Sustained lung inflation in extreme preterm infants

April 06, 2015


Lista G, Boni L, Scopesi F, et al. for the SLI Trial Investigators. Sustained lung inflation at birth for preterm infants: a randomized clinical trial. Pediatrics 2015;135:e457-64. PMID 25624390


Neeraj Gupta MD, DM
Associate Professor
Department of Neonatology
All India Institute of Medical Sciences,
Jodhpur-342005, India

Ramesh Agarwal MD, DM
Additional Professor
Department of Pediatrics
All India Institute of Medical Sciences
New Delhi-110029, India




Does application of prophylactic sustained lung inflation (SLI) combined with early nasal continuous positive airway pressure (nCPAP) after birth (I) as compared to early CPAP alone (C) reduce the need for mechanical ventilation (MV) (O) in first 72 hours of life (T) amongst preterm infants of 25 to 28 completed weeks of gestation (P)?


  • Design: Randomized controlled trial with stratified block-randomized design and an allocation ration of 1:1.
  • Allocation concealment: Subjects stratified according to center and gestational age (<27 weeks and ≥27 weeks). The random list was generated in permuted blocks of variable sizes. However, the method of generating random sequence has not been specified. Allocation was concealed through use of serially numbered, opaque, sealed envelopes.
  • Blinding: Due to obvious nature of intervention, blinding was not possible. However, the researchers who took the decision to start mechanical ventilation in first 72 hrs of life (i.e., primary outcome) and those assessing the study end points were blinded to the intervention. There is no comment about the same for the statistician involved in the data analysis.
  • Follow-up period: Infants followed until death or hospital discharge
  • Setting: Multiple Italian perinatal centers
  • Patients: All infants between the ages of 25+0 and 28+6 weeks of gestation irrespective of the respiratory status at birth were enrolled. Infants with major congenital malformations (congenital heart, cerebral, lung, abdominal malformations) and those with hydrops were excluded.
  • Intervention:
    • Intervention group (SLI group): Following standard initial resuscitation steps, a sustained pressure controlled inflation of 25 cm H2O was applied for a duration of 15 seconds using neonatal mask. This was followed by delivery of 5 cm H2O CPAP, using a neonatal mask and a T-piece ventilator (Neopuff, Fisher & Paykel, New Zealand). The initial flow rate set was 8 to 10 L/min before resuscitation which was not changed during resuscitation. Infants were observed for the next 6 to 10 seconds; if respiratory failure persisted (i.e., apnea, gasping) and/or the heart rate was >60 and <100 beats/min despite CPAP, the SLI maneuver was repeated. If the heart rate remained >60 and <100 beats/min after the second SLI maneuver, the infant was resuscitated following the standard guidelines.
    • Control group: Infants in the control group received nCPAP at 5 cm H2O and were assisted according to the standard guidelines. Infants in both groups who did not require any intubation in the delivery room were transferred to the NICU on nCPAP at 5 cm H2O with a FIO2 of 0.21 to 0.40.
    • Criteria for starting mechanical ventilation (MV): Mechanical ventilation was started in the delivery room only if the infants had a heart rate <60 beats/min despite optimum positive pressure ventilation, in agreement with standard guidelines. After transferring to NICU, MV was started according to well-defined criteria.
    • Other aspects of respiratory care: Surfactant (200 mg/kg; Curosurf, Chiesi, Italy) was given to infants on nCPAP who required an FIO2 of ≥0.40 to maintain targeted SpO2 (88% – 95%). It was followed by re-institution of nCPAP as soon as their vital signs were satisfactory. All infants who required mechanical ventilation also received surfactant. The need of additional doses of surfactant was at the discretion of the attending neonatologist. Infants received a loading dose of caffeine citrate before extubation when they met a pre-defined criteria.
  • Outcomes:
    • Primary: Proportion of infants requiring MV in first 72 hours of life in each group.
    • Secondary: The pre-specified secondary outcomes were MV in the first 3 hours of life, highest FiO2, duration of nCPAP, need and duration of bilevel nCPAP, nasal IMV, MV high frequency ventilation, duration of hospitalization, need and number of doses of surfactant, occurrence of respiratory distress syndrome (RDS) (defined as typical clinical signs and chest X-ray findings and exclusion of other causes of respiratory failure), bronchopulmonary dysplasia (BPD) (defined as need for supplemental oxygen to maintain adequate oxygenation at 36 weeks of postconceptional age) and mortality.
    • Additional data was collected on the following parameters not included under secondary outcomes: pneumothorax, pharmacologic treatment and surgical closure of patent ductus arteriosus, intraventricular hemorrhage (grade ≥3), periventricular leukomalacia, retinopathy of prematurity (grade ≥3), necrotizing enterocolitis, sepsis and length of stay in hospital.
  • Analysis and sample size: Published data from a previous study showed the baseline incidence of the need of MV within 72 hours after birth to be 35%. For reducing it to 20% with 80% power and alpha error of 0.05, a sample size of 138 neonates in each group was required. However, a total of 294 infants were randomized.
  • Patient follow-up: Subjects were followed until discharge or death. Intention to treat analysis was performed. A total of three infants were excluded (1 erroneously randomized to treatment twice, 2 stillbirths).


A total of 354 infants were screened of whom 294 were randomized to either arm (144 in control group and 150 in intervention group). The mean gestational age was 26.8 weeks in both the groups and mean birth weight was 894 g and 893 g in control and interventional groups, respectively. Baseline variables including antenatal steroids, prolonged premature rupture of membrane and chorioamnionitis were equally distributed in each group but there were more males in SLI group (58% vs. 45%). The main results are shown in Table 1:

Table 1: Primary and Secondary Outcomes

Primary outcome, n (%)
Outcome Control Group(n=143) SLI Group (n=148) Unadjusted Odds Ratio (95% CI@) P value Adjusted Odds Ratio (95% CI)*
Mechanical ventilation (MV) within first 72 h of life 93 (65) 79 (53) 0.62 (0.38-0.99) 0.04 0.57 (0.33-0.96)
Secondary outcome
Any MV 98 (69) 88 (59) 0.67 (0.42-1.10) 0.11 0.68 (0.41-1.13)
Bronchopulmonary dysplasia 50 (33) 57 (39) 1.17 (0.80 – 1.71) 0.42 1.14 (0.78-1.69)
Other Collected data
Pneumothorax 2 (1) 9 (6) 4.57 (0.97-21.50) 0.06
Interstitial emphysema 2 (1) 7 (5) 3.50 (0.72-17.10) 0.09

@ Confidence interval; *Adjusted for center and gestational age

The application of prophylactic SLI followed by early CPAP at birth reduced the need of MV by 43% (95% CI 4% – 67%) in first 72 hours of life as compared to early CPAP alone. However, there was no statistically significant difference in death (11% vs. 8%; p=0.40), BPD (39% vs. 35%; p=0.42) or death or BPD (50% vs. 43%) among the two groups. Moreover, there was a trend towards increase incidence of pneumothorax (6% vs. 1%; p=0.06) and interstitial emphysema (5% vs. 1%; p=0.09)) in the SLI group.

There was no difference in any of the other pre-defined secondary outcomes including overall need and duration of invasive or non-invasive ventilation.


The authors concluded that SLI followed by nCPAP in the delivery room decreased the need for MV in the first 72 hours of life in preterm infants at high risk of RDS as compared with nCPAP alone but did not decrease the need for respiratory support and the occurrence of BPD.

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The protection of preterm lungs should start immediately after birth and the current trial is a much awaited research in this direction. The current study (1) evaluates the role of application of prophylactic sustained lung inflation (SLI) immediately after birth as a lung protective strategy in decreasing the need of mechanical ventilation (MV) in first 72 hours of life and in preventing bronchopulmonary dysplasia (BPD) among extreme preterm infants. BPD is a multifactorial disease and the advantage of SLI over intermittent MV in terms of improving functional residual capacity(2, 3) forms the basis of this trial. The application of SLI immediately after birth is a new strategy which was first evaluated by Lindner et al in 1999 (4). Two additional studies showed beneficial effects of SLI, however, one was an observational study (5) and the other didn’t use positive end expiratory pressure (6).

The current randomized trial has used nCPAP immediately after birth in the control group and in the intervention group following SLI, thus overcoming the disadvantage of the previous trial. The investigators elucidated eligibility and exclusion criteria. The actual time of taking consent (antenatal or immediately after birth) is not clear. There was appropriate generation of the randomization sequence and allocation concealment. Though the researchers who decided to start MV and those assessing the study end points were blinded to the intervention however, the caregivers were not blinded which could have led to performance bias. Given the paucity of literature, the amount and duration of pressure chosen for providing SLI seems appropriate. Authors have set the SpO2 targets at 88%-95% against the currently recommended targets of 91-95%. The sample size was calculated a priori and the outcomes were clearly defined. All randomized subjects completed the trial as per protocol, and all pre-defined outcomes were reported. Authors have used intention-to-treat principle.

The current study has shown that the application of prophylactic SLI followed by nCPAP in the delivery room decreased the need for MV in the first 72 hours of life in extreme preterm infants. However, there is no effect on the robust clinical outcomes like death, BPD or death or BPD. Additionally, there is concern of a trend towards increased incidence of pneumothorax and interstitial emphysema, which may be related to the pressure and duration used in SLI. Moreover, there is no statistically significant difference in need and duration of any respiratory support. Though the trial has not resulted in reduction of BPD or death, the reduction in need of MV in first 72 hours may be beneficial in resource restricted settings where the availability of MV is limited.

Given these findings, the routine application of SLI at birth cannot be recommended in extreme preterm infants. More trials are required across different settings and gestations to establish its efficacy. Given the risk of air leak syndromes, future trials also need to establish the optimal pressure and duration of SLI. Moreover, the data regarding the neurodevelopmental outcome needs to be generated to establish its long-term safety.


  1. Lista G, Boni L, Scopesi F, Mosca F, Trevisanuto D, Messner H, et al. Sustained lung inflation at birth for preterm infants: a randomized clinical trial. Pediatrics. 2015; 135:e457-64
  2. Vyas H, Milner AD, Hopkin IE, Boon AW. Physiologic responses to prolonged and slow-rise inflation in the resuscitation of the asphyxiated newborn infant. J Pediatr. 1981; 99:635-9
  3. Boon AW, Milner AD, Hopkin IE. Lung expansion, tidal exchange, and formation of the functional residual capacity during resuscitation of asphyxiated neonates. J Pediatr. 1979; 95:1031-6
  4. Lindner W, Vossbeck S, Hummler H, Pohlandt F. Delivery room management of extremely low birth weight infants: spontaneous breathing or intubation? Pediatrics. 1999; 103:961-7
  5. Lista G, Fontana P, Castoldi F, Cavigioli F, Dani C. Does sustained lung inflation at birth improve outcome of preterm infants at risk for respiratory distress syndrome? Neonatology. 2011; 99:45-50
  6. te Pas AB, Walther FJ. A randomized, controlled trial of delivery-room respiratory management in very preterm infants. Pediatrics. 2007; 120:322-9


  • Stefan Johansson
    Stefan Johansson 9 years ago

    Very interesting study, but the safety issue seems a concern.
    I think the outcome (risk of mechanical ventilation) is good, but that choice also requires a study population in which MV is frequently needed, i.e. extremely preterm infants.
    It would have been interested to see a well-powered study of SLI and whether SLI affects indicators of pulmonary function/health in a study population of very preterm infants (week 28-31). Outcomes such as nb of days on CPAP and BPD would be also clinically relevant to know.

    MEGAN GOSSLING 9 years ago

    This is a very interesting study and adds to the conversation of how to best improve respiratory outcomes in very/extremely low birth weight infants. Does any one have thoughts or experience on combining the INSURE technique with SLI to optimize lung recruitment? I think from a pathophysiology standpoint this combination could be promising in prevention of mechanical ventilation and/or reduction of BPD in this population.

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