Oxygenation Instability during Bolus versus Continuous Feeding among Very Low Birth Weight Premature Infants, Supported by Noninvasive Ventilation: A Randomized Prospective Study.

OBJECTIVE: This study aimed to compare oxygenation instability, as documented by the oxygen saturation (SpO2) histograms, during bolus (over 30 minutes) versus continuous (over 2 hours) feeding among very low birth weight (VLBW) premature infants, supported with noninvasive ventilation (NIV). STUDY DESIGN: This was a randomized prospective study. VLBW infants supported with NIV received three consecutive feeds in a random order of bolus-continuous-bolus or continuous-bolus-continuous. During each feed, 30 minutes and 2 hours histograms were documented. RESULTS: Twenty-four infants (birth weight [mean ± standard deviation, SD] 820 ± 168 g, gestational age [mean ± SD] 27.0 ± 1.6 weeks) were included in our study (12 infants started with bolus feeding and 12 with continuous feeding) and 72 histograms were obtained (36 during bolus feeding and 36 during continuous feeding). No differences in mean fraction of inspired oxygen (FiO2), and number of apnea events were observed between the two feeding modes. Oxygenation instability as assessed by time spent in different SpO2 ranges and histogram types (stable or unstable) was comparable during bolus and continuous feedings. Changing feeding mode from bolus to continuous or vice versa did not significantly change the oxygenation instability of the group, though individual infants did show a consistence response to feeding length changes. CONCLUSION: Among VLBW infants supported with NIV, oxygenation instability, as documented by SpO2 histograms, was comparable between bolus and continuous feedings. Individual infants may benefit from specific feeding length, and this can be easily demonstrated by the SpO2 histograms. KEY POINTS: · Feeding length did not affect oxygenation instability of preterm infants on noninvasive respiratory Support.. · Oxygen saturation histograms allow objective quantification of oxygenation instability at the bedside.. · Individual infants benefit from specific feeding length, as demonstrated by SpO2 histograms..

The effect of changing respiratory rate settings on CO2 levels during nasal intermittent positive pressure ventilation (NIPPV) in premature infants.

OBJECTIVE: To examine the change in CO2, when applying NIPPV with either a low or a high rate in stable premature infants. STUDY DESIGN: Prospective, controlled, crossover study. Preterm infants on NIPPV were monitored by tcCO2 during two rate changes switching every hour between high (30 bpm) and low (10 bpm) set rates. RESULTS: Fifty premature infants (mean ± SD: 28.3 ± 2.4 weeks' gestation) were enrolled. Each infant had two rate changes; therefore, a hundred rate changes were studied. The mean change in tcCO2, i.e., ΔtcCO2 (95% confidence-interval), was -1.1 (-2.3 to 0.1) mmHg for increasing rate from low to high, and 0.46 (-0.49 to 1.41) mmHg for decreasing rate from high to low. CONCLUSION: Multiplying or dividing the rate settings by three did not significantly change the tcCO2 readings an hour after the change. These findings could affect the management of ventilation settings of NIPPV in premature infants. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov ID: NCT04836689 , The name of the trial registry: "Influence of Respiratory Rate Settings on CO2 Levels During Nasal Intermittent Positive Pressure Ventilation (NIPPV)."

Continuous versus Bolus Gastric Tube Feeding in Very Low Birth Weight Infants Supported with Noninvasive Respiratory Support: A Randomized, Pilot Study.

OBJECTIVES: This study aimed to compare time to full feeding (TFF) between continuous gastric feeding (CGF) and bolus feeding (BF) in very low birth weight (VLBW) infants supported with noninvasive ventilation (NIV) and to evaluate feasibility and identify methodological pitfalls for future large-scale studies. STUDY DESIGN: This study is a randomized controlled, prospective, pilot study. VLBW premature infants, supported with NIV, were randomized while still on trophic feeding <20 mL/kg/day to receive feeding over 2 hours of CGF or over 15- to 30-minute BF. The primary outcome was TFF. Analysis was done by intention to treat. RESULTS: Overall, 32 infants were included in this analysis, 17 in the CGF group and 15 in the BF group. Infants in the CGF group were significantly younger than the BF group (mean ± standard deviation [SD] gestational age [GA] 26.9 ± 1.2 vs. 28.9 ± 1.5 weeks, respectively). TFF was comparable with median (interquartile range [IQR]) for the two groups, 10.0 (10.0, 19.0) days in the BF group versus 12.0 (9.0, 13.0) days in the CGF group (p = 0.59). Feeding length was not found to significantly affect TFF in multivariate analysis correcting for GA. Groups were comparable in weight gain, gastrointestinal complications, length of NIV, bronchopulmonary dysplasia incidence, and age at discharge. Most infants from both groups (60% of BF and 70% of CGF) required changes in feeding length. CONCLUSION: In this pilot study, among VLBW infants supported with NIV, TFF was comparable between the BF and CGF groups. These results should be interpreted with caution due to the small sample size and despite the multivariate analysis correcting for the different GA. Interestingly, most infants required changes in feeding length regardless of their allocation. This feasibility study emphasizes the need for careful attention to randomization and strict feeding protocols including criteria for switching allocation in future large-scale studies aimed at determining the preferred feeding length during NIV in VLBW infants. KEY POINTS: · Among infants supported with NIV, length of feeding affects gastric venting.. · BF might increase gastrointestinal reflux, while continuous feeding hinders gastric decompression.. · Among infants supported by NIV, feeding tolerance was comparable between bolus and continuous groups..

Same baby, different care: variations in practice between neonatologists and pediatric intensivists.

The aim of the study was to identify and explore areas in neonatal care in which significant differences in clinical care exist, among neonatal intensive care (NICU) and pediatric intensive care (PICU) physicians. A questionnaire presenting three common scenarios in neonatal critical care-severe pneumonia, post-cardiac-surgery care, and congenital diaphragmatic hernia (CDH) was electronically sent to all PICU and NICU physicians in Israel. The survey was completed by 110 physicians. Significant differences were noted between NICU and PICU physicians' treatment choices. A non-cuffed endotracheal tube, initial high-frequency ventilation, and lower tidal volumes when applying synchronized-intermittent-mechanical-ventilation were selected more often by NICU physicians. For sedation/analgesia, NICU physicians treated as needed or by continuous infusion of a single agent, while PICU physicians more often chose to continuously infuse ≥ 2 medications. Fentanyl, midazolam, and muscle relaxants were chosen more often by PICU physicians. Morphine administration was similar for both groups. Treating CDH with pulmonary hypertension and systemic hypotension, NICU physicians more often began treatment with high dose dopamine and/or dobutamine, while PICU physicians chose low-dose adrenalin and/or milrinone. For vascular access NICU physicians chose umbilical lines most often, while PICU physicians preferred other central sites. CONCLUSION: Our study identified major differences in respiratory and hemodynamic care, sedation and analgesia, and vascular access between NICU and PICU physicians, resulting from field-specific consensus guidelines and practice traditions. We suggest to establish joint committees from both professions, aimed at finding the optimal treatment for this vulnerable population - be it in the NICU or in the PICU. WHAT IS KNOWN: • Variability in neonatal care between the neonatal and the pediatric intensive care units has been previously described. WHAT IS NEW: • This scenario-based survey study identified major differences in respiratory and hemodynamic care, sedation and analgesia, and vascular access between neonatologists and pediatric intensivists, resulting from lack of evidence-based literature to guide neonatal care, field-specific consensus guidelines, and practice traditions. • These findings indicate a need for joint committees, combining the unique skills and literature from both professions, to conduct clinical trials focusing on these specific areas of care, aimed at finding the optimal treatment for this vulnerable population - be it in the neonatal or the pediatric intensive care unit.

Respiratory morbidity in very low birth weight infants through childhood and adolescence.

OBJECTIVE: To describe the long-term (up to 18 years of age) respiratory outcomes of children and adolescents born at very low birth weight (VLBW; ≤1500 g) in comparison with that of children born >1500 g. METHODS: An observational, longitudinal, retrospective study comparing VLBW infants with matched controls, registered at a large health maintenance organization in Israel. Pulmonary outcomes collected anonymously from the electronic medical files included respiratory illness diagnoses, purchased medications for respiratory problems, office visits with either a pediatric pulmonologist or cardiologist and composite respiratory morbidity combining all these parameters. RESULTS: Our study included 5793 VLBW infants and 11,590 matched controls born between 1998 and 2012. The majority (99%) of VLBW infants were premature (born < 37 weeks' gestation), while 93% of controls were born at term. The composite respiratory morbidity was significantly higher in VLBW infants compared with controls in all age groups (relative risk [95% confidence interval]: 1 year: 1.22 [1.19-1.26], <2 years: 1.30 [1.27-1.34], 2-6 years: 1.29 [1.27-1.32], 6-12 years: 1.53 [1.47-1.59], 12-18 years: 1.46 [1.35-1.56]; respectively). Both VLBW infants and controls demonstrated a steady decline in the composite respiratory morbidity with aging. In VLBW infants, lower gestational age was associated with higher respiratory morbidity only until 2 years of age and the morbidity declined in each gestational age group until adolescence. CONCLUSION: Our study confirmed a strong association between VLBW and pulmonary morbidity. The higher prevalence of respiratory composite morbidity in VLBW infants persists over the years until adolescence. The respiratory morbidity is most evident in the first year of life and declines afterward.

Evaluation of audio-voice guided application for neonatal resuscitation: a prospective, randomized, pilot study.

OBJECTIVES: To examine whether audio-voice guidance application improves adherence to resuscitation sequence and recommended time frames during neonatal resuscitation. METHODS: A prospective, randomized, pilot study examining the use of an audio-voice application for guiding resuscitation on newborn mannequins, based on the Neonatal Resuscitation Program (NRP) algorithm. Two different scenarios, with and without voice guidance, were presented to 20 medical personnel (2 midwives, 8 nurses, and 10 physicians) in random order, and their performance videotaped. RESULTS: Audio-voice guided resuscitation compared with non-guided resuscitation, resulted in significantly better compliance with NRP order sequence (p<0.01), correct use of oxygen supplementation (p<0.01) and performance of MR SOPA (Mask, reposition, suction, open mouth, pressure, airway) (p<0.01), and shortened the time to "positive pressure ventilation" (p<0.01). CONCLUSIONS: In this pilot study, audio-voice guidance application for newborn resuscitation simulation on mannequins, based on the NRP algorithm, improved adherence and performance of NRP guidelines.

Cannula With Long and Narrow Tubing vs Short Binasal Prongs for Noninvasive Ventilation in Preterm Infants: Noninferiority Randomized Clinical Trial.

Importance: Use of cannulas with long and narrow tubing (CLNT) has gained increasing popularity for applying noninvasive respiratory support for newborn infants thanks to ease of use, perceived patient comfort, and reduced nasal trauma. However, there is concern that this interface delivers reduced and suboptimal support. Objective: To determine whether CLNT is noninferior to short binasal prongs and masks (SPM) when providing nasal intermittent positive pressure ventilation (NIPPV) in preterm infants. Design, Setting, and Participants: This randomized controlled, unblinded, prospective noninferiority trial was conducted between December 2017 and December 2019 at 2 tertiary neonatal intensive care units. Preterm infants born between 24 weeks' and 33 weeks and 6 days' gestation were eligible if presented with respiratory distress syndrome with the need for noninvasive ventilatory support either as initial treatment after birth or after first extubation. Analysis was performed by intention to treat. Interventions: Randomization to NIPPV with either CLNT or SPM interface. Main Outcomes and Measures: The primary outcome was the need for intubation within 72 hours after NIPPV treatment began. Noninferiority margin was defined as 15% or less absolute difference. Results: Overall, 166 infants were included in this analysis, and infant characteristics and clinical condition (including fraction of inspired oxygen, Pco2, and pH level) were comparable at recruitment in the CLNT group (n = 83) and SPM group (n = 83). The mean (SD) gestational age was 29.3 (2.2) weeks vs 29.2 (2.5) weeks, and the mean (SD) birth weight was 1237 (414) g vs 1254 (448) g in the CLNT and SPM groups, respectively. Intubation within 72 hours occurred in 12 of 83 infants (14%) in the CLNT group and in 15 of 83 infants (18%) in the SPM group (risk difference, -3.6%; 95% CI, -14.8 to 7.6 [within the noninferiority margin], χ2 P = .53). Moderate to severe nasal trauma was significantly less common in the CLNT group compared with the SPM group (4 [5%] vs 14 [17%]; P = .01). There were no differences in other adverse events or in the course during hospitalization. Conclusions and Relevance: In this study, CLNT was noninferior to SPM in providing NIPPV for preterm infants, while causing significantly less nasal trauma. Trial Registration: ClinicalTrials.gov Identifier: NCT03081611.

L1 cell adhesion molecule signaling is inhibited by ethanol in vivo.

BACKGROUND: Fetal alcohol spectrum disorder is an immense public health problem. In vitro studies support the hypothesis that L1 cell adhesion molecule (L1) is a target for ethanol (EtOH) developmental neurotoxicity. L1 is critical for the development of the central nervous system. It functions through signal transduction leading to phosphorylation and dephosphorylation of tyrosines on its cytoplasmic domain. The function of L1 is also dependent on trafficking through lipid rafts (LRs). Our hypothesis is that L1 is a target for EtOH neurotoxicity in vivo. Our objective is to demonstrate changes in L1 phosphorylation/dephosphorylation and LR association in vivo. METHODS: Rat pups on postnatal day 6 are administered 4.5, 5.25, and 6 g/kg of EtOH divided into 2 doses 2 hours apart, then killed. Cerebella are rapidly frozen for assay. Blood is analyzed for blood EtOH concentration. L1 tyrosine phosphorylation is determined by immunoprecipitation and dephosphorylation of tyrosine 1176 determined by immunoblot. LRs are isolated by sucrose density gradient, and the distribution of L1 in LRs is determined. RESULTS: EtOH at all doses reduced the relative amount of Y1176 dephosphorylation as well as the relative amount of L1 phosphorylated on other tyrosines. The proportion of L1 present in LRs is significantly increased in pups who received 6 g/kg EtOH compared to intubated controls. CONCLUSIONS: L1 is a target for EtOH developmental neurotoxicity in vivo.

Rescue of neuronal migration deficits in a mouse model of fetal Minamata disease by increasing neuronal Ca2+ spike frequency.

In the brains of patients with fetal Minamata disease (FMD), which is caused by exposure to methylmercury (MeHg) during development, many neurons are hypoplastic, ectopic, and disoriented, indicating disrupted migration, maturation, and growth. MeHg affects a myriad of signaling molecules, but little is known about which signals are primary targets for MeHg-induced deficits in neuronal development. In this study, using a mouse model of FMD, we examined how MeHg affects the migration of cerebellar granule cells during early postnatal development. The cerebellum is one of the most susceptible brain regions to MeHg exposure, and profound loss of cerebellar granule cells is detected in the brains of patients with FMD. We show that MeHg inhibits granule cell migration by reducing the frequency of somal Ca(2+) spikes through alterations in Ca(2+), cAMP, and insulin-like growth factor 1 (IGF1) signaling. First, MeHg slows the speed of granule cell migration in a dose-dependent manner, independent of the mode of migration. Second, MeHg reduces the frequency of spontaneous Ca(2+) spikes in granule cell somata in a dose-dependent manner. Third, a unique in vivo live-imaging system for cell migration reveals that reducing the inhibitory effects of MeHg on somal Ca(2+) spike frequency by stimulating internal Ca(2+) release and Ca(2+) influxes, inhibiting cAMP activity, or activating IGF1 receptors ameliorates the inhibitory effects of MeHg on granule cell migration. These results suggest that alteration of Ca(2+) spike frequency and Ca(2+), cAMP, and IGF1 signaling could be potential therapeutic targets for infants with MeHg intoxication.

Ethanol causes the redistribution of L1 cell adhesion molecule in lipid rafts.

Fetal alcohol spectrum disorder is estimated to affect 1% of live births. The similarities between children with fetal alcohol syndrome and those with mutations in the gene encoding L1 cell adhesion molecule (L1) implicates L1 as a target of ethanol developmental neurotoxicity. Ethanol specifically inhibits the neurite outgrowth promoting function of L1 at pharmacologic concentrations. Emerging evidence shows that localized disruption of the lipid rafts reduces L1-mediated neurite outgrowth. We hypothesize that ethanol impairment of the association of L1 with lipid rafts is a mechanism underlying ethanol's inhibition of L1-mediated neurite outgrowth. In this study, we examine the effects of ethanol on the association of L1 and lipid rafts. We show that, in vitro, L1 but not N-cadherin shifts into lipid rafts following treatment with 25 mM ethanol. The ethanol concentrations causing this effect are similar to those inhibiting L1-mediated neurite outgrowth. Increasing chain length of the alcohol demonstrates the same cutoff as that previously shown for inhibition of L1-L1 binding. In addition, in cerebellar granule neurons in which lipid rafts are disrupted with methyl-beta-cyclodextrin, the rate of L1-mediated neurite outgrowth on L1-Fc is reduced to background rate and that this background rate is not ethanol sensitive. These data indicate that ethanol may inhibit L1-mediated neurite outgrowth by retarding L1 trafficking through a lipid raft compartment.