MANUSCRIPT CITATION:

Gallup JA, Ndakor SM, Pezzano C, Pinheiro JMB. Randomized Trial of Surfactant Therapy via Laryngeal Mask Airway Versus Brief Tracheal Intubation in Neonates Born Preterm. J Pediatr. 2023 Mar;254:17-24.e2. doi: 10.1016/j.jpeds.2022.10.009. Epub 2022 Oct 12. PMID: 36241051

AUTHORS:

Mary Eileen Foster

Harsha Gowda

Affiliations: Neonatal Unit, Birmingham Heartlands Hospital, UHB.

Corresponding Author:

Mary Eileen Foster

Neonatal Unit, Birmingham Heartlands Hospital, UHB

eileen.foster@nhs.net

Type of investigation: Randomized control study.

QUESTION:

Infants born between 27⁺⁰ and 36⁺⁶ with respiratory distress syndrome requiring non-invasive respiratory support in the form of CPAP or NIPPV (P) administration of surfactant via laryngeal mask airway (I) non-inferior to administration of surfactant via endotracheal tube (C) to avoid the need for mechanical ventilation (O) within 72 hours post administration (T)

METHODS:

Design:  Randomised controlled trial, single centre. Originally planned to be a multi-centric trial.

Allocation and Stratification:

Stratification: Eligible infants were born at 27⁺⁰ to 36⁺⁶. Weighing more than 800 grams, with clinical evidence of Respiratory Distress Syndrome (RDS) requiring noninvasive respiratory support, either CPAP >5cm H₂O or nasal intermittent positive pressure ventilation (NIPPV) with oxygen requirements between 30 and 60% for two hours or more to maintain saturations >88% which initially in the protocol of this paper was mentioned to be 90 – 95% within 48 hours of life.

Allocation: Initial randomisation ratio was 1:1 LMA:ETT, which was then changed to 2:1 LMA : ETT when the operators stated that LMA was their preferable method of surfactant administration and the preference of families for the less invasive approach, especially after there was published evidence on its effectiveness.

Exclusion criteria: Infants with pneumothorax, previous intubations, congenital malformations, APGAR score <3 at 5 minutes of life, or encephalopathy.

Blinding:  With signed parental consent, the study group assignment was concealed in opaque, sealed, serially numbered envelopes by staff unrelated to the study. After randomisation, there was no blinding of allocation to clinicians, family members, or investigators.

Setting: The neonatal intensive care unit at Albany Medical Center from November 2014 to April 2020

Procedures:  Infants on the endotracheal tube (ETT) which were to receive surfactant via the InSuRe (Intubate- SURfactant- Extubate), group received premedication with atropine and remifentanil before intubation. ETT position was confirmed with the use of a CO2 detector. Calfactant (Surfactant) 3 mL/kg was administered in 2 aliquots. Subsequently, positive pressure ventilation (PPV) using a flow-inflating bag with PEEP 5 cmH2O and the lowest peak inspiratory pressure needed to support gas exchange was continued for 5 minutes before planned extubation was done within 15 minutes of premedication if possible, with the resumption of either CPAP or NIPPV  Inexperienced trainees were not allowed to conduct the procedure and consultant neonatologists needed to be present during the InSuRe procedure..

For patients assigned to the laryngeal mask airway(LMA) group, the only premedication used was atropine, prior to the insertion of a size 1 LMA, a CO2 detector was used to verify position in this group too. Calfactant (Surfactant) 3 mL/kg was administered in 2 aliquots via a shortened T-connector terminating near the distal end of the LMA.

LMA insertions were permitted for staff with varying levels of experience.

Patients

Interventions: Infants born between 27⁺⁰ to 36⁺⁶ weeks gestation, weighing more than 800 grams, with clinical signs of RDS and receiving ventilatory support either with NIPPV or CPAP with oxygen requirements, were randomised to receiving surfactant either via ETT or LMA. They were then followed up until they were discharged from NICU.

Control: Both groups received surfactant, but the ETT group is considered the control group, while the LMA group is placed in the interventional arm.

Sample size: The authors set a non-inferiority margin for the LMA method at 20 percentage points above the InSuRE method’s failure rate, accommodating up to one additional treatment failure in every five infants, based on preferences to bypass laryngoscopy and intubation, ensuring the LMA’s non-inferior to InSuRE.

For the clinically desired noninferiority margin of 20% they calculated that a sample of 130 patients (65 per group) would be needed to conclude noninferiority of the LMA method compared with the InSuRE approach.

Primary outcomes: To assess the failure rate of early surfactant therapy in preterm infants with respiratory distress syndrome (RDS). This was defined by the need for mechanical ventilation within one hour after surfactant administration, the necessity for more than two doses of surfactant, or the requirement of sustained FiO2 levels greater than 0.60 to maintain target oxygen saturations, as well as the need for a second dose of surfactant within eight hours of the first dose​

Secondary outcomes: included a variety of clinical indicators such as the incidence of RDS resolution, the need for additional doses of surfactant, the occurrence of air leak syndromes, the duration of hospital stay, and the rates of neonatal mortality and major morbidities such as bronchopulmonary dysplasia (BPD), intraventricular haemorrhage (IVH), and necrotising enterocolitis (NEC). 

Analysis and Sample size: 329 patients were assessed for eligibility, and 93 were randomised with 42 allocated to the ETT group and 51 to the LMA group.

Characteristics and outcomes of the ETT and LMA groups were compared using the chi- square or Fisher exact test for categorical values, and unpaired t-tests for continuous variables. Wilcoxon nonparametric tests were used to compare non-normally distributed values (mean number of surfactant doses, length of stay, days on supplemental oxygen and respiratory support).

Measured variables and follow up: Patients’ baseline characteristics, FiO2, and respiratory support at 3 hours and 1 hour before surfactant therapy, at the time of surfactant therapy, and 30 minutes, 3 hours, 8 hours, 24 hours, 48 hours, 7 days, and 28 days after the first dose of surfactant. Patients were followed up until they were discharged from NICU. 

Main Results:

Failure rate (need for invasive mechanical ventilation) was 29% in the ETT group and 20% in the LMA group (P = .311). This difference was due to early failures (within 1 hour), with 12.5% in the ETT group and 2% in the LMA group (P = .044). Surfactant therapy via LMA was non-inferior to administration via ETT; failure risk difference −9.0% (CI –∞ to 5.7%). Efficacy in decreasing fraction of inspired oxygen, number of surfactant doses administered, time to wean off all respiratory support, rates of adverse events, and outcomes including pneumothorax and BPD diagnosis did not differ between groups.

Outcomes or events	ETT group n = 42	LMA group n = 51	P value
Surfactant therapy failures, no (%)	12 (29%)	10 (20%)	0.311
– Early Failure	5 (12%)	1 (2%)	0.044
– Late Failure	7 (17%)	9 (18%)	0.985
Secondary clinical outcomes, No. (%)
– Late, unrelated intubations	4 (10%)	1 (2%)	0.108
– Pneumothorax	5 (11.9%)	6 (11.8%)	1.00
– Pulmonary haemorrhage	1 (2.4%)	0 (0%)	0.452
– Bronchopulmonary dysplasia	2 (4.8%)	1 (2%)	0.587
– Death	1 (2.4%)	0 (0%)	0.452
Events during surfactant administration	No. (% of doses)	No. (%of doses)
– Total surfactant doses, No.	62	80
– Desaturation, No (%)	2 (3.2%)	7 (8.8%)	0.299
– Bradycardia	1 (1.6%)	1 (1.2%)	1.00
– Surfactant reflux	6 (9.7%)	0 (0%)	0.006
– Airway obstruction	2 (3.2%)	0 (0%)	0.189
– (Re) intubation	3 (4.8%)	1 (1.2%)	0.318
– LMA re-insertion	N/A	2.5%
– Cardiopulmonary resuscitation	1 (1.6%)	0 (0%)	0.437
– Naloxone administration	1 (1.6%)	N/a

 

Early failure was defined as the need for invasive mechanical ventilation within 1 hour of surfactant administration. Late failure included subsequent invasive mechanical ventilation before 120 hours of life, which changed from the initial 72 hours mentioned in the protocol of this paper.  Later requirement for mechanical ventilation that would not be attributable to RDS, was not classified under the primary outcome.

CONCLUSION:

The study concluded that surfactant administration via LMA is a feasible, effective, and potentially less invasive alternative to the traditional ETT method for preterm neonates with RDS.

The LMA approach showed non-inferiority to ETT in terms of the primary outcome of avoiding mechanical ventilation within 72 hours post-treatment. Furthermore, there were no significant differences in secondary outcomes, such as neonatal mortality and major morbidities between the two groups. This suggests that LMA could be considered a viable option for surfactant delivery in preterm infants, potentially minimising the need for mechanical ventilation and its associated risks.

Commentary:

Globally, neonatal practices are intensely focused on reducing the prevalence of bronchopulmonary dysplasia (BPD) and its associated comorbidities. The administration of surfactant has been shown to reduce the risk of death and BPD in preterm infants.

 

Since its introduction in 1980¹, surfactant administration has revolutionised the treatment of respiratory distress syndrome (RDS), consequently diminishing the risk of developing BPD⁴. Over the decades, the strategies for surfactant delivery have evolved significantly, encompassing a range of different techniques from INSURE method (Intubation-SURfactant-Extubation) to less invasive surfactant administration (LISA). INSURE was developed to reduce the amount of time neonates remained intubated and ventilated to reduce its complications while still receiving surfactant and reducing BPD, meanwhile LISA was developed after a neonates failed to come off the ventilator with the INSURE method⁷. However, the standard approach to administering surfactant still involves the use of laryngoscope either direct or video for endotracheal intubation with ETT or LISA catheter for surfactant administration.  These approaches may need pain relief or sedation.

 

In 2013, the laryngeal mask airway (LMA) has emerged as an effective method for surfactant delivery, showcasing a significantly reduces the need for intubation and mechanical ventilation in premature infants with moderate respiratory distress syndrome (RDS)². The advantages of utilising LMA are significant, including the obviation of laryngoscope use, which simplifies the procedure for operators. This, in turn, reduces the necessity for sedative medications. Furthermore, LMA presents minimal contraindications, which primarily encompass maxillofacial, tracheal, or established pulmonary malformations. However, a notable limitation of LMA use is the absence of sizes appropriate for very low birth weight or extremely premature infants, with the smallest available size being 1, which is only licensed to be used in infants who are more than 2 kilograms⁶. Additionally, there is a noticeable gap in scientific validation for this approach.

 

In this current study, we can see that LMA had a lower failure rate (20%) compared to ETT (29%), demonstrating its non-inferiority when it came to this paper’s primary outcome. This paper shows that administering surfactant via LMA can have advantages over the more traditional methods. Some of these advantages include that it is more user friendly, and less training required for its use. Sedative medications, such as remifentanil, can themselves increase the failure rate in more traditional methods such as InSuRe.

 

These findings provide valuable insight into the ongoing discourse on minimally invasive surfactant administration, with a method that could potentially decrease the need for mechanical ventilation and its associated risks. However, the non-inferiority margin of 20% is notably generous, potentially obscuring clinically significant differences between the two methods. This choice, coupled with the small sample size, attenuates the study’s statistical power, rendering the conclusion of non-inferiority less compelling than it might otherwise be.

 

Furthermore, the methodological divergence in pre-medication between groups injects an additional variable into the comparative analysis this could have been attenuated if the comparison would have been done between LMA and another less invasive surfactant administration technique such as LISA. Another limitation is failure to reach the target sample size due to slow recruitment and Covid 19 pandemic. It is worth mentioning that there was also a mid-protocol change which can affect the way we interpret the results. The changes included difference in timings to define failure of procedure (ventilation in the first 72 hours rather than 120 hours), saturations target in eligibility criteria (90-95% vs 85%), changing randomization allocation from 1:1 to 2:1 favoring LMA, which can introduce contextual bias to units were LMA is not seen as favorable, and lastly that it was intended as a multi-centric trial.

 

While the study presents an intriguing alternative to traditional surfactant administration methods, its findings must be interpreted with caution. The pursuit of innovation in neonatal care is commendable, but it must be grounded in solid, evidence-based research to ensure that new practices offer tangible benefits without compromising patient safety. As such, this trial represents an important step in an ongoing journey rather than a definitive destination. Further large multi-centric RCT data is required before the results can be generalised and adopted for routine practice.

References:

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3) Glenn T, Fischer L, Markowski A, Carr CB, Malay S, Hibbs AM. Complicated Intubations are Associated with Bronchopulmonary Dysplasia in Very Low Birth Weight Infants. Am J Perinatol. 2023 Aug;40(11):1245-1252. doi: 10.1055/s-0041-1736130. Epub 2021 Sep 9. PMID: 34500482; PMCID: PMC9239052.

4) Hsiu-Lin Chen, Shu-Ting Yang, Pin-Chun Su, & Hao-Wei Chung. (2024). The outcomes of preterm infants with neonatal respiratory distress syndrome treated by minimally invasive surfactant therapy and non-invasive ventilation. Biomedicines, 12(4), 838. https://doi.org/10.3390/biomedicines12040838

5) Roberts, K. D., Brown, R., Lampland, A. L., Leone, T. A., Rudser, K. D., & Finer, N. N., et al. (2018). Laryngeal mask airway for surfactant administration in neonates: A randomized, controlled trial. Journal of Pediatrics, 193, 40-46. https://doi.org/10.1016/j.jpeds.2017.09.080

6) Aitken, J., & O’Shea, J. (2021). Could laryngeal mask airways be used to stabilise neonates at birth by those with limited intubation experience? *Archives of Disease in Childhood, 106*(2), 197-200. https://doi.org/10.1136/archdischild-2020-321441

7) Bugter, I. A. L., Janssen, L. C. E., Dieleman, J., Kramer, B. W., Andriessen, P., & Niemarkt, H. J. (2020). Introduction of less invasive surfactant administration (LISA), impact on diagnostic and therapeutic procedures in early life: A historical cohort study. BMC Pediatrics, 20, Article 421. https://doi.org/10.1186/s12887-020-02325-0