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Critical appraisal of the evidence underpinning the efficacy of less invasive surfactant administration
  1. Stefano Nobile1,
  2. Anthea Bottoni1,
  3. Lucia Giordano1,
  4. Angela Paladini1,
  5. Giovanni Vento1,2
  1. 1Neonatology Unit, Department of Mother, Child and Public Health, Agostino Gemelli University Hospital Foundation IRCCS, Rome, Italy
  2. 2Catholic University of the Sacred Heart, Rome, Italy
  1. Correspondence to Dr Stefano Nobile, Division of Neonatology, Department of Mother, Child and Public Health, Agostino Gemelli University Hospital Foundation IRCCS - Catholic University of the Sacred Heart, Rome 8,00168, Italy; stefano.nobile{at}

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We read with great interest the network meta-analysis by Bellos and colleagues1 aimed at comparing less invasive surfactant administration (LISA, via thin catheters, laryngeal mask, nebulisation, pharyngeal instillation), intubation and surfactant administration followed by immediate extubation (InSurE) and no surfactant administration among preterm infants born <37 weeks of gestation. Primary outcomes were mortality, mechanical ventilation (MV) and bronchopulmonary dysplasia (BPD). Secondary outcomes were necrotising enterocolitis, intraventricular haemorrhage, pneumothorax, periventricular leukomalacia, patent ductus arteriosus and need of repeat dose of surfactant. The authors included 16 randomised controlled trials (RCTs) and 20 observational studies with overall 13 234 patients. They concluded that surfactant administration via thin catheters was associated with lower likelihood of mortality, need for MV and BPD compared with InSurE, even if, in RCTs, thin catheter administration lowered the rates of MV but not the incidence of the remaining outcomes.

After a deeper appraisal of the included papers, we would like to highlight some concerns about the validity and generalisability of authors’ conclusions, particularly regarding the comparison between InSurE and LISA. Out of the 27 papers comparing LISA with InSurE, 10 (mainly conducted in Germany) compared LISA with mechanical ventilation (not properly InSurE); 5 were retrospective studies with historical cohorts; 2 were quality improvement studies; 1 was retracted. Out of the remaining nine, two employed cerebral near-infrared spectroscopy to assess short-term cerebral oxygenation with conflicting results; one was a 24-month follow-up study showing no differences between groups; one included infants born >32 weeks of gestation (at low risk of mortality, BPD and prolonged MV).2 Five studies (four randomised and one retrospective) conducted in low/middle-income healthcare settings recruited 1169 infants (596 treated with LISA and 573 with InSurE). These studies showed that infants treated with LISA versus InSurE had less need for MV, lower incidence of BPD and (in one study) lower mortality. We respectfully feel that considering baseline data from these studies such as the relatively low proportion of infants receiving antenatal steroids (60%–80%) and the wide variability of practices (ie, caesarean section rate, etc), the generalisability of the results should be questioned.

Moreover, less than 300 extremely low gestational age newborns (ELGANs) were recruited in these five studies; therefore, the safety and efficacy of LISA in this population remain to be confirmed, also considering that extreme prematurity is an independent risk factor for LISA failure.3

A recent multicentre RCT from Italy (n=218 ELGANs) comparing InSurE with a lung recruitment manoeuvre just before surfactant administration followed by rapid extubation (IN-REC-SURE) showed that the latter was associated with significantly lower rates of MV at 72 hours and mortality.4

It would be interesting to compare LISA with IN-REC-SURE, particularly among ELGANs, before definitive conclusions about the safety and efficacy of LISA could be provided.

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  • Collaborators INRECSURE study group.

  • Contributors SN and GV conceived the work, revised it critically for important intellectual content, approved the final version and agree to be accountable for all aspects of the work. AB, LG and AP analysed data, revised it critically for important intellectual content, approved the final version and agree to be accountable for all aspects of the work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.