing 4 units. The study time period will be 20 months. The education program will be implemented within each cluster following a random sequence with a control period, a 4-month transition period and a post-educational intervention period. Eligibility criteria: for clusters: 6 NICUs from Ile-de-France and 6 NICUs from different regions in France; for patients: in-hospital during the study period (November 23, 2015 and November 2, 2017 [inclusion start dates varying by unit]) in one of the 12 NICUs; corrected gestational age ≤42 weeks upon admission; hospitalization period >2 days; and parents informed and not opposed to the use of their newborn's data. A routine occurrence reporting of medical errors and their consequence will take place during the entire study period. The intervention will combine an education to implement a standardized root cause analysis method, creation of bundles (insertion, daily goals, maintenance bundles) to prevent catheter-associated blood-stream infection and a poster to prevent extravasation injuries. OUTCOME: We hypothesize a reduction from 60 (control) to 50 (intervention) AE/1000 patient-days. The primary outcome will be the rate of AE/1000 patient-days in the NICU. TRIAL REGISTRATION NUMBER: NCT02598609, trial registered November 6, 2015. https://clinicaltrials.gov/ct2/show/NCT02598609. ETHICS AND DISSEMINATION: Study approved by the regional ethic committee CPP Ile-de-France III (no 2014-A01751-46). The results will be published in peer-reviewed journals.

Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency Intubation: A Randomized Clinical Trial.

Importance: Propofol or a combination of a synthetic opioid and muscle relaxant are both recommended for premedication before neonatal intubation but have yet to be compared. Objective: To compare prolonged desaturation during neonatal nasotracheal intubation after premedication with atropine-propofol vs atropine-atracurium-sufentanil treatment. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial (2012-2016) in 6 NICUs in France that included 173 neonates requiring nonemergency intubation. The study was interrupted due to expired study kits and lack of funding. Interventions: Eighty-nine participants were randomly assigned to the atropine-propofol group and 82 to the atropine-atracurium-sufentanil group before nasotracheal intubation. Main Outcomes and Measures: The primary outcome was prolonged desaturation (Spo2 <80% lasting > 60 seconds), using intention-to-treat analysis using mixed models. Secondary outcomes assessed the characteristics of the procedure and its tolerance. Results: Of 173 neonates randomized (mean gestational age, 30.6 weeks; mean birth weight, 1502 g; 71 girls), 171 (99%) completed the trial. Of 89 infants, 53 (59.6%) in the atropine-propofol group vs 54 of 82 (65.9%) in the atropine-atracurium-sufentanil group achieved the primary outcome (adjusted RD, -6.4; 95% CI, -21.0 to 8.1; P = .38). The atropine-propofol group had a longer mean procedure duration than did the atropine-atracurium-sufentanil group (adjusted RD, 1.7 minutes; 95% CI, 0.1-3.3 minutes; P = .04); a less frequent excellent quality of sedation rate, 51.7% (45 of 87) vs 92.6% (75 of 81; P < .001); a shorter median time to respiratory recovery, 14 minutes (IQR, 8-34 minutes) vs 33 minutes (IQR, 15-56 minutes; P = .002), and shorter median time to limb movement recovery, 18 minutes (IQR, 10-43 minutes) vs 36 minutes (IQR, 19-65 minutes; P = .003). In the 60 minutes after inclusion, Spo2 was preserved significantly better in the atropine-propofol group (time × treatment interaction P = .02). Of the atropine-propofol group 20.6% had head ultrasound scans that showed worsening intracranial hemorrhaging (any or increased intraventricular hemorrhage) in the 7 days after randomization vs 17.6% in the atropine-atracurium-sufentanil group (adjusted RD, 1.2; 95% CI, -13.1 to 15.5, P = .87). Severe adverse events occurred in 11% of the atropine-propofol group and in 20% of the atropine-atracurium-sufentanil group. Conclusions and Relevance: Among neonates undergoing nonemergency nasotracheal intubation, the frequency of prolonged desaturation did not differ significantly between atropine used with propofol or atropine used with atracurium and sufentanil. However, the study may have been underpowered to detect a clinically important difference, and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01490580, EudraCT number: 2009-014885-25.

Genome-wide association study of bronchopulmonary dysplasia: a potential role for variants near the CRP gene.

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [OR] 3.2, p = 3.4 × 10-6). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 × 10-4) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 × 10-5), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.

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.

Does neonatal pain management in intensive care units differ between night and day? An observational study.

OBJECTIVE: To determine whether analgesic use for painful procedures performed in neonates in the neonatal intensive care unit (NICU) differs during nights and days and during each of the 6 h period of the day. DESIGN: Conducted as part of the prospective observational Epidemiology of Painful Procedures in Neonates study which was designed to collect in real time and around-the-clock bedside data on all painful or stressful procedures. SETTING: 13 NICUs and paediatric intensive care units in the Paris Region, France. PARTICIPANTS: All 430 neonates admitted to the participating units during a 6-week period between September 2005 and January 2006. DATA COLLECTION: During the first 14 days of admission, data were collected on all painful procedures and analgesic therapy. The five most frequent procedures representing 38 012 of all 42 413 (90%) painful procedures were analysed. INTERVENTION: Observational study. MAIN OUTCOME ASSESSMENT: We compared the use of specific analgesic for procedures performed during each of the 6 h period of a day: morning (7:00 to 12:59), afternoon, early night and late night and during daytime (morning+afternoon) and night-time (early night+late night). RESULTS: 7724 of 38 012 (20.3%) painful procedures were carried out with a specific analgesic treatment. For morning, afternoon, early night and late night, respectively, the use of analgesic was 25.8%, 18.9%, 18.3% and 18%. The relative reduction of analgesia was 18.3%, p<0.01, between daytime and night-time and 28.8%, p<0.001, between morning and the rest of the day. Parental presence, nurses on 8 h shifts and written protocols for analgesia were associated with a decrease in this difference. CONCLUSIONS: The substantial differences in the use of analgesics around-the-clock may be questioned on quality of care grounds.

Parents' expectations of staff in the early bonding process with their premature babies in the intensive care setting: a qualitative multicenter study with 60 parents.

BACKGROUND: During the first weeks of hospitalization, premature babies and their parents encounter difficulties in establishing early bonds and interactions. Only a few studies have explored what caregivers can do to meet parents' needs in relation to these interactions and help optimize them. This study sought to explore parents' perception of these first interactions and to identify the actions of caregivers that help or hinder its development. METHODS: Prospective study, qualitative discourse analysis of 60 face-to-face interviews conducted with 30 mothers and 30 fathers of infants born before 32 weeks of gestation (mean ± SD: 27 ± 2 weeks of gestational age), during their child's stay in one out of three NICUs in France. Interviews explored parental experience, from before birth up to the first month of life. RESULTS: Data analysis uncovered two main themes, which were independent of parents' geographical or cultural origin but differed between mothers and fathers. First, fathers described the bond with their child as composed more of words and looks and involving distance, while mothers experienced the bond more physically. Secondly, two aspects of the caregivers' influence were decisive: nurses' caring attitude towards baby and parents, and their communication with parents, which reduced stress and made interactions with the baby possible. This communication appeared to be the locus of a supportive and fulfilling encounter between parents and caregivers that reinforced parents' perception of a developing bond. CONCLUSIONS: At birth and during the first weeks in the NICU, the creation of a bond between mothers and fathers and their premature baby is rooted in their relationship with the caregivers. Nurses' caring attitude and regular communication adapted to specific needs are perceived by parents as necessary preconditions for parents' interaction and development of a bond with their baby. These results might allow NICU staff to provide better support to parents and facilitate the emergence of a feeling of parenthood.

Perceived role in end-of-life decision making in the NICU affects long-term parental grief response.

BACKGROUND: Shared decision making (DM) is increasingly advocated as the most appropriate model to support parents confronted with end-of-life (EoL) decisions for a child in the neonatal intensive care unit (NICU). However, few studies have explored its impact on their long-term grief. OBJECTIVES: The aim of this study was to investigate whether parental perception of the type of involvement in the EoL decision-making process (EoL DMP) for their child in the NICU is related to their long-term grief outcome. METHODS: A retrospective study with mixed methods. The study included parents whose child died from 2002 through 2005 in one of four NICUs in different areas in France, with interviews of 78 individual parents of 53 children, 2.7 ± 0.6 years after the child's death. Parental perception of the type of involvement in the EoL DMP was determined by qualitative analysis of face-to-face interviews and classified as follows: shared, medical, informed parental and no decision. Grief reactions were assessed with the Texas Revised Inventory of Grief (TRIG-F). RESULTS: Current grief scores differed significantly according to the perceived type of EoL DM. Shared DM was associated with lower TRIG-F scores (less grief) than were the other types of EoL DM (F=7.95; p=0.05). The baby's perceived suffering was also associated with higher grief scores (F=6.51, p=0.01). CONCLUSIONS: In decisions to forego life-sustaining treatment in the NICU, the perception of a shared decision is associated in the long term with lower grief scores than perceptions of the other types of DM.

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.

Living with a crucial decision: a qualitative study of parental narratives three years after the loss of their newborn in the NICU.

BACKGROUND: The importance of involving parents in the end-of-life decision-making-process (EOL DMP) for their child in the neonatal intensive care unit (NICU) is recognised by ethical guidelines in numerous countries. However, studies exploring parents' opinions on the type of involvement report conflicting results. This study sought to explore parents' experience of the EOL DMP for their child in the NICU. METHODS: The study used a retrospective longitudinal design with a qualitative analysis of parental experience 3 years after the death of their child in four NICUs in France. 53 face-to-face interviews and 80 telephone interviews were conducted with 164 individuals. Semi-structured interviews were conducted to explore how parents perceived their role in the decision process, what they valued about physicians' attitudes in this situation and whether their long-term emotional well being varied according to their perceived role in the EOL DMP. FINDINGS: Qualitative analysis identified four types of perceived role in the DMP: shared, medical, informed parental decision, and no decision. Shared DM was the most appreciated by parents. Medical DM was experienced as positive only when it was associated with communication. Informed parental DM was associated with feelings of anxiousness and abandonment. The physicians' attitudes that were perceived as helpful in the long term were explicit sharing of responsibility, clear expression of staff preferences, and respectful care and language toward the child. INTERPRETATION: Parents find it valuable to express their opinion in the EOL DMP of their child. Nonetheless, they do need continuous emotional support and an explicit share of the responsibility for the decision. As involvement preferences and associated feelings can vary, parents should be able to decide what role they want to play. However, our study suggests that fully autonomous decisions should be misadvised in these types of tragic choices.

Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants. Genetic factors might contribute to bronchopulmonary dysplasia susceptibility. OBJECTIVES: To identify genetic variants involved in bronchopulmonary dysplasia through a genome-wide association study. METHODS: We prospectively evaluated 418 premature neonates (gestational age <28 wk), of whom 22% developed bronchopulmonary dysplasia. Two discovery series were created, using a DNA pooling strategy in neonates from white and African ancestry. Polymorphisms associated with the disease were confirmed in an independent replication population. Genes were then explored by fine mapping and associations were replicated in an external Finnish population of 213 neonates. Validated genes expression patterns were studied in rat lung, after air or hyperoxia exposure. MEASUREMENTS AND MAIN RESULTS: SPOCK2 gene was identified by both discovery series. The most significant polymorphism (rs1245560; P = 1.66 × 10(-7)) was confirmed by individual genotyping, and in the replication population (P = 0.002). Fine mapping confirmed the association of rs1245560 with bronchopulmonary dysplasia in both white and African populations with adjusted odds ratios of 2.96 (95% confidence interval [CI], 1.37-6.40) and 4.87 (95% CI, 1.88-12.63), respectively. In white neonates, rs1049269 was also associated with the disease (odds ratio, 3.21; 95% CI, 1.51-6.82). These associations were replicated in the Finnish population. In newborn rat lungs, SPOCK2 mRNA levels markedly increased during the alveolar stage of lung development. After rat exposure to hyperoxia, SPOCK2 expression increased relative to air-exposed controls. CONCLUSIONS: We identified SPOCK2 as a new possible candidate susceptibility gene for bronchopulmonary dysplasia. Its lung expression pattern points toward a potential role in alveolarization.

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.

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.

Epidemiology and treatment of painful procedures in neonates in intensive care units.

CONTEXT: Effective strategies to improve pain management in neonates require a clear understanding of the epidemiology and management of procedural pain. OBJECTIVE: To report epidemiological data on neonatal pain collected from a geographically defined region, based on direct bedside observation of neonates. DESIGN, SETTING, AND PATIENTS: Between September 2005 and January 2006, data on all painful and stressful procedures and corresponding analgesic therapy from the first 14 days of admission were prospectively collected within a 6-week period from 430 neonates admitted to tertiary care centers in the Paris region of France (11.3 millions inhabitants) for the Epidemiology of Procedural Pain in Neonates (EPIPPAIN) study. MAIN OUTCOME MEASURE: Number of procedures considered painful or stressful by health personnel and corresponding analgesic therapy. RESULTS: The mean (SD) gestational age and intensive care unit stay were 33.0 (4.6) weeks and 8.4 (4.6) calendar days, respectively. Neonates experienced 60,969 first-attempt procedures, with 42,413 (69.6%) painful and 18,556 (30.4%) stressful procedures; 11,546 supplemental attempts were performed during procedures including 10,366 (89.8%) for painful and 1180 (10.2%) for stressful procedures. Each neonate experienced a median of 115 (range, 4-613) procedures during the study period and 16 (range, 0-62) procedures per day of hospitalization. Of these, each neonate experienced a median of 75 (range, 3-364) painful procedures during the study period and 10 (range, 0-51) painful procedures per day of hospitalization. Of the 42,413 painful procedures, 2.1% were performed with pharmacological-only therapy; 18.2% with nonpharmacological-only interventions, 20.8% with pharmacological, nonpharmacological, or both types of therapy; and 79.2% without specific analgesia, and 34.2% were performed while the neonate was receiving concurrent analgesic or anesthetic infusions for other reasons. Prematurity, category of procedure, parental presence, surgery, daytime, and day of procedure after the first day of admission were associated with greater use of specific preprocedural analgesia, whereas mechanical ventilation, noninvasive ventilation and administration of nonspecific concurrent analgesia were associated with lower use of specific preprocedural analgesia. CONCLUSION: During neonatal intensive care in the Paris region, large numbers of painful and stressful procedures were performed, the majority of which were not accompanied by analgesia.

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.

Bilateral periventricular heterotopias in an X-linked dominant transmission in a family with two affected males.

We report on the case of dizygotic twin boys, born prematurely to an asymptomatic mother. Bilateral periventricular heterotopias with enlarged ventricles were discovered at birth in both twins. One of the twins died prematurely of bronchopulmonary complications, and was shown to have several neuropathological anomalies (microgyria, thin corpus callosum, and reduced white matter). The surviving twin had mental retardation, without epilepsy. MRI of the mother showed asymptomatic periventricular heterotopias without ventricular enlargement. She had two affected daughters also with asymptomatic periventricular heterotopias. A point mutation in the last coding exon 48 of the Filamin A (FLNA) gene (7922c > t) was discovered on sequencing and segregated with the affected individuals. This family has a classical X-linked dominant BPNH pathology, with greater severity in males than females. The location of the FLNA mutation is discussed in light of the neuropathological anomalies and mental retardation in male patients.

Gelatinase activities in the airways of premature infants and development of bronchopulmonary dysplasia.

Matrix-degrading metalloproteinases may play a role in the pathophysiology of bronchopulmonary dysplasia (BDP). We, therefore, evaluated correlations between gelatinase activities [metalloproteinase (MMP)-2 and MMP-9] or tissue inhibitor of metalloproteinase (TIMP)-1 levels present in the airways during the initial phase of hyaline membrane disease and the onset of BPD. Tracheal aspirates were obtained within 6 h of birth (day 0) from 64 intubated neonates with a gestational age < or =30 wk. Forty-five neonates were resampled on day 3 or 5. Total MMP-2 level measured by zymography fell with time, whereas total MMP-9 level and TIMP-1 levels, assayed by ELISA, increased; the MMP-9 increase correlated with the increase in airway inflammatory cell numbers. Among the parameters measured on day 0, 3, or 5, lower total MMP-2 level, lower birth weight, and higher fraction of inspired oxygen on day 0 were significantly and independently associated with the development of BPD. In conclusion, MMP-9 level and TIMP-1 levels increased after birth but are not linked to BPD outcome. In contrast, low MMP-2 level at birth is strongly associated with the development of BPD.