First intention high-frequency oscillatory and conventional mechanical ventilation in premature infants without antenatal glucocorticoid prophylaxis.

OBJECTIVE: Data comparing the effectiveness of high-frequency oscillatory ventilation and of conventional mechanical ventilation in the treatment of respiratory distress syndrome of very low birth weight infants are, to date, still matter of debate. We investigated the effects of first intention high-frequency oscillatory ventilation or conventional mechanical ventilation support on selected primary and secondary outcomes in very low birth weight infants complicated by respiratory distress syndrome in which antenatal glucocorticoid prophylaxis was not performed. DESIGN: Multicenter randomized control trial. SETTING: Three tertiary centers of neonatal intensive care units from December 2004 to December 2007. POPULATION: Eighty-eight very low birth weight infants complicated by respiratory distress syndrome, without antenatal glucocorticoids, supported by first intention high-frequency oscillatory ventilation (n = 44) or conventional mechanical ventilation (n = 44). INTERVENTIONS: All newborns were monitored by standard monitoring procedure, including routine laboratory variables, neurologic patterns, and ultrasound imaging. Primary outcomes were: the length of ventilatory support, the need of reintubation, and the length of nasal continuous positive airway pressure support in the postextubation period. Secondary outcomes were: the length of stay in neonatal intensive care unit and in hospital, death before discharge, adverse short- and long-term pulmonary and neonatal outcomes, and the need for a second dose of surfactant and of postnatal glucocorticoid treatment. RESULTS: High-frequency oscillatory ventilation infants showed a significant lower duration (p < .001 for all) of ventilator dependency, lower need of reintubation and of duration of nasal continuous positive airway pressure support in the postextubation period. Among secondary outcomes in the high-frequency oscillatory ventilation infants, the need of a second dose of surfactant administration, and the length of stay in the neonatal intensive care unit and in hospital were significantly lower (p < .05 for all). CONCLUSIONS: We found that high-frequency oscillatory ventilation in very low birth weight infants without antenatal glucocorticoid prophylaxis reduced the need of ventilatory support, surfactant therapy, and reintubation, and shortened neonatal intensive care unit and hospital stay, thus reducing unit and hospital costs. These data would support the usefulness of first intention high-frequency oscillatory ventilation strategy in managing in a selected population, such as very low birth weight newborns complicated by severe respiratory distress syndrome not antenatally treated with glucocorticoids.

Comparison of three non-invasive ventilation strategies (NSIPPV/BiPAP/NCPAP) for RDS in VLBW infants.

BACKGROUND: Non-invasive ventilation (NIV) significantly changed the management of respiratory distress syndrome (RDS) in preterm infants. Further perspectives for neonatologists regard the assessment of different NIV strategies in terms of availability, effectiveness, and failure. OBJECTIVE: The aim of the present study is to evaluate the effectiveness of three different NIV strategies: nasal continuous positive airway pressure (N-CPAP), nasal synchronized intermittent positive pressure ventilation (N-SIPPV), and nasal bilevel-CPAP (BiPAP), as first intention treatment for RDS in very low birth-weight infants (VLBW). METHODS: A multicenter retrospective study was conducted in three neonatal intensive care unit (NICUs) that enrolled 191 VLBW infants complicated by RDS, who received, as first intention treatment for RDS, three different NIV approaches (N-CPAP: n = 66; N-SIPPV: n = 62, BiPAP: n = 63). We evaluated the performance of different NIV strategies by primary (failure within the first 5 d of life) and some selected secondary end-points. RESULTS: The incidence of NIV failure was significantly higher in the N-CPAP group (22/66) versus N-SIPPV/BiPAP groups (11/62; 11/63) (p < .05 for both), while no difference was observed between N-SIPPV and BiPAP groups. Moreover, no differences were found between the three groups regarding secondary outcomes. CONCLUSIONS: The present study shows that first intention N-SIPPV/BiPAP, as NIV support, augment the beneficial effects of N-CPAP contributing to a reduced risk of failure in VLBW infants complicated by RDS. Data open up to further RCTs on a wider population to evaluate NIV effectiveness on long-term outcomes.

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. METHODS/DESIGN: In this study, 206 spontaneously breathing infants born at 24(+0)-27(+6) weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. DISCUSSION: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02482766 . Registered on 1 June 2015.

Noninvasive ventilation strategies for early treatment of RDS in preterm infants: an RCT.

BACKGROUND AND OBJECTIVES: There is evidence that new methods of noninvasive ventilation (NIV) support have significantly changed respiratory distress syndrome (RDS) management in preterm infants. Further perspectives for neonatologists involve the assessment of different NIV strategies in terms of availability, effectiveness, and failure. This study evaluates the efficacy of 2 different NIV strategies for RDS treatment in very low birth weight (VLBW) infants: nasal synchronized intermittent positive pressure ventilation (NSIPPV), which is a modality of conventional ventilation with intermittent peak inspiratory pressure, and bilevel continuous positive airway pressure (BiPAP), not synchronized, with 2 alternate levels of continuous positive airway pressure. METHODS: We conducted a 2-center randomized control study in 124 VLBW infants (<1500 g and <32 weeks of gestational age) with RDS who received NIV support (NSIPPV, n = 62; BiPAP, n = 62) within 2 hours of birth. We evaluated the performance of NIV strategies by selected primary outcomes (failure rate and duration of ventilation) and secondary outcomes. RESULTS: The number of failures and duration of ventilation support did not differ between NSIPPV and BiPAP strategies (P > .05 for both). Moreover, no differences between groups were found regarding secondary outcomes (P > .05 for all). CONCLUSIONS: The present data show no statistically significant differences between NSIPPV and BiPAP strategies in terms of duration of ventilation and failures, suggesting that both NIV techniques are effective in the early treatment of RDS in VLBW infants. Further randomized investigations on wider populations are needed to evaluate the effect of NIV techniques on long-term outcomes.

N-SIPPV versus bi-level N-CPAP for early treatment of respiratory distress syndrome in preterm infants.

OBJECTIVE: Non-invasive ventilation (NIV) for RDS in extremely/very low birth-weight infants represents the new challenge for neonatologists. In this regard, data comparing the effectiveness of Bi-Level-NCPAP (BiPAP) versus nasal synchronized intermittent positive pressure ventilation (NSIPPV) as primary mode of treatment for RDS are lacking. STUDY DESIGN: We conducted a retrospective study from December 2007 to December 2010 in seventy-eight infants, who received NIV (N-SIPPV: 33; BiPAP: 45). The primary outcomes were the length and failure of NIV. Secondary outcomes were adverse short-long term pulmonary outcomes, multiple doses of surfactant and others. RESULTS: There were no significant differences (p > 0.05) between the two different NIV modes. CONCLUSION: The present findings suggest that N-SIPPV and BiPAP gives similar results in the RDS treatment. We did not find a benefit of one over the other ventilation mode and both could be constitute a valid option to conventional mechanical ventilation. The theoretical benefits of these two different methods of NIV are tidal volume enhancement, improvements of the functional residual capacity and of the mean airway pressure and reducing apnea episodes. Further randomized studies to assess the advantages and the efficacy of different methods of NIV for the treatment of the RDS are needed.

Next generation biomarkers for brain injury.

In perinatal medicine, there is an emerging interest on the potential usefulness of non-invasive brain biochemical monitoring in infants at risk for brain injury. To date, several biomarkers such as neuro-proteins, calcium binding proteins, oxidative stress markers, vasoactive agents, inflammatory mediators, have been investigated. Results showed that hypoxia insult, under different conditions, triggers a biochemical pathophysiological cascade of events leading to brain damage. In this setting, increased biomarkers concentrations in different biological fluids have been found to correlate with the occurrence of brain damage at short-long term both in preterm and term fetuses/newborns. However, before inclusion of any biomarker in guidelines, USA and European institutions have recently stated a panel of criteria that have to be fulfilled. Therefore, the present review offers an overview of the main biomarkers currently studied in perinatal medicine and their progresses according to institutions' criteria.

Biomarkers of brain damage in preterm infants.

OBJECTIVE: There is growing evidence on the usefulness of biomarkers in the early detection of preterm infants at risk for brain damage. However, among different tools Activin A, S100B protein and adrenomedullin assessment offer the possibility to investigate brain/multiorgan function and development. This could be especially useful in perinatal medicine that requires even more non-invasive techniques in order to fulfill the minimal handling in diagnostic and therapeutic strategy performance. MATERIALS AND METHODS: The concept of Unconventional Biological Fluid (UBF: urine and saliva) is becoming even stronger and regards the assessment in non-invasive biological fluids of biochemical markers involved in the cascade of events leading to brain damage. RESULTS: Activin A, S100B protein and adrenomedullin in UBF were increased in preterm newborns developing brain damage and/or ominous outcome. CONCLUSIONS: The present manuscript offers an update on the usefulness of Activin A, S100B protein an adrenomedullin in UBF as brain damage markers. The findings open a new cue on the use of these markers in daily neonatal intensive care unit (NICU) activities.

Neuromarkers and unconventional biological fluids.

There is a growing evidence on the use of biomarkers in daily practice both as of markers of brain/multiorgan damage and/or trophic factors. However, among different tools, Activin A, S100B protein, and Hemeoxygenase-1 (HO-1 or Heat Shock Protein 32, HSP32) assessment offer the possibility to investigate brain/multiorgan function and development. This could be especially useful in perinatal medicine that requires even more noninvasive techniques to fulfill the minimal handling diagnostic and therapeutic strategy. In this regard, among different biological fluids, human milk for its unique composition can constitute a wide source of knowledge useful both in clinical daily practice and in research.Therefore, this mini-review reports recent data on the presence and the usefulness of Activin A, S100B protein, and HO-1/HSP32 assessment in human milk as brain/multiorgan development markers. Results open up a new cue on the use of these markers in perinatal medicine as a key protein for investigations focusing on fetal/neonatal development.

New markers of neonatal neurology.

Hypoxia-ischemia (H-I) constitutes the main phenomenon responsible for brain-blood barrier permeability modifications leading to cerebral vascular auto-regulation loss in newborns. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation loss leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents, of calcium mediated effects could be responsible for reperfusion injury (R-I), which, in turns, leads to cerebral hemorrhage and damage. These phenomena represent a common repertoire in newborns complicated by perinatal acute or chronic hypoxia treated by risky procedures such as mechanical ventilation, nitric oxide supplementation, brain cooling, and extracorporeal membrane oxygenation (ECMO). Despite accurate monitoring, the post-insult period is crucial, as clinical symptoms and standard monitoring parameters may be silent at a time when brain damage is already occurring and the therapeutic window for pharmacological intervention is limited. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk newborns. The present review is aimed at investigating the role of biochemical markers such as adrenomedullin, a vasoactive peptide; S100B, a calcium binding protein, activin A, a glycoprotein, in the cascade of events leading to I-R injury in newborns complicated by perinatal asphyxia.