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

Neonatal Early Onset Sepsis: Impact of Kaiser Calculator in an Italian Tertiary Perinatal Center

Background: Suspected early-onset sepsis (EOS) results in antibiotic treatment and blood withdraw of a substantial number of neonates who are uninfected. We evaluated if the EOS calculator can reduce antibiotic exposure and invasive procedures for suspected EOS in term and late preterm neonates, without any significant increase in adverse outcomes. Methods: The proportion of EOS risk in neonates >= 35 weeks gestation exposed to antibiotics, intensive monitoring and blood withdrawal was compared between a baseline period (January 2018-May 2018), when Centers for Disease Control guidelines approach was used, and a post-EOS calculator-implementation period (June 2018-December 2019). Results: We included 4363 newborn infants with gestational age >= 35 weeks, respectively 824 in baseline period and 3539 in the EOS calculator period. Among them, 1021 (23.4%) infants presented risk factors for neonatal sepsis. There was a halving in empirical antibiotics exposure: 3% in the baseline and 1.4% in the post-EOS-implementation period, P < 0.05. Blood culture and laboratory evaluations had fallen from 30.6% to 15.4% (P < 0.05). Close monitoring of vital parameters decreased from 25.4% to 4.8% (P < 0.05). The number of antibiotic days per 100 live births decreased from 15.05 to 6.36 days (P <0.05). The incidence of culture-confirmed sepsis and clinical sepsis was very low in 2 periods. Only one infant identified at low-risk by Kaiser calculator at birth developed symptoms after 12 h from birth. We had no readmissions for EOS. Conclusions: Application of the EOS calculator more than halved the burden of intensive monitoring and antibiotic exposure, without compromising safety in a population with a relatively low incidence of culture-proven EOS and good access to follow-up care

Surfactant synthesis and kinetics in infants with congenital diaphragmatic hernia

In animal models of congenital diaphragmatic hernia (CDH), surfactant deficiency contributes to the pathophysiology of the disease; however, information on CDH in humans is limited. We compared surfactant disaturated phosphatidylcholine (DSPC) synthesis and metabolism, by stable isotope technology, in newborn infants with CDH and in control subjects. DSPC amount, total proteins, and surfactant protein-A (SP-A) from tracheal aspirates were also measured. DSPC and SP-A were significantly lower in 14 infants with CDH than in the eight control subjects. Mean DSPC was 2.3 \ub1 1.3 mg/ml of epithelial lining fluid (ELF) in infants with CDH and 4.6 \ub1 1.5 mg/ml of ELF in control subjects (p = 0.001). Mean SP-A in infants with CDH and in control subjects was 16.2 \ub1 9.3 and 61.2 \ub1 30.6 \u3bcg/ml of ELF, respectively (p = 0.03). DSPC kinetics was measured in 12 of 14 infants with CDH and in 5 of 8 control subjects. Secretion time was 8.3 \ub1 5.5 and 8.5 \ub1 2.5 hours and peak time 51.9 \ub1 1.5.2 and 51 \ub1 13 hours in infants with CDH and in control subjects, respectively. Fractional synthesis rate was not different for infants with CDH and control subjects (p = 0.4). In conclusion, surfactant DSPC synthesis and kinetics were not significantly deranged in infants with CDH compared with control subjects. Other factors, such as lower surface area or increased DSPC catabolism, may contribute to surfactant pool alteration in CDH

Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial

Background: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E]). Methods: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766. Findings: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57–0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7–135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111). Interpretation: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy. Funding: None

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