Stimulating the motor development of very premature infants: effects of early crawling training on a mini-skateboard.

Aim: To examine the effects of an early home-based 8-week crawling intervention performed by trained therapists on the motor and general development of very premature infants during the first year of life. Methods: At term-equivalent age, immediately following discharge from the Neonatal Intensive Care Unit (NICU), we randomly allocated 44 premature infants born before 32 weeks' gestation without major brain damage to one of three conditions in our intervention study: crawling on a mini-skateboard, the Crawliskate (Crawli), prone positioning control (Mattress), or standard care (Control). The Crawli and Mattress groups received 5 min daily at-home training administered by trained therapists for 8 consecutive weeks upon discharge from the NICU. The outcomes of greatest interest included gross motor development (Bayley-III) at 2, 6, 9, and 12 months (primary outcome) corrected age (CA), mature crawling at 9 months CA and general development at 9 and 12 months CA [Ages and Stages Questionnaires-3 (ASQ-3)]. The study was registered at www.clinicaltrials.gov; registration number: NCT05278286. Results: A 3 (Condition) × 4 (Age) repeated measures ANOVA revealed that Crawli group infants had significantly higher Bayley-III gross motor development scores than Mattress and Control group infants. Crawli group infants also scored significantly higher on groups of Bayley-III items related to specific motor skills than infants in the other groups, including crawling at 9 months CA. We found significant differences in favor of the Crawli group in separate one-way ANOVAs at each of the ages we examined. A 3 (Condition) × 2 (Age) repeated measures ANOVA revealed that the Crawli group scored significantly higher than the Control group for the ASQ-3 total score and communication score and significantly higher for the fine motor score than the Control and Mattress groups. We found additional significant differences in favor of the Crawli group for other dimensions of the ASQ-3 in separate one-way ANOVAs at 9 and 12 months CA. Interpretation: Early crawling training on a Crawliskate provides an effective way to promote motor and general development in very premature infants. The findings also provide clear evidence for a link between newborn crawling and more mature crawling later in development.

Error disclosure in neonatal intensive care: a multicentre, prospective, observational study.

IMPORTANCE: Surveys based on hypothetical situations suggest that health-care providers agree that disclosure of errors and adverse events to patients and families is a professional obligation but do not always disclose them. Disclosure rates and reasons for the choice have not previously been studied. OBJECTIVE: To measure the proportion of errors disclosed by neonatal intensive care unit (NICU) professionals to parents and identify motives for and barriers to disclosure. DESIGN: Prospective, observational study nested in a randomised controlled trial (Study on Preventing Adverse Events in Neonates (SEPREVEN); ClinicalTrials.gov). Event disclosure was not intended to be related to the intervention tested. SETTING: 10 NICUs in France with a 20-month follow-up, starting November 2015. PARTICIPANTS: n=1019 patients with NICU stay ≥2 days with ≥1 error. EXPOSURE: Characteristics of errors (type, severity, timing of discovery), patients and professionals, self-reported motives for disclosure and non-disclosure. MAIN OUTCOME AND MEASURES: Rate of error disclosure reported anonymously and voluntarily by physicians and nurses; perceived parental reaction to disclosure. RESULTS: Among 1822 errors concerning 1019 patients (mean gestational age: 30.8±4.5 weeks), 752 (41.3%) were disclosed. Independent risk factors for non-disclosure were nighttime discovery of error (OR 2.40; 95% CI 1.75 to 3.30), milder consequence (for moderate consequence: OR 1.85; 95% CI 0.89 to 3.86; no consequence: OR 6.49; 95% CI 2.99 to 14.11), a shorter interval between admission and error, error type and fewer beds. The most frequent reported reasons for non-disclosure were parental absence at its discovery and a perceived lack of serious consequence. CONCLUSION AND RELEVANCE: In the particular context of the SEPREVEN randomised controlled trial of NICUs, staff did not disclose the majority of errors to parents, especially in the absence of moderate consequence for the infant. TRIAL REGISTRATION NUMBER: NCT02598609.

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.

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.

Trust and consent: a prospective study on parents' perspective during a neonatal trial.

OBJECTIVE: This study aimed to describe how parents and physicians experienced the informed consent interview and to investigate the aspects of the relationship that influenced parents' decision during the consent process for a randomised clinical trial in a tertiary neonatal intensive care unit (NICU). The secondary objective was to describe the perspectives of parents and physicians in the specific situation of prenatal informed consent. SETTING: Single centre study in NICU of the Centre Hospitalier Intercommunal de Créteil, France, using a convenience period from February to May 2016. DESIGN: Ancillary study to a randomised clinical trial: Prettineo. Records of interviews for consent. POPULATION: parents and physicians. Mixed study including qualitative and quantitative interview data about participants' recall and feelings about the consent process. Interviews were reviewed using thematic discourse analysis. RESULTS: Parents' recall and understanding of the study's main goal and design was good. Parents and physicians had a positive experience, and trust was one of the main reasons for parents to consent. Misunderstanding (bad comprehension) was the main reason for refusal.Before birth, three situations can compromise parents' consent: the mother already consented to participate in other studies, the absence of the father during the interview and the feeling that the baby's birth is not an imminent possibility. CONCLUSIONS: Confronting parents and physicians' perspectives in research can help us reach answers to sensitive issues such as content and timing of information. Each different types of study raises different ethical dilemmas for consent that might be discussed in a more individual way.

Continuous-Infusion Vancomycin in Neonates: Assessment of a Dosing Regimen and Therapeutic Proposal.

Introduction: Vancomycin remains the reference antibiotic in neonates for care-related infections caused by ß-lactam-resistant Gram-positive bacteria. Achieving the optimal serum vancomycin level is challenging because of high inter-individual variability and the drug's narrow therapeutic window. Continuous infusion might offer pharmacokinetic and practical advantages, but we lack consensus on the dosing regimen. The aim was to determine the proportion of neonates achieving an optimal therapeutic vancomycin level at the first vancomycin concentration assay and which dosing regimen is the most suitable for neonates. Methods: All neonates receiving continuous-infusion vancomycin (loading dose 15 mg/kg and maintenance dose 30 mg/kg/d) in a neonatal intensive care unit were retrospectively analyzed. The proportion of neonates reaching the target serum vancomycin level was calculated. After reviewing the literature to identify all published articles proposing a dosing regimen for continuous-infusion vancomycin for neonates, regimens were theoretically applied to our population by using maintenance doses according to covariate(s) proposed in the original publication. Results: Between January 2013 and December 2014, 75 neonates received 91 vancomycin courses by continuous infusion. Median gestational age, birth weight, and postnatal age were 27 weeks (interquartile range 26-30.5), 815 g (685-1,240), and 15 days (9-33). At the first assay, only 28/91 (30.8%) courses resulted in vancomycin levels between 20 and 30 mg/L (target level), 23/91 (25.3%) >30 mg/L and 40/91 (43.9%) <20 mg/L. We applied six published dosing regimens to our patients. One of these dosing regimens based on corrected gestational age (CGA) and serum creatinine level (SCR) would have allowed us to prescribe lower doses to neonates with high vancomycin levels and higher doses to neonates with low levels. Conclusions: A simplified dosing regimen of continuous-infusion vancomycin did not achieve therapeutic ranges in neonates; a patient-tailored dosing regimen taking into account CGA and SCR level or an individualized pharmacokinetic model can help to anticipate the inter-individual variability in neonates and would have been more suitable.

Hydrocortisone use in ventilated extremely preterm infants decreased bronchopulmonary dysplasia with no effects on neurodevelopment after two years.

AIM: We assessed the outcomes of ventilated extremely premature infants treated with late postnatal corticosteroids from 2005-2008, according to permissive or restrictive policies in two centres. METHODS: This retrospective study included inborn infants below 27 weeks of gestational age who were ventilator dependent after 14 days. Centre P permitted postnatal corticosteroids but centre R restricted their use. The effects on infants were assessed in hospital and after two years using multivariable analysis. RESULTS: We compared 62 infants from centre P, including 92% who received hydrocortisone, and 48 infants from centre R, including 13% who received betamethasone. Infants from both centres had comparable baseline characteristics and perinatal management, but bronchopulmonary dysplasia (BPD) rates were significantly lower in centre P (30% versus 71%, p < 0.001) and this centre was significantly associated with a younger post-conceptional age at oxygen weaning, with an adjusted hazard ratio (aHR) of 0.45 and an aHR of 0.51at discharge. At two years of corrected age, 18% of centre P infants and 30% of centre R infants showed poor neurodevelopmental outcome (p = 0.18). CONCLUSION: Using hydrocortisone after 14 days on ventilated extremely preterm infants was associated with decreased BPD, with no apparent effects on neurodevelopment at two years of corrected age.

Shielding Parenteral Nutrition Solutions From Light: A Randomized Controlled Trial.

INTRODUCTION: Oxidant stress is implicated in the pathogenesis of bronchopulmonary dysplasia (BPD). Light induces peroxide generation in parenteral nutrition (PN) solutions, creating an oxidant stress. Shielding PN from light decreases its peroxide content, which has nutrition and biochemical benefits in animals and humans. This study aims at determining whether full light protection of PN decreases the rate of bronchopulmonary dysplasia and/or death in very low-birth-weight infants. METHODS: Multicenter randomized controlled trial of photoprotection, using amber bags and tubing initiated during compounding of PN and maintained throughout infusion in the light-protected (LP) group. The control group (light exposed [LE]) received PN exposed to ambient light. Depending on centers, lipids were infused either separately or as all-in-one PN. RESULTS: In total, 590 infants born <30 weeks gestational age were included. At randomization, LE and LP groups did not differ clinically except for maximal FiO2 before 12 hours. The rate of BPD/death was not different between groups at 28 days (77% LP vs 72% LE, P = .16) or at 36 weeks corrected age (30% LP vs 27% LE, P = .55). Multivariate analysis showed no significant effect of photoprotection on BPD and/or death. The rate of BPD/death was significantly lower (odds ratio, 0.54; 95% confidence interval, 0.32-0.93; P = .02) in infants receiving all-in-one PN vs those who received lipids separately. CONCLUSION: This study did not show significant beneficial effects of photoprotection. Since the decreased rate of BPD/death found with all-in-one PN relates to a center-dependent variable, this warrants further investigation.

Assessment of atropine-sufentanil-atracurium anaesthesia for endotracheal intubation: an observational study in very premature infants.

BACKGROUND: Premedication before neonatal intubation is heterogeneous and contentious. The combination of a short acting, rapid onset opioid with a muscle relaxant is considered suitable by many experts. The purpose of this study was to describe the tolerance and conditions of intubation following anaesthesia with atropine, sufentanil and atracurium in very premature infants. METHODS: Monocentric, prospective observational study in premature infants born before 32 weeks of gestational age, hospitalised in the NICU and requiring semi-urgent or elective intubation. Intubation conditions, heart rate, pulse oxymetry (SpO2), arterial blood pressure and transcutaneous PCO2 (TcPCO2) were collected in real time during 30 minutes following the first drug injection. Repeated physiological measurements were analysed using mixed linear models. RESULTS: Thirty five intubations were performed in 24 infants with a median post conceptional age of 27.6 weeks and a median weight of 850 g at the time of intubation. The first attempt was successful in 74% and was similar for junior (75%) and senior (74%) operators. The operator rated conditions as "excellent" or "good" in 94% of intubations. A persistent increase in TcPCO2 as compared to baseline was observed whereas other vital parameters showed no significant variations 5, 10, 15 and 30 minutes after the first drug injection. Eighteen (51%) desaturations (SpO2 less than or equal to 80% for more than 60 seconds) and 2 (6%) bradycardia (heart rate less than 100 bpm for more than 60 seconds) were observed. CONCLUSION: This drug combination offers satisfactory success rate for first attempt and intubation conditions for the operator without any significant change in heart rate and blood pressure for the patient. However it is associated with frequent desaturations and a possible persistent hypercapnia. SpO2 and PCO2 can be significantly modified during neonatal intubation and should be cautiously followed in this high-risk population.

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.

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.

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.

Mosaic trisomy 9 and lobar holoprosencephaly.

The main features of trisomy 9 syndrome in mosaic and non-mosaic forms have been thoroughly described. Characteristic traits are low-set malformed ears, micrognathia, broad nose with bulbous tip, abnormal brain, congenital heart defects, abnormal hands and feet, genital abnormalities, and early death. We report a case of mosaic trisomy 9 with holoprosencephaly (HPE). The propositi was born at 37 weeks, with intra-uterine growth retardation, hypotelorism and single nostril, ventricular septal defect, anterior placement of anus, clenched hands with thumb adduction and ulnar deviation. Facial anomalies characteristic of trisomy 9 included deeply set eyes and short palpebral fissures, flat face with maxillary hypoplasia, small mouth, and low-set posteriorly angulated ears. Cytogenetic analysis showed mosaic trisomy 9 with 17% trisomic cells. Pathology confirmed lobar HPE. In literature, isolated arrhinia, related to the HPE spectrum, was reported in one case of mosaic trisomy 9. Our case raises the question of the causative role of trisomy 9 in full blown HPE.

High concentrations of keratinocyte growth factor in airways of premature infants predicted absence of bronchopulmonary dysplasia.

Premature lungs are highly susceptible to lung injuries, leading to bronchopulmonary dysplasia (BPD). Keratinocyte growth factor (KGF) is produced by the developing lung and may reduce the risk of BPD by preventing injury to the lung epithelium and enhancing its repair. To determine whether KGF concentrations in the airways during the initial phase of hyaline membrane disease are correlated with subsequent development of BPD defined as the need for supplemental oxygen at a postconceptional age of 36 weeks, we obtained tracheal aspirates within 3 hours of birth (Day 0) from 91 intubated neonates with a gestational age of 30 weeks or less. Repeat samples were obtained from 42 neonates within 5 days after birth. KGF in aspirate supernatants was measured by enzyme-linked immunosorbent assay. On Day 0, KGF was detected in all but six neonates. A significant increase in KGF concentration was found from the first to the second samples. The highest KGF concentration within 5 days after birth (KGF(max)) was significantly higher in survivors without BPD than in those with BPD. A KGF(max) value higher than 110 pg/ml had a positive predictive value of 95% for absence of BPD. KGF may hold promise for the treatment of very premature neonates.