Nutritional interventions to reduce rates of infection, necrotizing enterocolitis and mortality in very preterm infants.

Observational studies demonstrating reduced rates of infections, necrotizing enterocolitis (NEC), and mortality in preterm infants fed their own mother's milk, as opposed to formula, have prompted endeavors to achieve similar effects with the right choice of food and food additives. In a systematic review of meta-analyses and randomized controlled trials (RCTs), we considered nutritional interventions aimed at reducing the rates of infections, NEC, or mortality in very preterm infants. The overall effects of particular interventions were presented as risk ratios with 95% confidence intervals. In RCTs, pasteurized human donor milk, as opposed to formula, reduced NEC but not infections or mortality. No differences emerged between infants receiving human or bovine milk-based fortifiers. Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections, NEC, or mortality. Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality. Enteral L-glutamine (six RCTs) lowered infection rates, and enteral L-arginine (three RCTs) reduced NEC. A meta-analysis sensitivity approach found multiple-strain (but not single-strain) probiotics to be highly effective in reducing NEC and mortality. Thus, selected food components may help to improve outcomes in preterm infants.

Early Exchange Transfusion to Treat Neonates With Gestational Alloimmune Liver Disease: An 11-Year Cohort Study.

OBJECTIVES: Exchange transfusion (ET) and intravenous immunoglobulin are potentially life-saving treatment options in newborns with gestational alloimmune liver disease (GALD). Since 2008, early ET has been the standard of care for symptomatic neonates with suspected GALD in our unit. The present study's aim was to investigate the outcomes of this approach. METHODS: From 2008 to 2018, all neonates who received ET for suspected GALD were identified, and their clinical course and outcomes were analyzed in a descriptive cohort study. In survivors, liver function parameters before ET and maximum values after ET and at discharge were compared. RESULTS: During the 11-year period, 12 infants received ET for suspected GALD at a median (range) chronological age of 11 (1-23) days and gestational age of 38 (32-40) weeks. Signs of impaired liver function, most frequently postnatal hypoglycemia, hyperferritinemia, direct hyperbilirubinemia, and coagulopathy, were present in all infants. Survival without a liver transplant in the overall cohort was 10 of 12 (83.3%) and 7 of 9 (78%) in those fulfilling the criteria of acute liver failure. Two patients died, one of them after liver transplantation. Direct bilirubin typically increased after ET, even in survivors. All survivors recovered and were discharged from the pediatric hepatology outpatient clinic after 8 (3-11) months of follow-up. CONCLUSIONS: In newborns with suspected GALD, a limited diagnostic work-up followed by early ET may lead to favorable outcomes. More data are required to develop an evidence-based clinical approach to GALD.

Nasal high-frequency oscillation ventilation in neonates: a survey in five European countries.

UNLABELLED: Nasal high-frequency oscillation ventilation (nHFOV) is a non-invasive ventilation mode that applies an oscillatory pressure waveform to the airways using a nasal interface. nHFOV has been shown to facilitate carbon dioxide expiration, but little is known about its use in neonates. In a questionnaire-based survey, we assessed nHFOV use in neonatal intensive care units (NICUs) in Austria, Switzerland, Germany, the Netherlands, and Sweden. Questions included indications for nHFOV, equipment used, ventilator settings, and observed side effects. Of the clinical directors of 186 NICUs contacted, 172 (92 %) participated. Among those responding, 30/172 (17 %) used nHFOV, most frequently in premature infants <1500 g (27/30) for the indication nasal continuous positive airway pressure (nCPAP) failure (27/30). Binasal prongs (22/30) were the most common interfaces. The median (range) mean airway pressure when starting nHFOV was 8 (6-12) cm H2O, and the maximum mean airway pressure was 10 (7-18) cm H2O. The nHFOV frequency was 10 (6-13) Hz. Abdominal distension (11/30), upper airway obstruction due to secretions (8/30), and highly viscous secretions (7/30) were the most common nHFOV side effects. CONCLUSION: In a number of European NICUs, clinicians use nHFOV. The present survey identified differences in nHFOV equipment, indications, and settings. Controlled clinical trials are needed to investigate the efficacy and side effects of nHFOV in neonates.

Validation of computerized wheeze detection in young infants during the first months of life.

BACKGROUND: Several respiratory diseases are associated with specific respiratory sounds. In contrast to auscultation, computerized lung sound analysis is objective and can be performed continuously over an extended period. Moreover, audio recordings can be stored. Computerized lung sounds have rarely been assessed in neonates during the first year of life. This study was designed to determine and validate optimal cut-off values for computerized wheeze detection, based on the assessment by trained clinicians of stored records of lung sounds, in infants aged <1 year. METHODS: Lung sounds in 120 sleeping infants, of median (interquartile range) postmenstrual age of 51 (44.5-67.5) weeks, were recorded on 144 test occasions by an automatic wheeze detection device (PulmoTrack®). The records were retrospectively evaluated by three trained clinicians blinded to the results. Optimal cut-off values for the automatically determined relative durations of inspiratory and expiratory wheezing were determined by receiver operating curve analysis, and sensitivity and specificity were calculated. RESULTS: The optimal cut-off values for the automatically detected durations of inspiratory and expiratory wheezing were 2% and 3%, respectively. These cutoffs had a sensitivity and specificity of 85.7% and 80.7%, respectively, for inspiratory wheezing and 84.6% and 82.5%, respectively, for expiratory wheezing. Inter-observer reliability among the experts was moderate, with a Fleiss' Kappa (95% confidence interval) of 0.59 (0.57-0.62) for inspiratory and 0.54 (0.52 - 0.57) for expiratory wheezing. CONCLUSION: Computerized wheeze detection is feasible during the first year of life. This method is more objective and can be more readily standardized than subjective auscultation, providing quantitative and noninvasive information about the extent of wheezing.

Retinal blood flow velocities in infants with retinopathy of prematurity after intravitreal administration of bevacizumab.

BACKGROUND/OBJECTIVES: Progression of retinopathy of prematurity (ROP) is associated with increased retinal blood flow velocities. We investigated changes of central retinal arterial and venous blood flow after intravitreal administration of bevacizumab. SUBJECTS/METHODS: Prospective observational study using serial ultrasound Doppler imaging in preterm infants with bevacizumab-treated ROP. Eyes were examined 1 [0-2] days before injection (median [interquartile range]), and at three time points after injection (1 [1-2] days, 6 [3-8] days, and 17 [9-28] days). Preterm infants with ROP stage 2 displaying spontaneous regression served as controls. RESULTS: In 21 eyes of 12 infants with bevacizumab-treated ROP, peak arterial systolic velocity declined from 13.6 [11.0-16.3] cm/s prior to intravitreal bevacizumab to 11.2 [9.4-13.9] cm/s, 10.6 [9.2-13.3] cm/s and 9.3 [8.2-11.0] cm/s at discharge (p = .002). There was also a decline of the arterial velocity time integral (from 3.1 [2.3-3.9] cm to 2.9 [2.4-3.5], 2.7 [2.3-3.2] cm and 2.2 [2.0-2.7], p = .021) and mean velocity in the central retinal vein (from 4.5 [3.6-5.8] cm/s to 3.7 [2.6-4.1] cm/s, 3.5 [3.0-4.3] cm/s, and 3.2 [2.8-4.6] cm/s, p = .012). Arterial end-diastolic velocity and resistance index remained unchanged. Blood flow velocities in bevacizumab-treated eyes examined before injection were significantly higher than those measured in untreated eyes that ultimately showed spontaneous regression of ROP. Sequential examinations in these controls did not reveal any declines of retinal blood flow velocities. CONCLUSION: Increased retinal arterial and venous blood flow velocities in infants with threshold ROP decline following intravitreal bevacizumab injection.

Mechanism of action of novel lung edema therapeutic AP301 by activation of the epithelial sodium channel.

AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human tumor necrosis factor lectin-like domain (TIP domain) sequence, is currently being developed as a treatment for lung edema and has been shown to reduce extravascular lung water and improve lung function in mouse, rat, and pig models. The current paradigm for liquid homeostasis in the adult mammalian lung is that passive apical uptake of sodium via the amiloride-sensitive epithelial Na⁺ channel (ENaC) and nonselective cyclic-nucleotide-gated cation channels creates the major driving force for reabsorption of water through the alveolar epithelium in addition to other ion channels such as potassium and chloride channels. AP301 can increase amiloride-sensitive current in A549 cells as well as in freshly isolated type II alveolar epithelial cells from different species. ENaC is expressed endogenously in all of these cell types. Consequently, this study was undertaken to determine whether ENaC is the specific target of AP301. The effect of AP301 in A549 cells as well as in human embryonic kidney cells and Chinese hamster ovary cells heterologously expressing human ENaC subunits (α, ß, γ, and δ) was measured in patch clamp experiments. The congener TIP peptide AP318 [Cyclo(4-aminobutanoic acid-GQRETPEGAEAKPWYD)] activated ENaC by increasing single-channel open probability. AP301 increased current in proteolytically activated (cleaved) but not near-silent (uncleaved) ENaC in a reversible manner. αßγ- or δßγ-ENaC coexpression was required for maximal activity. No increase in current was observed after deglycosylation of extracellular domains of ENaC. Thus, our data suggest that the specific interaction of AP301 with both endogenously and heterologously expressed ENaC requires precedent binding to glycosylated extracellular loop(s).

AP301, a synthetic peptide mimicking the lectin-like domain of TNF, enhances amiloride-sensitive Na(+) current in primary dog, pig and rat alveolar type II cells.

Pulmonary permeability oedema is a frequent complication in a number of life-threatening lung conditions, such as ALI and ARDS. Apart from ventilation strategies, no specific therapy yet exists for treatment of these potentially fatal illnesses. The oedema-reducing capacity of the lectin-like domain of TNF (TIP) and of synthetic peptides, mTIP and hTIP, which mimic the TIP domain of mouse and human TNF, have been demonstrated in various studies in rodents. Cell-based electrophysiological studies have revealed that the alveolar fluid clearing capacity of TNF and the TIP peptides is due to activation of the amiloride-sensitive Na(+) current in alveolar epithelial cells and that the primary site of action is on the apical side of these cells. AP301, a synthetic cyclic peptide mimicking the TIP domain of human TNF is currently undergoing clinical trials as a therapy for pulmonary permeability oedema. AP301 has been shown to improve alveolar liquid clearance and lung function in a porcine model of ALI. For non-clinical regulatory assessment, dog, pig and rat are standard animal models; accordingly, pre-clinical toxicological and pharmacological safety studies have been conducted with AP301 in dogs and rats. Hitherto, no studies have assessed the pharmacodynamic effect of AP301 on primary canine or porcine type II AEC. The current study describes the effect of AP301 on the amiloride-sensitive Na(+) current in type II AEC isolated from dog, pig and rat lungs. In whole cell patch clamp experiments with dog type II AEC, an increase in the amiloride-sensitive Na(+) current from 3.7 pA to 49.4 pA was observed in the presence of AP301; in pig type II AEC, an increase from 10.0 pA to 159.6 pA was observed, and in rat AEC, from 6.9 pA to 62.4 pA. In whole cell patch clamp experiments in A549 cells, AP301-induced enhancement of the amiloride-sensitive current was eliminated when Na(+) in the bath solution was replaced with N-methyl-d-glucamine (NMDG), and when the cells were pre-incubated with 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR), an inhibitor of ENaC, but enhancement was unaffected by addition of cyclic nucleotide-gated (CNG) channel inhibitors Zn(2+) or l-cis-diltiazem prior to AP301. These results provide strong evidence that AP301 activates the amiloride-sensitive Na(+) current through ENaC in type II AEC from dog, pig and rat. To our knowledge, this is the first cell-based analysis of the oedema-clearing effect of AP301 observed in the porcine model of pulmonary oedema. Furthermore, the results validate the dog and pig models in non-clinical assessment of AP301.

Effect of Early Erythropoietin on Retinopathy of Prematurity: A Stratified Meta-Analysis.

BACKGROUND: Recombinant human erythropoietin (rhEPO) lost its role in minimizing red blood cell transfusion in very preterm infants after it had been associated with severe retinopathy of prematurity (ROP). Previous systematic reviews did not stratify ROP by gestation and birth weight (BW). OBJECTIVES: The aim of this study was to investigate the effect of early prophylactic rhEPO on ROP in a stratified meta-analysis of randomized controlled trials (RCTs). METHODS: The databases EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched in January 2022 and complemented by citation searching. RCTs comparing early rhEPO treatment with no treatment or placebo were selected if they were published in a peer-reviewed journal and reported ROP outcomes. Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW. Data were extracted and analyzed using the standard methods of the Cochrane Neonatal Review Group. Pre-specified outcomes were "ROP stage ≥3" (primary outcome) and "any ROP." RESULTS: Fourteen RCTs, comprising 2,040 infants of <29 weeks of GA, were included for meta-analysis. Data syntheses showed no effects of rhEPO on ROP stage ≥3 or on any ROP, neither in infants of <29 weeks GA, nor in infants of <1,000 g BW, nor in any GA strata. The risk ratio (95% confidence interval) for ROP stage ≥3 in infants of <29 weeks of GA was 1.13 (0.84, 1.53), p = 0.41 (quality of evidence: moderate). CONCLUSIONS: The present meta-analysis detected no effects of early rhEPO on ROP in any comparison, but most stratified analyses were limited by low statistical power.

Conformational ensemble of the TNF-derived peptide solnatide in solution.

Tumor necrosis factor (TNF) is a homotrimer that has two spatially distinct binding regions, three lectin-like domains (LLD) at the TIP of the protein and three basolaterally located receptor-binding sites, the latter of which are responsible for the inflammatory and cell death-inducing properties of the cytokine. Solnatide (a.k.a. TIP peptide, AP301) is a 17-mer cyclic peptide that mimics the LLD of human TNF which activates the amiloride-sensitive epithelial sodium channel (ENaC) and, as such, recapitulates the capacity of TNF to enhance alveolar fluid clearance, as demonstrated in numerous preclinical studies. TNF and solnatide interact with glycoproteins and these interactions are necessary for their trypanolytic and ENaC-activating activities. In view of the crucial role of ENaC in lung liquid clearance, solnatide is currently being evaluated as a novel therapeutic agent to treat pulmonary edema in patients with moderate-to-severe acute respiratory distress syndrome (ARDS), as well as severe COVID-19 patients with ARDS. To facilitate the description of the functional properties of solnatide in detail, as well as to further target-docking studies, we have analyzed its folding properties by NMR. In solution, solnatide populates a set of conformations characterized by a small hydrophobic core and two electrostatically charged poles. Using the structural information determined here and also that available for the ENaC protein, we propose a model to describe solnatide interaction with the C-terminal domain of the ENaCα subunit. This model may serve to guide future experiments to validate specific interactions with ENaCα and the design of new solnatide analogs with unexplored functionalities.

Prophylactic Erythropoietin for Neuroprotection in Very Preterm Infants: A Meta-Analysis Update.

A meta-analysis update of randomized controlled trials investigating recombinant human erythropoietin suggests improved neurodevelopmental outcome in preterm infants. There was substantial heterogeneity, which could be ascribed to a single trial. Exclusion of this trial featuring a high risk of bias abolished heterogeneity and any effects of recombinant human erythropoietin treatment.

Feasibility of Umbilical Cord Blood Collection in Neonates at Risk of Brain Damage-A Step Toward Autologous Cell Therapy for a High-risk Population.

Evidence for umbilical cord blood (UCB) cell therapies as a potential intervention for neurological diseases is emerging. To date, most existing trials worked with allogenic cells, as the collection of autologous UCB from high-risk patients is challenging. In obstetric emergencies the collection cannot be planned. In preterm infants, late cord clamping and anatomic conditions may reduce the availability. The aim of the present study was to assess the feasibility of UCB collection in neonates at increased risk of brain damage. Infants from four high-risk groups were included: newborns with perinatal hypoxemia, gestational age (GA) ≤30 + 0 weeks and/or birthweight <1,500 g, intrauterine growth restriction (IUGR), or monochorionic twins with twin-to-twin transfusion syndrome (TTTS). Feasibility of collection, quantity and quality of obtained UCB [total nucleated cell count (TNC), volume, sterility, and cell viability], and neonatal outcome were assessed. UCB collection was successful in 141 of 177 enrolled patients (hypoxemia n = 10; GA ≤30 + 0 weeks n = 54; IUGR n = 71; TTTS n = 6). Twenty-six cases were missed. The amount of missed cases per month declined over the time. Volume of collected UCB ranged widely (median: 24.5 ml, range: 5.0-102 ml) and contained a median of 0.77 × 108 TNC (range: 0.01-13.0 × 108). TNC and UCB volume correlated significantly with GA. A total of 10.7% (19/177) of included neonates developed brain lesions. To conclude, collection of UCB in neonates at high risk of brain damage is feasible with a multidisciplinary approach and intensive training. High prevalence of brain damage makes UCB collection worthwhile. Collected autologous UCB from mature neonates harbors a sufficient cell count for potential therapy. However, quality and quantity of obtained UCB are critical for potential therapy in preterm infants. Therefore, for extremely preterm infants alternative cell sources such as UCB tissue should be investigated for autologous treatment options because of the low yield of UCB.

Interventional creation of an endogenous reverse Potts shunt in an infant with pulmonary hypertension and genetic surfactant disorder-a case report.

Reverse Potts shunt is a palliative procedure aimed at decompressing the pressure-overloaded right ventricle in severe pulmonary hypertension (PH). We, herein, report the first case of an interventional creation of an "endogenous" reverse Potts shunt by stenting a pre-existing small but patent ductus arteriosus (PDA) in a 2 months old female infant with severe, supra-systemic PH, associated with a novel combination of a compound heterozygous ABCA3 mutation and additional heterozygous genetic variants of surfactant protein B (SFTPB) and C (SFTPC). The aforementioned combination of human genetic mutations has not been described before in viable infants, children or adults. The catheter intervention was performed via percutaneous femoral arterial access and was well-tolerated. Subsequently, the infant improved by means of clinical status, echocardiographic systolic right ventricular (RV) function, and serum NT-proBNP levels as biomarker of right atrial and RV pressure load. In conclusion, this single case report suggests that interventional stenting of a pre-existing PDA to create an "endogenous" reverse Potts shunt is feasible and efficacious in infants less than 3 months old with severe PH and impending RV failure associated with developmental lung disease.

Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition.

Fibroblast growth factors (FGF) and their high-affinity receptors (FGFR) represent an extensive cellular growth and survival system. Aim of this study was to evaluate the contribution of FGF/FGFR-mediated signals to the malignant growth of non-small cell lung cancer (NSCLC) and to assess their potential as targets for therapeutic interventions. Multiple FGFR mRNA splice variants were coexpressed in NSCLC cells (n = 16) with predominance of FGFR1. Accordingly, both expression of a dominant-negative FGFR1 (dnFGFR1) IIIc-green fluorescent protein fusion protein and application of FGFR small-molecule inhibitors (SU5402 and PD166866) significantly reduced growth, survival, clonogenicity, and migratory potential of the majority of NSCLC cell lines. Moreover, dnFGFR1 expression completely blocked or at least significantly attenuated s.c. tumor formation of NSCLC cells in severe combined immunodeficient mice. Xenograft tumors expressing dnFGFR1 exhibited significantly reduced size and mitosis rate, enhanced cell death, and decreased tissue invasion. When FGFR inhibitors were combined with chemotherapy, antagonistic to synergistic in vitro anticancer activities were obtained depending on the application schedule. In contrast, simultaneous blockage of FGFR- and epidermal growth factor receptor-mediated signals exerted synergistic effects. In summary, FGFR-mediated signals in cooperation with those transmitted by epidermal growth factor receptor are involved in growth and survival of human NSCLC cells and should be considered as targets for combined therapeutic approaches.

Hazards to avoid in future neonatal studies of nasal high-frequency oscillatory ventilation: lessons from an early terminated trial.

OBJECTIVE: To investigate whether nasal high-frequency oscillatory ventilation (nHFOV) started immediately after extubation of mechanically ventilated very low birth weight infants reduces the partial pressure of carbon dioxide at 72 h after extubation in comparison with nasal continuous positive airway pressure. This randomised controlled single-centre trial aimed to include 68 preterm infants at high risk of extubation failure. RESULTS: Implementation of the study protocol was feasible. However, from 2015 to 2017, only six patients could be recruited, leading to early termination of the trial. The slow recruitment was due to the introduction of new strategies to avoid endotracheal mechanical ventilation, which reduced the number of eligible infants. Moreover, the included infants failed their extubation more often than anticipated, thereby increasing the required sample size. Based on our single-centre experience, we provide information for study planning and discuss the specific requirements for future trial protocols on nHFOV. The extubation of high-risk infants into nHFOV could well be beneficial, but a multicentric approach is necessary to investigate this hypothesis. Trial Registration Clinicaltrials.gov NCT02340299, on 16 January 2015.

FGF18 in colorectal tumour cells: autocrine and paracrine effects.

Fibroblast growth factors (FGFs) and their high-affinity receptors contribute to the autocrine growth stimulation in several human malignancies. Here, we describe that FGF18 expression is up-regulated in 34/38 colorectal tumours and is progressively enhanced during colon carcinogenesis reaching very high levels in carcinoma. Moreover, our data suggest that FGF18 affects both tumour cells and tumour microenvironment in a pro-tumorigenic and pro-metastatic way. Addition of recombinant FGF18 to the culture media of slowly growing colorectal tumour cell lines LT97 and Caco-2 stimulated proliferation. Phosphorylation of externally regulated kinase 1/2 and S6 was increased already 5 min after growth factor addition. SW480 cells, endogenously producing large amounts of FGF18, were not affected in this setting, but recombinant FGF18 supported tumour cell survival under conditions of serum starvation. Down-modulation of endogenous FGF18 production by small interference RNA (siRNA) significantly reduced clonogenicity of SW480 cells and restored sensitivity to exogenous FGF18. With respect to the tumour microenvironment, both recombinant and tumour-derived FGF18 stimulated growth of colon-associated fibroblasts at 0.1 ng/ml and migration at 10 ng/ml. In addition, recombinant FGF18 (10 ng/ml) induced tube formation in human umbilical vein endothelial cells. siRNA knock down demonstrated that tube-forming activity of colon cancer cell supernatants depended to a large part on tumour cell-derived FGF18. In summary, this study demonstrates that FGF18 is almost generally over-expressed in colon cancer and exerts pro-tumorigenic effects both in the epithelial and the stromal compartments by stimulating growth and survival of tumour cells, migration of fibroblasts and neovascularization. Together, these data strongly support an oncogenic role of FGF18 in colorectal cancer.

Sustained inflations and avoiding mechanical ventilation to prevent death or bronchopulmonary dysplasia: a meta-analysis.

Sustained inflations and avoidance of endotracheal mechanical ventilation (eMV) are delivery room interventions aimed at preventing bronchopulmonary dysplasia (BPD). Their effectiveness is the subject of the present meta-analysis.The databases MEDLINE, EMBASE and CENTRAL were searched for randomised controlled trials (RCTs) of preterm infants that compared: 1) sustained inflations with intermittent positive-pressure ventilation; and 2) a non-intubated strategy of respiratory support with one that prescribed eMV at an earlier stage. Data extraction and analysis followed the standard methods of the Cochrane Collaboration. The primary outcome was death or BPD, defined as need for oxygen or positive pressure treatment at 36 weeks' postmenstrual age.Avoiding eMV (nine RCTs, 3486 infants) reduced the risk of death or BPD, with a risk ratio of 0.90 (95% CI 0.84-0.97) and a number needed to treat of 35. After sustained inflations (six RCTs, 854 infants), the risk ratio was 0.85 (95% CI 0.65-1.12). A current multicentre RCT of sustained inflations in very preterm infants was halted for increased early mortality in the sustained inflations arm.While strategies aimed at avoiding eMV had a small but significant impact on preventing BPD, sustained inflations had no effect and may even increase mortality in very preterm infants.

Differential impact of flow and mouth leak on oropharyngeal humidification during high-flow nasal cannula: a neonatal bench study.

BACKGROUND: Heated humidification is paramount during neonatal high-flow nasal cannula (HFNC) therapy. However, there is little knowledge about the influence of flow rate and mouth leak on oropharyngeal humidification and temperature. METHODS: The effect of the Optiflow HFNC on oropharyngeal gas conditioning was investigated at flow rates of 4, 6 and 8 L min-1 with and without mouth leak in a bench model simulating physiological oropharyngeal air conditions during spontaneous breathing. Temperature and absolute humidity (AH) were measured using a digital thermo-hygrosensor. RESULTS: Without mouth leak, oropharyngeal temperature and AH increased significantly with increasing flow (P < 0.001). Mouth leak did not affect this increase up to 6 L min-1, but at 8 L min-1, temperature and AH plateaued, and the effect of mouth leak became statistically significant (P < 0.001). CONCLUSIONS: Mouth leak during HFNC had a negative impact on oropharyngeal gas conditioning when high flows were applied. However, temperature and AH always remained clinically acceptable.

Nasal high-frequency oscillatory ventilation impairs heated humidification: A neonatal bench study.

OBJECTIVE: Nasal high-frequency oscillatory ventilation (nHFOV) is a novel mode of non-invasive ventilation used in neonates. However, upper airway obstructions due to viscous secretions have been described as specific adverse effects. We hypothesized that high-frequency oscillations reduce air humidity in the oropharynx, resulting in upper airway desiccation. Therefore, we aimed to investigate the effects of nHFOV ventilatory settings on oropharyngeal gas conditions. METHODS: NHFOV or nasal continuous positive airway pressure (nCPAP) was applied, along with heated humidification, to a previously established neonatal bench model that simulates oropharyngeal gas conditions during spontaneous breathing through an open mouth. A digital thermo-hygro sensor measured oropharyngeal temperature (T) and humidity at various nHFOV frequencies (7, 10, 13 Hz), amplitudes (10, 20, 30 cmH2 O), and inspiratory-to-expiratory (I:E) ratios (25:75, 33:66, 50:50), and also during nCPAP. RESULTS: Relative humidity was always >99%, but nHFOV resulted in lower mean T and absolute humidity (AH) in comparison to nCPAP (P < 0.001). Specifically, decreasing the nHFOV frequency and increasing nHFOV amplitude caused a decline in T and AH (P < 0.001). Mean T and AH were highest during nCPAP (T 34.8 ± 0.6°C, AH 39.3 ± 1.3 g · m-3 ) and lowest during nHFOV at a frequency of 7 Hz and an amplitude of 30 cmH2 O (T 32.4 ± 0.3°C, AH 34.7 ± 0.5 g · m-3 ). Increasing the I:E ratio also reduced T and AH (P = 0.03). CONCLUSION: Intensified nHFOV settings with low frequencies, high amplitudes, and high I:E ratios may place infants at an increased risk of upper airway desiccation. Future studies should investigate strategies to optimize heated humidification during nHFOV.

Prophylactic Early Erythropoietin for Neuroprotection in Preterm Infants: A Meta-analysis.

CONTEXT: Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates. OBJECTIVE: To investigate whether prophylactic rhEPO administration in very preterm infants improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources. STUDY SELECTION: RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months' corrected age. DATA EXTRACTION: Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment. RESULTS: Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31-0.81), P < .005. The number needed to treat was 14. There was no statistically significant effect on any secondary outcome. CONCLUSIONS: Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.