#396 - [Journal Club] - 📌 Surfactant Thresholds: Is 40% FiO2 as Safe as 30%?

In this episode of Journal Club, Ben and Daphna review a non-inferiority trial from the European Journal of Pediatrics exploring surfactant administration thresholds in preterm neonates. The study, conducted in India, compares a 30% versus 40% FiO2 threshold for babies 26-32 weeks gestational age. The hosts break down the counterintuitive findings regarding respiratory support duration in younger subgroups and discuss the broader implications of using rigid FiO2 heuristics versus individualized patient assessment. They also debate how resource availability influences clinical protocols and the potential benefits of "LISA" (Less Invasive Surfactant Administration) for avoiding intubation.

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Higher (40%) versus lower (30%) FiO2 threshold for surfactant administration in preterm neonates between 26 and 32 weeks of gestational age: a non-inferiority randomized controlled trial. Haq MI, Datta V, Bandyopadhyay T, Nangia S, Anand P, Murukesan VM.Eur J Pediatr. 2025 Nov 25;184(12):793. doi: 10.1007/s00431-025-06628-1.PMID: 41288797 Clinical Trial.

Transcript

[00:00.688] Ben Courchia MD Hello everybody, welcome back to the Incubator Podcast. We're back today for another episode of Journal Club.

[00:07.31] Daphna Yasova Barbeau MD Good morning, good morning. I'm doing well. I'm gonna stick with the same line of questioning that we had yesterday. I’ll stick with some oxygen saturation parameters, FiO2 parameters. This article is coming from the European Journal of Pediatrics and it was one that has been in my folder for some time also. It is entitled "Higher 40% versus Lower 30% FiO2 Threshold for Surfactant Administration in Preterm Neonates Between 26 and 32 Weeks of Gestational Age: A Non-Inferiority Randomized Controlled Trial." The lead author is Mir Inamal Haq, senior author Vishnu Mohan Marukasan. And I think this goes back to what we were talking about. There are lots of things that, depending on where you trained, become dogma when you do certain things.

[00:37.236] Daphna Yasova Barbeau MD So I really like this paper. It's coming to us from an institution in India. And basically, they had a duration of 20 months. They took babies that arrived to the unit spontaneously breathing between 26 and 32 weeks of gestation. And then within one hour of birth, they included babies that were requiring at least CPAP of +6. They had—I won't go into their protocol—but they had very strict criteria for who would get on CPAP +5 and then who would advance to +6 using some respiratory severity scores. And then those babies would be randomized to either wait until 30% for surfactant or wait until 40% for surfactant. That was the setup. They excluded babies with major congenital anomalies, shock prior to randomization, severe asphyxia (using an Apgar score less than four at one minute), those intubated in the delivery room, or any concern for pulmonary hemorrhage at the time of randomization.

[00:37.236] Daphna Yasova Barbeau MD They actually were using LISA. They were giving surfactant through a six French orogastric tube using direct laryngoscopy while the infant remained on their nasal CPAP settings. They described their non-pharmacological comfort measures. They used medications like sucrose and then swaddling and gentle containment. They also looked at repeat surfactants. A repeat dose was considered at 12 hours if the need for oxygen remained above 30% in either group. Both groups were given the standard of care in the unit. So all things were pretty much the same: Kangaroo Care, caffeine, early enteral feeding, and developmental care. They also had a predefined clinical protocol for weaning non-invasive respiratory support, especially since this relates to their outcome measures.

[00:37.236] Daphna Yasova Barbeau MDSo the primary outcome of the study was to compare the total duration of respiratory support between the two FiO2 thresholds for surfactant administration. Secondary outcomes were the requirement of surfactant within six hours after birth, the requirement for a repeat dose of surfactant after 12 hours, and then a list of common morbidities: BPD stage two or greater, IVH grade greater than or equal to grade two (for the Volpe classification), ROP, air leaks, a hemodynamically significant PDA requiring treatment, all-cause mortality, and total duration of hospital stay.

[00:37.236] Daphna Yasova Barbeau MDIn total, they had 205 babies that were randomized. In the 40% group, the total cohort was 105, and 35 out of the 105 were treated with surfactant. In the 30% group, they had an N of 100, and 45 out of 100 were treated with surfactant. The baseline characteristics of neonates were comparable in both groups. I'll just mention some of those things. There were less SGA babies in the 40% group. There were more babies who got complete antenatal steroid coverage in the 40% group. There were slightly more moms with gestational diabetes. There were less who underwent vaginal delivery, but none of those were statistically significant.

[00:37.236] Daphna Yasova Barbeau MDThe closest thing to a p-value of 0.05 was the Apgar score at five minutes. It was seven in the 40% group and eight in the 30% group. The mean birth weight was about 1200 grams and the mean gestational age of the whole cohort was about 30 weeks. 55% were male, 54% of the mothers received complete antenatal steroids, and approximately half—just more than half, 55%—were delivered by C-section.

[06:07.693] Daphna Yasova Barbeau MDSo they told you the primary outcome was the mean duration of respiratory support. The mean duration of respiratory support was 140 hours in the babies who were in the 40% group and 153.9 hours in the 30% group. So this was not statistically significant. You can decide if it's clinically significant, a difference of about 13 hours. But that's important because later they buried the lede, in my opinion. Then they looked at this group, the younger group of infants, 26 to 29-weekers. The way they describe this in the first section is a little bit confusing, but what I can understand is that the difference between the 30% and the 40% group in this smaller cohort of 26 to 29-weekers was 56 hours. So that's two and a half additional days of respiratory support. So for the smaller group, it did make quite a bit of difference.

[07:04.809] Ben Courchia MDIn which direction again?

[07:07.181] Daphna Yasova Barbeau MDLess time for the babies who are in the 40% group.

[07:12.824] Ben Courchia MDWow, that's counterintuitive.

[07:13.919] Daphna Yasova Barbeau MD I know. Agreed. You think if I give them surfactant, they don't need to stay on as long, for sure. And then again, for their primary outcome, they found that the 40% group was non-inferior to the 30% group regarding duration of respiratory support.

[07:20.26] Ben Courchia MDYeah.

[07:41.966] Daphna Yasova Barbeau MDThe mean ventilator-free days were slightly higher in the 40% group, 26.6 days versus 25.7 days. That was not statistically significant. I told you 32% of the 40% FiO2 group got surfactant versus 45% in the 30% FiO2 group. This was statistically significant. In the 40% FiO2 group, 1.9% versus 7% in the 30% group required a repeat dose of surfactant. This was statistically significant. So again, even though the repeat surfactant threshold was 30% for both groups, less babies in the 40% group required the repeat dose.

[07:41.966] Daphna Yasova Barbeau MDThere were no statistically significant differences in the incidence of BPD, IVH, ROP, ROP requiring treatment, air leak syndromes, or hemodynamically significant PDA requiring treatment. There was no difference in mortality or any difference in the total duration of hospital stay in days. Basically, this was a non-inferiority trial. They found that 40% was non-inferior, but I think it's very interesting to see that in their youngest group for this cohort, the 26 to 29-weekers, it made somewhat of a difference. And again, we were talking about parents in the last group. Intubation and InSurE/LISA is a procedure that we're pretty comfortable with. We do really well, but I think from the parent perspective regarding their baby needing to be intubated even briefly, it can be dramatic. I think this is a big deal for families and it's a big deal for infants to see if we can avoid that procedure for them. Thoughts?

[09:54.629] Ben Courchia MDYeah, I mean, I think that one of the big components of this paper is—no issues there—the fact that it's coming out of India. There's a big difference between whether you are a low resource environment, a middle resource environment, or a high resource environment. The needs and the objectives can be very different. So I can see that for resource-limited settings, this could be very helpful. Though for us, I feel like we do need to go beyond the pure FiO2 strategy. I don't mean to say this about India because I don't know exactly the geography of India. There are some very high and very well developed centers. There are some amazing clinicians out of India, so I'm not really trying to say anything negative. But I'm just saying, I do believe that the discussion of 30% versus 40% is one that is limited. I feel like what kind of ventilation, regardless of where you are...

[11:03.841] Daphna Yasova Barbeau MDYeah, I mean, I think that's true regardless of where you are, right? Is there respiratory distress? Is there hypercarbia? There are so many other factors.

[11:10.137] Ben Courchia MDAnd I feel like if you have the tools to make a proper assessment of the patient and tailor your strategies—whether it is the use of specific modes of ventilation, specific use of pressures, specific use of other things like lung ultrasound, chest x-ray findings—and then make a decision informed on all these different factors, that is better. You have to look at time as well, how is the baby doing in the first couple of hours. I think this is, in my opinion, the way to assess whether a baby needs surfactant rather than just because the therapist decided to boost the baby and now the baby is on 35% and it's like, "Oh, that's it, threshold reached, you must give surfactant." I don't like these heuristics when we're talking about the NICU. But I can see how it can be helpful if the setting dictates that this might be helpful. Interesting.

[12:04.365] Daphna Yasova Barbeau MDYeah, and I think in general, our team uses a higher threshold. Not all of us, but in general, our team uses a higher threshold. And there are just some babies that are really just comfortable, happy, not hypercarbic, on 35%. And then by the next day they're in 21% and they didn't get...

[12:25.041] Ben Courchia MDWhat about the patient that's on CPAP 30% that then goes to an IMV and is fine for a couple of hours and then comes back to CPAP and is OK? At what point do you arrest the thought of FiO2 when you say, "Now this is the threshold?" Or do you say, "No, I can work with this patient a bit more." But it's interesting. It's interesting to see that data. Because again, a lot of the stuff you presented, I was surprised by. I was not expecting those kinds of numbers. And it's a pretty large cohort, so good for them. All right, buddy, see you tomorrow. Bye.

[12:57.207] Daphna Yasova Barbeau MDAll right, buddy, sounds good.