MANUSCRIPT CITATION

Gallini F, De Rose DU, Iuliano R, et.al. Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates: 2-Year Follow-Up of a Randomized Clinical Trial. JAMA Netw Open. 2024 Sep 3;7(9):e2435347. doi: 10.1001/jamanetworkopen.2024.35347. PMID: 39320892; PMCID: PMC11425149.

REVIEWED BY

David M. Rub, MD
Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine
rubd@chop.edu

Elizabeth E. Foglia, MD MSCE
Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine
foglia@chop.edu

TYPE OF INVESTIGATION

Prevention

QUESTION

P: Among extremely preterm infants born between 24 weeks and 27 weeks 6 days gestation reaching ‘failure’ criteria for continuous positive airway pressure (CPAP) within the first 24 hours of life,
I: Does a lung recruitment maneuver prior to the administration of surfactant via endotracheal tube (IN-REC-SURE),
C: Compared to the standard intubation-surfactant-extubation (INSURE) protocol,
O: Improve the proportion of death after discharge or major disability,
T: At 2 years corrected post-natal age (PNA)

METHODS

Design: 2-year follow up of the IN-REC-SURE Trial, a multi-center, unblinded, randomised control trial.

Allocation: Random, 1:1 allocation using minimization algorithm, stratified by clinical site and gestational age

Blinding: Original RCT was unblinded. However, follow-up assessors were blinded to treatment allocation.

Follow-up period: 2 years.

Setting: 35 tertiary neonatal intensive care units in Italy.

Participants: Extremely preterm infants, GA 24 0/7 and 27 6/7, born in a tertiary NICU participating in the trial between November 2015 and September 2018, who were spontaneously breathing on nasal CPAP and met criteria for surfactant administration within the first 24 hours of life. Infants were excluded if they had a 5-minute Apgar <3, severe birth asphyxia, required endotracheal intubation in the delivery room, were born after prolonged (>21 days) premature rupture of membranes, had a major congenital anomaly, inborn error of metabolism or hydrops fetalis.
• Criteria for surfactant administration: fractional concentration of oxygen (FiO2) of 0.3 or greater to maintain an SpO2 between 87% to 94% for at least 30 minutes OR respiratory acidosis defined as pCO2 > 65 mmHg and pH < 7.20 OR rapid clinical deterioration.

Intervention: Infants were intubated and placed on high-frequency oscillatory ventilation (HFOV) at the following settings: mean airway pressure 8 cmH2O, amplitude (∆P) 15 cmH2O, and frequency of 15 Hz. Infants then underwent a stepwise recruitment procedure using the de Jager method.(1)

Outcomes:
• Primary outcome: Death or Major disability at 2 years corrected PNA.
• Secondary outcomes:
o Neurodevelopmental outcomes: major disability, cerebral palsy, cognitive impariment, visual deficit, or auditory deficit
o Anthropometric measurements: weight, length, head circumference
o Respiratory outcomes: Recurrent respiratory infections and hospitalizations secondary to respiratory causes by 2 years corrected PNA

Analysis and Sample Size: 218 infants enrolled in initial RCT. 156 infants survived to discharge. All 156 surviving infants were enrolled in the 2 year follow-up study (74 INSURE, 82 IN-REC-SURE).
Patient follow-up: 137 infants (88% follow-up rate) evaluated at 2-year follow-up (64 INSURE, 73 IN-REC-SURE).

MAIN RESULTS

Study Population: 137 children were included in the analysis. Reported baseline demographics were reported by intervention arm as follows:

INSURE (n = 62) IN-REC-SURE (n = 69) P value
Gestational Age, weeks, median (IQR) 26.86 (25.71-27.29) 26.29 (25.86-27.43) .59
Birthweight, g, mean (SD) 819.82 (192.97) 873.54 (189.53) .11
Female, n (%) 34 (54.8) 38 (55.1) .98

There were no significant differences in antenatal steroid exposure, PPROM, or chorio rates between groups. However, there was a significant difference in vaginal delivery rates (12.9% INSURE vs. 27.5% IN-REC-SURE). This difference in mode of delivery was not present in the original randomized cohort.

Primary Outcome: No significant difference in death after discharge or major disability at 2 years corrected PNA (13/64 (20.3%) INSURE vs. 10/73 (13.7%) IN-REC-SURE).

Secondary Outcomes: No significant differences in major developmental disability, cerebral palsy, cognitive impairment, visual or auditory deficits at 2 years corrected PNA. Regarding anthropometric outcomes, there were no significant differences in weight, height, or head circumference between groups at 2 years corrected PNA. Finally, although respiratory follow-up data was incomplete (47 INSURE vs. 53 IN-REC-SURE), there were no significant differences in incidence of recurrent respiratory infections or hospitalization secondary to respiratory causes.

CONCLUSION

Performance of a recruitment maneuver prior to administration of surfactant did not reduce rates of mortality or major developmental disability at 2 years of age among extremely preterm infants.

COMMENTARY

Few therapies have impacted a field like surfactant has neonatology. Since its discovery in the 1980s, surfactant replacement therapy revolutionized the management of respiratory distress syndrome (RDS), reducing immediate associated mortality and subsequent development of bronchopulmonary dysplasia (BPD).(2) Historically, surfactant was delivered via endotracheal tube, followed by a prolonged course of invasive mechanical ventilation (IMV). However, as the link between prolonged IMV and development of BPD became more apparent, research efforts shifted to novel delivery methods to minimize IMV exposure.

 

The original IMV-sparing technique is the intubate-surfactant-extubate (INSURE) method, which called for the immediate removal of the endotracheal tube following surfactant administration.(3) While newer methods of surfactant administration avoid an endotracheal tube altogether, either by using a thin catheter or supraglottic airway, INSURE remains the most commonly used method of surfactant administration in the US.(4–6)

 

This study from Gallini et. al. presents the 2-year follow-up data from the IN-REC-SURE Trial, an unblinded, randomized control trial comparing the use of a recruitment maneuver prior to selective administration of surfactant to standard INSURE protocol.(7) The physiologic rationale for this study being that a “well-recruited” lung facilitates the homogenous distribution of surfactant and improves its efficacy.(8)

 

Although the primary outcome did not show statistically significant differences between groups, the overall mortality benefit when including deaths during the NICU stay is striking (35.1% vs. 22.8%; P = 0.05). (7) However, it is important to note that statistical significance was only met in the per-protocol analysis. Of the 6 patients excluded from the ITT analysis (3 for meeting exclusion criteria post-enrollment and 3 who did not receive the assigned recruitment maneuver; all in the IN-REC-SURE arm) 4 died during their NICU stay. Furthermore, nearly 70% of infants in the trial received at least one sustained inflation (SI) during initial delivery room resuscitation. It has since been shown that exposure to SI in the delivery room increases risk of early mortality.(9) While the authors argued in the primary analysis of the IN-REC-SURE Trial (10) that this should not influence the results since infants in both groups received SI and there was no differential exposure, an increased baseline mortality risk may exaggerate the observed mortality benefit and may not be applicable to populations with lower baseline mortality risks.

 

In considering the dissemination of this approach, clinicians must remain mindful of the technical demands, including the need for high-frequency ventilators and specific training to perform recruitment maneuvers safely. Despite these challenges, the study provides encouraging safety data regarding the IN-REC-SURE procedure with a possible signal for improved mortality. Future investigations, such as the proposed IN-REC-LISA Trial (11), should compare IN-REC-SURE with other commonly used less invasive strategies to further elucidate the optimal balance between effective lung recruitment and the benefits of avoiding endotracheal intubation to improve the outcomes of extremely preterm infants.

REFERENCES

1. de Jager P, Kamp T, Dijkstra SK, Burgerhof JGM, Markhorst DG, Curley MAQ, et al. Feasibility of an alternative, physiologic, individualized open-lung approach to high-frequency oscillatory ventilation in children. Ann Intensive Care. 2019 Jan 18;9(1):9.
2. Merritt TA, Hallman M, Bloom BT, Berry C, Benirschke K, Sahn D, et al. Prophylactic Treatment of Very Premature Infants with Human Surfactant. N Engl J Med. 1986 Sep 25;315(13):785–90.
3. Rojas MA, Lozano JM, Rojas MX, Laughon M, Bose CL, Rondon MA, et al. Very early surfactant without mandatory ventilation in premature infants treated with early continuous positive airway pressure: a randomized, controlled trial. Pediatrics. 2009 Jan;123(1):137–42.
4. Ahn N, Derrick M, Hussain W. A Survey of Minimally Invasive Surfactant Use in the United States. Am J Perinatol. 2024 Nov 25;
5. Dargaville PA, Kamlin COF, Orsini F, Wang X, De Paoli AG, Kanmaz Kutman HG, et al. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA. 2021 Dec 28;326(24):2478–87.
6. Göpel W, Kribs A, Ziegler A, Laux R, Hoehn T, Wieg C, et al. Avoidance of mechanical ventilation by surfactant treatment of spontaneously breathing preterm infants (AMV): an open-label, randomised, controlled trial. Lancet Lond Engl. 2011 Nov 5;378(9803):1627–34.
7. Gallini F, De Rose DU, Iuliano R, Romeo DM, Tana M, Paladini A, et al. Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates: 2-Year Follow-Up of a Randomized Clinical Trial. JAMA Netw Open. 2024 Sep 3;7(9):e2435347.
8. Tingay DG, Togo A, Pereira-Fantini PM, Miedema M, McCall KE, Perkins EJ, et al. Aeration strategy at birth influences the physiological response to surfactant in preterm lambs. Arch Dis Child – Fetal Neonatal Ed. 2019 Nov;104(6):F587–93.
9. Kirpalani H, Ratcliffe SJ, Keszler M, Davis PG, Foglia EE, te Pas A, et al. Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants: The SAIL Randomized Clinical Trial. JAMA. 2019 Mar 26;321(12):1165–75.
10. Vento G, Ventura ML, Pastorino R, Kaam AH van, Carnielli V, Cools F, 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. 2021 Feb 1;9(2):159–66.
11. Vento G, Paladini A, Aurilia C, Ozdemir SA, Carnielli VP, Cools F, et al. Comparison of “IN-REC-SUR-E” and LISA in preterm neonates with respiratory distress syndrome: a randomized controlled trial (IN-REC-LISA trial). Trials. 2024 Jul 2;25(1):433.

FUNDING

Dr. Rub is supported by the NIH Eunice Kennedy Shriver National Institute of Childhood Health and Human Development under T32HD060550 and the NIH National Heart and Lung Biology Institute under 1L40HL176224-01.

CONFLICTS OF INTEREST

a. Dr. Foglia discloses personal consulting fees for Chiesi USA
b. Dr. Foglia is the PI for a grant from Chiesi USA to her institution for research focused on Less Invasive Surfactant Administration