MANUSCRIPT CITATION

Vento G, Ventura ML, Pastorino R, van Kaam AH, Carnielli V, Cools F, Dani C et al. Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial. Lancet Respir Med. 2020 Jul 17;S2213-2600(20)30179-X. doi: 10.1016/S2213-2600(20)30179-X. Online ahead of print. PMID: 32687801

REVIEWED BY

Benjamin W. Ackermann, MD
Division of Neonatology, Department of Women’s and Children’s Health
University of Leipzig Medical Center, Leipzig, Germany

Kirsten Glaser, MD
Division of Neonatology, Department of Women’s and Children’s Health
University of Leipzig Medical Center, Leipzig, Germany

TYPE OF INVESTIGATION

Prevention, treatment

QUESTION

In (P) spontaneously breathing preterm infants born between 24 0/7 and 27 6/7 weeks’ gestation presenting with respiratory failure on CPAP, does (I) lung recruitment maneuver prior to surfactant administration (intubate-recruite-surfactant-extubate [IN-REC-SUR-E]) (C) compared to standard intubation-surfactant-extubation (IN-SUR-E) procedure (O) reduce the need for mechanical ventilation (T) in the first 72h of life?

METHODS

• Design: multi-center, unblinded, randomized controlled trial. Trial registration number NCT02482766.
• Allocation: Allocation based on a web-based electronic system. 1:1 randomization stratified by center and gestational age (24 0/7 – 25 6/7 or 26 0/7 – 27 6/7).
• Blinding: Patients, parents, and those delivering the intervention were not blinded to allocation.
• Follow-up period: Infants were followed up till first hospital discharge or death.
• Setting: 35 Italian tertiary neonatal intensive care units
• Patients:
  • Inclusion criteria:
    • Preterm infants born at 24 0/7 to 27 6/7 weeks’ gestation presenting with respiratory failure on CPAP in the first 24h of life. CPAP failure was defined as FiO₂ > 0.3 at CPAP 6-7 cm H₂O to maintain SpO₂ levels of 87 – 94% for at least 30 min, or respiratory acidosis with PCO₂ > 65mm Hg and pH < 7.20
    • Written informed consent from both parents before enrollment.
  • Exclusion criteria:
    • Prolonged premature rupture of membranes (> 21d)
    • Severe asphyxia or 5-minute Apgar score < 3
    • Need for intubation in the delivery room for resuscitation or insufficient respiratory drive
    • Major congenital abnormalities
    • Inherited disorder of metabolism
    • Hydrops fetalis
    • Withdrawn consent
• Intervention:
  • IN-REC-SUR-E: After intubation, high-frequency oscillatory ventilation (HFOV) was started (mean airway pressure of 8 cm H₂O, frequency of 15 Hz, ΔP of 15 cm H₂O, and inspiration to expiration ratio of 1:2). Lung recruitment was performed using stepwise increments and decrements according to the de Jaegere method. After decreasing the mean airway pressure to a pressure 1-2 cm H₂O above the closing pressure, 200mg/kg of surfactant (poractant alfa) was applied.
  • Control group (IN-SUR-E): Infants were intubated and received 200mg/kg of surfactant (poractant alfa) immediately afterwards while being ventilated manually using a T-device (inspiratory pressure of 20 – 22 cm H₂O, PEEP of 5 – 6 cm H₂O, and respiratory rate of 30–40 breaths per minute), without previous lung recruitment.
  • Both groups initially received 1-2 sustained lung inflations (25 cm H₂O for 10–15 s) as standard management in the delivery room. Infants who transitioned successfully to spontaneous breathing were treated with CPAP (6 – 7 cm H₂O) administered via nasal prongs or nasal mask according to the standard methode of each study centre. All infants were started on early caffeine. In the event of CPAP failure, all study patients received opioid drugs prior to intubation according to local protocols. In both groups, infants with adequate respiratory drive were extubated 30 min after surfactant and recommenced on CPAP. Study patients who met CPAP failure criteria again within the next 24h received a second dose of surfactant (100mg/kg of poractant alfa) according to randomization.
• Outcomes:
  • Primary outcome: Need for mechanical ventilation in the first 72h of life, defined as oxygenation failure (FiO₂ > 0.40), respiratory acidosis (PCO₂ > 65 mm Hg, pH < 7.20), or more than four apnea episodes per hour, or more than 2 bag and mask ventilations per hour.
  • Secondary outcomes: mortality, duration of invasive and non-invasive respiratory support, oxygen therapy, number of surfactant doses, rate of moderate or severe BPD, pneumothorax, pulmonary interstitial emphysema, pulmonary hemorrhage; need for patent ductus arteriosus treatment, intraventricular hemorrhage grade 3-4, periventricular leukomalacia, retinopathy of prematurity > grade 2, NEC, sepsis, rate of postnatal systemic steroids.
• Analysis and Sample Size:
  • Sample size was determined targeting a decrease in the need of mechanical ventilation during the first 72h of life from 50% to 30%. A minimum of 103 infants in each group was calculated (α = 0.05, β = 0.80), and 218 patients were randomly assigned.
  • Data were analyzed following the intention-to-treat and per-protocol principles, with the primary outcome assessed in the intention-to-treat population.
  • Intention-to-treat analysis included all infants assigned to study intervention; per-protocol analysis included all those infants, who received and completed the study intervention and met the inclusion criteria.
  • The primary outcome was calculated using a log-binominal regression model correcting for stratification factors (gestational age, study centre).
  • Multivariable log-binomial regression analysis was used to test for an independent role of gestational age, sex, antenatal steroids, and 5-min Apgar score in predicting clinical outcome.
  • Interim-analysis for safety was done at 50% recruitment.
• Patient follow-up: Of 556 eligible infants, 107 were allocated to IN-REC-SUR-E, 111 were allocated to IN-SUR-E. In the intervention group, six patients were excluded from the per-protocol analysis for the reason of not having received the allocated recruitment maneuver (n=3), having met the exclusion criteria of prolonged (> 3 weeks) premature rupture of membranes (n=2), or presence of congenital malformation (n=1). 4 of these 6 patients formerly allocated to IN-REC-SUR-E died during hospital stay. The intention-to-treat analysis comprised 218 patients, per-protocol analysis 212 patients.

MAIN RESULTS

No differences in baseline characteristics were observed. All infants received fentanyl (89% vs. 90%) or remifentanil (11% vs. 10%) prior to intubation. The high-frequency oscillatory recruitment maneuver had a median duration of 30 min (IQR 20–45 min), contributing to an increased age in hours of life at first surfactant application (IN-REC-SUR-E: 4h [3h – 9h]; IN-SUR-E: 3h [2h – 5h]). FiO₂ at the optimal mean airway pressure (post-recruitment) in IN-REC-SUR-E infants was lower than FiO₂ upon surfactant administration in IN-SUR-E babies (0.28 vs. 0.42, p < 0.0001). All infants in the intervention and control group were extubated to CPAP within 30 min after surfactant (7.0 cm H₂O, SD 0.4 with FiO₂ 0.25, SD 0.04 vs. 7 cm H₂O, SD 0.4 with FIO₂ 0.26, SD 0.06) followed by comparable proportions of non-invasive ventilatory strategies.

Primary outcome: The need for mechanical ventilation was significantly reduced in infants allocated to IN-REC-SUR-E (40% vs. 54%; adjusted RR 0.75, 95% CI 0.57 – 0.98, p = 0.037) with a number needed to treat of 7.2. The main reason for mechanical ventilation was acute respiratory failure (84% vs. 85%). Other reasons were infection (5% vs. 8%), patent ductus arteriosus (7% vs. 5%) and surgery (5% vs. 2%). Per-protocol analysis supported the finding of reduced need of mechanical ventilation in the first 72h in IN-REC-SUR-E babies (39% vs. 54%; adjusted RR 0.71, 95% CI 0.53 – 0.96, p = 0.028). Multi-variable analysis in the per-protocol population showed that older gestational age (RR 0.88, 95% CI 0.78 – 0.99) and IN-REC-SUR-E treatment (RR 0.73, 95% CI 0.54 – 0.98) were associated with reduced need for mechanical ventilation within the first 72h of life. HFOV recruitment maneuver took 30 min in median.

Secondary outcomes: IN-REC-SUR-E was associated with decreased mortality according to per-protocol analysis (19% vs. 33%, p = 0.020), and there was a trend towards less mortality in IN-REC-SUR-E treated infants upon intention-to-treat analysis as well (21% vs. 33% in IN-SUR-E infants, p = 0.055). Differences were observed in deaths secondary to respiratory failure, with 9 cases noted in the IN-REC-SUR-E group (severe RDS [n=5], severe RDS and persistent pulmonary hypertension (PPHN) [n=3], pneumothorax [n=1]) but 17 cases in infants allocated to IN-SUR-E (severe RDS [n=7], pulmonary hemorrhage [n=6], severe RDS and PPHN [n=3], pneumothorax [n=1]). Of note, pulmonary hemorrhage was the main cause of death during the first 24h of life after surfactant administration. All four cases occurred in IN-SUR-E treated infants, although the overall incidence of pulmonary hemorrhage was not different between both study groups.

Rates of moderate and severe bronchopulmonary dysplasia did not differ among study groups nor did the rates of other secondary outcomes. However, there was a trend towards lower numbers of infants requiring two doses of surfactant in the IN-REC-SUR-E group (41% vs. 52%; RR 0.79, 95% CI 0.59–1.05, p=0.10) (table 2).

^a Defined by the use of supplemental oxygen or nasal CPAP or mechanical ventilation at a post-menstrual age of 36 weeks.

CONCLUSION

In preterm infants born at 24 0/7 to 27 6/7 weeks’ gestation requiring non-invasive ventilation and meeting CPAP failure criteria, HFOV lung recruitment prior to surfactant administration (IN-REC-SUR-E) reduced the need for mechanical ventilation in the first 72h of life compared to standard IN-SUR-E. This short-term effect was not reflected by reduced duration of ventilatory support or decreased rates of moderate to severe bronchopulmonary dysplasia. Further adequately powered trials are needed to assess potential benefits or harms of IN-REC-SUR-E versus standard IN-SUR-E for short and long-term outcome.

COMMENTARY

Surfactant deficiency is a major cause of CPAP failure in extremely preterm infants. To avoid harmful effects associated with invasive mechanical ventilation, alternative techniques of surfactant administration have evolved, combining the positive effects of surfactant and early CPAP. The INtubation-SURfactant-Extubation (IN-SUR-E) procedure comprises intubation, intra-tracheal surfactant administration and immediate extubation to CPAP (1, 2). It is widely used, although not always successful (3). In preterm animal models of respiratory distress, lung recruitment prior to surfactant was shown to improve homogenous distribution and efficacy (4).

This prospective unblinded RCT sought to evaluate efficacy and safety of a modified IN-SUR-E approach applying high-frequency oscillatory ventilation (HFOV) lung recruitment prior to surfactant (IN-REC-SUR-E) compared to standard IN-SUR-E. It is an important study – since being the first large trial addressing this question in very immature preterm infants. The authors present intention-to-treat analysis as gold standard to address missing data as well as per-protocol analysis. The study showed a reduced need for mechanical ventilation in the first 72h of life in the intervention group – with a number needed to treat of 7.2 –, without adversely affecting in-hospital mortality and other secondary outcomes. The current findings suggest that IN-REC-SUR-E is a safe and effective approach of surfactant administration in preterm infants managed on and failing early CPAP.

However, it is important to acknowledge some limitations. As far as the primary outcome is concerned, it seems critical that the protocol lacked precise criteria for extubation and re-intubation. Given the missing blinding this study design potentially introduced significant bias among intervention and study group. Differences in time intervals between sedation and extubation display further weaknesses. While extubation directly followed intubation and surfactant administration in infants randomized to IN-SUR-E, it took 30min in median to establish successful lung recruitment in patients allocated to IN-REC-SUR-E, with subsequently more time passing for metabolism of sedative drugs. This fact may have had significant impact on the likelihood of failure or success of post-surfactant non-invasive ventilatory support. Heterogeneity of ventilation strategies is a major limitation. While infants allocated to IN-SUR-E received surfactant during manual ventilation, surfactant was administered to IN-REC-SUR-E babies while continuing HFOV. According to the given ventilation parameters this approach may not have been maximally lung protective in the control group – potentially reflected by higher numbers of death secondary to respiratory failure in IN-SUR-E infants including six cases of fatal pulmonary hemorrhage. Of note, in both groups the study protocol included 1–2 maneuvers of sustained lung inflation (SLI) as standard management in the delivery room, although SLI is no longer recommended in extremely premature infants (5-7).

Despite some limitations, the present study indicates that lung recruitment prior to surfactant application in IN-SUR-E is safe and may improve efficacy of the maneuver. Further RCTs in very immature preterm infants are needed to evaluate IN-REC-SUR-E as an alternative method of surfactant application with regard to short-term and long-term outcomes. Moreover, comparison with less invasive surfactant administration (LISA) procedures applied in spontaneously breathing infants completely avoiding invasive mechanical ventilation is desirable (8, 9).

REFERENCES

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