#396 - [Journal Club] - 📌 TORPIDO 30/60: Is Higher Initial Oxygen Safer for Preterm Infants?

In this episode of The Incubator, Ben and Daphna return from the Delphi Conference to dive back into Journal Club. They review the highly anticipated TORPIDO 30/60 trial published in JAMA, comparing initial oxygen concentrations of 30% versus 60% for preterm resuscitation. The hosts discuss the primary outcomes of survival and brain injury, while highlighting intriguing secondary findings regarding chest compressions and epinephrine use in the delivery room. They also share exciting updates on the Vermont Oxford Network collaboration and a new family study from the GFCNI.

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Targeted Oxygen for Initial Resuscitation of Preterm Infants: The TORPIDO 30/60 Randomized Clinical Trial. Oei JL, Kirby A, Travadi J, Davis P, Wright I, Ghadge A, Yeung C, Cruz M, Keech A, Hague W, Lui K, Vento M, Gordon A, De Waal K, Chaudhari T, Hong TSL, Morris S, Kushnir A, Bonney D, Tracy M, Kumar K, Chhnia AS, Baral VR, Muniyappa P, Cheah FC, Sarnadgouda P, Rajadurai VS, Balakrishnan U, Oleti TP, Aldecoa-Bilbao V, Couce ML, Collados CT, Fernández RE, Moliner E, Ruiz Gonzalez MD, Singhal M, Agrawal G, Singh J, Pal S, Nayya S, Arora R, Amboiram P, Simes J, Tarnow-Mordi W; TORPIDO30/60 Collaborative Group.JAMA. 2025 Dec 10:e2523327. doi: 10.1001/jama.2025.23327. Online ahead of print.PMID: 41369162

Transcript

[00:00.878] Ben Courchia MD Hello everybody, welcome back to the Incubator Podcast. We're back today for another episode of Journal Club.

[00:10.351] Daphna Yasova Barbeau MD We're back after the Delphi break. Delphi break. I don't know if it was a break. We've been very...

[00:14.424] Ben Courchia MD For us, it wasn't a break. For the people who missed the episodes, they're like, "You guys took a break?" But we don't stop.

[00:18.819] Daphna Yasova Barbeau MD That's true. Delphi was so fun, we could spend the whole episode talking about that. But I miss Journal Club a little bit.

[00:28.738] Ben Courchia MD Yeah, that's the thing that really got us in this space to begin with. And it feels like we are cheating on Journal Club when we're not doing it for a while. We're very thankful for the quality of the episodes. The next one coming out after this week of Journal Club is going to be with VON. We are finally releasing the first episode of our collaboration with the Vermont Oxford Network.

[00:39.365] Daphna Yasova Barbeau MD Well, we had some good episodes come out in our absence. And it's very exciting.

[00:56.582] Ben Courchia MD So I think the quality of the episodes and just reflection of the quality of our field are just getting better and better. So can't be much happier about that. Thank you to everybody who attended the Delphi Conference. Thank you to everybody who gave us feedback. We're very thankful for the attendees who were there both in person and online. I think we were amazed by the viewing numbers online for the Delphi conference on the streaming. That was quite cool. These videos are still up right now on the live portion of the YouTube channel. We're actually cutting each talk individually and we're going to release them once they're ready, probably in a couple of weeks. So if you feel like there's no pressure and you just want to wait for these videos to land on your notification page, fine. Otherwise, you can always go and scroll through the different talks.

[02:02.373] Ben Courchia MD Before we begin Journal Club, I wanted to give a shout out to our friends at the GFCNI. It's this global collaboration for neonates that we interviewed on the podcast in the past. They have a new project they asked us to give a shout out to. It's the BronQ Family study. They're conducting an online survey exploring how BPD affects children and their families' quality of life over time, which I think is something that is always very interesting. The study is being carried until the end of the month. So please check them out. It's happening in the US and six European countries. People are invited to participate. So they asked that we spread the word within our network.

[02:22.671] Daphna Yasova Barbeau MD Mm-hmm. Yeah.

[02:44.782] Ben Courchia MD If this reaches you and you feel like you're not the right person, then share it with whoever. I feel like they have an information page on their website. The people who can take part in it are parents or primary caregivers. So for people in your unit who want to maybe share their perspective, I think it's a great opportunity to involve families in research. Check out the GFCNI website for more information.

[03:07.151] Daphna Yasova Barbeau MD Love that. And did you give us that website?

[03:14.99] Ben Courchia MD No, because I don't have it in front of me. So it's GFCNI.org. And then on their website, you can look for the BronQ Family, B-R-O-N-Q family. You will have this whole page on this particular research and all the information is there. There, have I helped enough? Okay.

[03:35.941] Daphna Yasova Barbeau MD Here, let's help the people out. Perfect. Thanks, buddy.

[03:42.988] Ben Courchia MD I guess I'm going to get us started today. We have one paper that's been sitting in my folder for some time now that definitely needs review. It's a paper that was published in JAMA, and that is the Torpedo Trial. It's called Targeted Oxygen for Initial Resuscitation of Preterm Infants, the TORPIDO 30/60 Randomized Clinical Trial. Definitely a big trial, definitely something that was way overdue for us to review on the podcast.

[04:12.29] Ben Courchia MD The introduction is very interesting. It takes us through the history of our resuscitation practices and talks about how the optimal concentration of oxygen to initiate respiratory support of preterm infants at birth remains a topic of conversation, and that we've evolved. Before the 1990s, pure oxygen, 100% FiO2, was the standard based on the assumption that newborn cardiorespiratory depression was due to hypoxia. Then, in the 1990s, Dr. Saugstad, who we've had on the podcast—you should definitely check out his interview—showed that using room air instead of 100% oxygen for full term or near full term infants reduced the time to first breath and the rates of oxidative injury without any adverse outcomes.

[05:42.574] Ben Courchia MD Now, the Torpedo trial has existed before. It was first published in 2017. It was a randomized clinical trial of FiO2 21% versus 100% for initial resuscitation of preterm infants with the primary outcome being death or disability at two years. Now the trial at the time—the podcast did not exist at that point, so we did not get a chance to review or go that far back—but the trial was stopped early because of slow enrollment. The reason for this slow enrollment was due to the clinicians' reluctance to accept that infants might be assigned to the 100% FiO2 group. Not that they were going to get less, but that they were going get too much.

[05:42.574] Daphna Yasova Barbeau MD They did not have equipoise.

[06:07.714] Ben Courchia MD That's exactly right. And no difference was seen. Despite that, whatever data they had showed no difference in the primary outcome. And when they did an exploratory analysis suggesting that maybe mortality was increased in infants born less than 29 weeks who underwent resuscitation with 21%? So it's kind of funny that the trial was halted because people didn't want to give 100%, when in truth giving 21% was probably not so beneficial. So now they're coming to us with the new trial, the TORPIDO 30/60, which was initiated to test the hypothesis that for infants born before 29 weeks, maybe if we could compare starting 30% versus 60%, we could see if that would improve survival without brain injury at 36 weeks corrected age.

[08:12.352] Ben Courchia MD So this is the background and now we're going to dive into the methods. This was a randomized clinical parallel two-group superiority trial conducted in 31 hospitals in six countries: eight in Australia, 13 in India, one in Malaysia, two in Singapore, six in Spain, and one in the United States of America. Randomization was stratified by site, by gestational age—they looked at babies more or less than 26 weeks—and pregnancy multiplicity. The newborns were considered eligible if they were born between 23 and 28 weeks of gestation and required respiratory support at birth. Those with major cardiopulmonary anomalies or congenital malformations that could eventually affect their development were excluded.

[08:54.146] Ben Courchia MD So what does the intervention for this particular trial look like? The infants eligible for active care were placed on a resuscitation bed after the umbilical cord was cut. Initial FiO2 of 60% or 30% was delivered via an oxygen blender. The trial protocol required that the initial level of FiO2 be maintained for at least five minutes. If possible, to maintain separation between the groups, you could then adjust after that time period in aliquots of 10% to 20% FiO2 every 30 to 60 seconds using pulse oximetry. So you could move away from that initial threshold based on your target SATs, saying, "Hey, I actually want to reach my SATs," or maybe, "I'm over-SATing," and you could obviously titrate based on that. The target SATs were basically what you expect: 80% to 85% at five minutes, 85% to 95% at 10 minutes, and until admission to the neonatal ICU.

[08:54.146] Ben Courchia MD The primary outcome was death and brain injury at 36 weeks. Brain injury was defined by neuroimaging. We're talking about IVH, echodense intraparenchymal lesions, PVL, or porencephalic cysts. They had some predefined exploratory outcomes that they looked at as well, and we'll talk about them in a little bit. So in terms of sample size, they wanted to see a difference in brain injury-free survival going from 24% to 32%, and for that they needed about 740 babies in each group—735 to be exact.

[11:16.246] Ben Courchia MD Okay, so they did get their numbers. 728 infants were randomized to the 60% FiO2, 741 were randomized to the 30% group. Most of the newborns were singletons, most were born in Australia, and 58% were born via cesarean delivery. 97% had some antenatal exposure. Overall, 39% of the cohort required escalation of their FiO2 to 100% due to inadequate clinical response. That means, by the way, we're talking about both groups here. This occurred specifically in 38% of the 60% group and 41% of the 30% group. So kind of similar numbers between the two. 20 newborns or 1% of the cohort died in the delivery room. No adverse events attributed to the intervention.

[11:16.246] Ben Courchia MD So how do we do when it comes to the primary outcome? They were able to get the primary outcome data in over 95% of their cohort and there was no difference in the primary outcome of death or major brain injury by 36 weeks of gestation between those randomized to receive 60% or 30%. In the 60% FiO2 group, the rate of the primary outcome was 46.9%, and in the 30% group, 47.8%. When looking at the components of the primary outcome, rates of brain injury were similar: 42.4% in the 60% group, 43.2% in the 30% group. Death by 36 weeks, also similar: 15% in the 60% group, 15.8% in the 30% group.

[13:32.431] Ben Courchia MD In terms of exploratory and physiological outcomes, when they looked at the area under the curve analysis, they showed that saturation, fraction of inspired oxygen, and heart rate were higher in newborns assigned to receive the higher FiO2 for both the first five and 10 minutes from birth. So it looks like while there was no difference in the primary outcome that this study was powered for, some secondary data on SATs, oxygen requirement, and heart rate might have been better in the 60% group. Newborns in the 60% FiO2 group were less likely to receive chest compression, 2% versus 5%. They were less likely to receive epinephrine, 1% versus 2%. And they were more likely to reach SATs of 80% by five minutes—58% versus 44%. They also had a higher initial saturation. No difference was observed in the time for the first spontaneous breath or respiratory management on admission to the NICU.

[13:32.431] Ben Courchia MD In terms of some of the safety outcomes, they mentioned that infants assigned to the 60% FiO2 group had a bit of a higher rate of ventriculomegaly—6.4% versus 2.4%. It's hard to understand whether this has to do with something else or with the intervention itself. Otherwise, they mention no group difference observed in rates of other types of brain injury, including grade 3 and 4 IVH and PVL. So I'm going to leave you here to explore this paper further. There's a lot of ancillary material, a nice editorial, and a nice summary paper. But the authors do conclude that this trial finds no difference in survival without brain injury at 36 weeks corrected age when babies are resuscitated with an initial FiO2 concentration of 60% when compared to 30%, followed by titration for SATs targets.

[13:32.431] Ben Courchia MD Although they mentioned that the infants who initially received 60% were less likely to experience early hypoxemia, bradycardia, or receive advanced resuscitation, these findings were not accompanied by improvement in major neonatal outcomes, underscoring again the continuing uncertainty about the optimal initial concentration. They say that this is finding the foundation for future trials. I think what you will see when you read the discussion is that these authors are basically asking the question: Did we just go too low with 60%? Should we have gone much higher? I think there was this concern of the initial TORPIDO trial where they were like, "Maybe 100% is too frightening for the community," so they went to 60%. But now you can hear the hesitation in the discussion, like maybe it should have been a bigger difference. Maybe comparing 30% to 60% was not good enough. You might see that the next TORPIDO trial is going to be 30% to 80% or something, or 30% to 90%. But there is definitely a bit of a signal when it comes to advanced resuscitation that is interesting. We'll see what comes out of that.

[14:24.772] Daphna Yasova Barbeau MD Yeah, it's super interesting. I mean, okay, there's a composite outcome, but not needing chest compressions and epinephrine in the delivery room is no small thing. Just from the strain on the body, the stress of the parents... we don't know what that does to the brain. That's, in my opinion, something that we had to look at.

[14:35.413] Ben Courchia MD No, it's a big deal, right? It's a big deal. I always put myself in the position of a parent and if you told me, "We're gonna either do 30% or 60%, the outcomes are the same, but we did find that 60% kids have less need for chest compression..." I don't think in my right mind I would say no.

[15:00.77] Daphna Yasova Barbeau MD I'm sorry, it's not funny at all, but it's a huge deal.

[15:04.783] Ben Courchia MD It's a huge deal. The issue is how you present the data. Obviously, you have to say that this is not what the study was powered for. This is not the hypothesis that this particular study was testing. And I think you have to remember that while I mentioned the percentages, as we get into the nitty gritty of this kind of data, it becomes small numbers. The number of babies who received epinephrine: four in the 60% group, 14 in the 30% group. We're not even talking about 30 patients. Hard to know if these numbers are gonna be generalizable. In terms of receiving chest compression: 11 in the 60% group, 30 in the 30% group. Again, that heavy sample size that you had for your primary outcome of 700-plus babies suddenly dwindles down to less than 30 patients. I think this will be very interesting to see if that carries through on further studies. Whether you want to turn up the oxygen when you go to that next delivery for that ELBW, that is up to you.

[16:06.67] Daphna Yasova Barbeau MD I was surprised that it didn't change the initial respiratory need on admission. I thought that was interesting.

[16:24.367] Ben Courchia MD Yeah, I mean, I haven't looked in depth into what that meant in terms of actual support. So when you look at the table, I think this refers to table three, they break down basically the different modes of ventilation: high flow, high frequency, CPAP, IMV, and so on. And you wonder if this is due sometimes to protocol. Like for example in our unit, if you're born at 23 weeks, you come in and you're gonna be on the jet, right? We have first intention jet. So if a baby comes in our unit and is on the jet, it's not a reflection of their clinical status, it's our protocol. I don't know how much of that is a reflection of the need of the patients, because then it's not broken down by gestational age. So it's hard to know.

[17:25.176] Daphna Yasova Barbeau MD Well, I just wanted to refer people back. You mentioned our Giants in Neonatology episode. It's number 203 with Dr. Saugstad. I'm going to disclose, this was pretty eye-opening for me. I didn't realize the history of how we have selected our initial oxygen parameters. So I think it's important for people to know what we know and know what we don't know, you know?

[17:49.359] Ben Courchia MD And no offense, our field has already entered a transition phase where our pioneers have passed away. We are a specialty that still has the privilege of being able to talk to people who have influenced our specialty in a major way. I mean, no internist can actually go and interview William Osler. It's not something that they have the opportunity to do, yet we kind of do. You can go to a Saugstad and be like, "Hey, you've moved our field in a direction in a pretty significant way and we get to talk to you." It is mind boggling.

[18:11.554] Daphna Yasova Barbeau MD Yeah, super cool.

[18:16.521] Ben Courchia MD All right, everybody. This was our episode for today. We'll see you next time for another episode.