#413 - [Journal Club] - 📌 Should We Increase Caffeine Dosing for Extremely Preterm Infants?

In this episode of Journal Club, Ben and Daphna review a retrospective cohort study exploring the effects of higher caffeine maintenance dosing on BPD and neurodevelopmental outcomes. They discuss the transition from the standard CAP trial doses to higher regimens for infants born at or before 28 weeks gestation. Does an average daily dose of over six milligrams per kilogram reduce severe BPD or improve Bayley cognitive scores at six months? Tune in as they debate the safety, clinical implications, and their own unit's practices regarding caffeine management in the NICU!

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Effects of higher caffeine dosing on rates of bronchopulmonary dysplasia and neurodevelopmental outcomes. Fleishaker S, Kazmi SH, Mavrogiannis N, Street H, Ravuri H, Moinuddin T, Pierce K, Verma S.J Perinatol. 2026 Feb 23. doi: 10.1038/s41372-026-02593-1. Online ahead of print.PMID: 41731043

Transcript

Ben Courchia MD (00:00.654) Hello everybody, welcome back to the Incubator podcast. We're back today for Journal Club; it is Thursday. Daphna, good morning. Where are you taking us today?

Daphna Yasova Barbeau MD (00:06.814) Good morning, good morning. I told you I'm going to finish out the week with another medication paper. One of my favorite topics, caffeine.

Ben Courchia MD (00:12.136) You're on a roll.

Daphna Yasova Barbeau MD (00:16.318) I am.

Ben Courchia MD (00:17.132) I know which paper you're doing, and I'm quite excited for the review of that paper.

Daphna Yasova Barbeau MD (00:22.462) I'm glad to hear that. Well, I know you're a fan of strong coffee and BPD papers, so this is one for you for sure. This is in the Journal of Perinatology. It's entitled "Effects of Higher Caffeine Dosing on Rates of Bronchopulmonary Dysplasia and Neurodevelopmental Outcomes". Lead author Sarah Fleischacher and senior author Sourabh Verma.

Ben Courchia MD (00:32.994) It combines both of my interests.

Daphna Yasova Barbeau MD (00:52.83) This is coming from NYU Hassenfeld Children's Hospital. The background is useful, and we've done a pretty good review of the CAP trial and caffeine for people who want to take a listen to that. We interviewed Dr. Barbara Schmidt on episode 136; she is one of our giants of neonatology. And we have a board review PowerPoint on caffeine for apnea of prematurity.

Ben Courchia MD (01:25.546) For the people who ask, we get emails a lot about where to find these series. We did a few topics during a lull between two board exams. If you go to the neonatology review page on the website and click on "Show Notes," there will be a list. It's one of the tabs called "Show Notes" on the neonatology review tab. One of the first series is caffeine for the management of apnea.

Daphna Yasova Barbeau MD (01:30.102) Mmm. Yeah.

Daphna Yasova Barbeau MD (01:39.272) Website.

Daphna Yasova Barbeau MD (01:54.234) Mm-hmm. That was a fun one. The background states BPD is the most common complication associated with prematurity. Caffeine is one of the most common medications used in the NICU based on its utility in the CAP trial, the Caffeine Therapy for Apnea of Prematurity Study.

Ben Courchia MD (01:55.246) Yeah.

Daphna Yasova Barbeau MD (02:20.83) In that study, they looked at infants between 500 and 1,250 grams who received a loading dose of 20 mgs per kilo, followed by a maintenance dose of five mgs per kilo of caffeine. Babies who were in the intervention arm had reduced rates of BPD compared to the placebo group. So it pretty much became the standard of care practice to give a caffeine bolus and continue on a maintenance dose to infants born less than 34 weeks until 34 weeks post-menstrual age. Notably, since the CAP trial, our definitions for BPD have changed a little bit. As we proceed through this conversation, it should be noted that the BPD criteria used is the Jensen criteria, the newest NICHD definition from 2019. Subsequently, other studies were done looking at high-dose caffeine compared to standard-dose caffeine in preterm newborns who are at risk of lung disease, which showed it was unclear if higher doses improve neurodevelopmental disability or duration of hospitalizations. But there was a signal that higher doses may reduce rates of BPD. Most of these studies were in large groups of babies that included more mature babies, kind of all babies less than 32 weeks gestation. So they really wanted to evaluate the efficacy and safety of using a higher maintenance caffeine dosing in infants born less than or equal to 28 weeks gestation. And again, its impact on neurodevelopmental outcomes and the outcome of BPD. This was a retrospective observational cohort study, a single-center study at New York University, which is a level four regional perinatal center. Eligible infants were born at less than or equal to 28 weeks gestation. They must have received caffeine between 2017 and 2023.

Daphna Yasova Barbeau MD (04:27.869) They were excluded if they didn't receive caffeine in the first week of life, if they had congenital anomalies or congenital heart disease requiring surgical intervention that might affect respiratory drive, or if they had anomalies of lung development or anomalies that were felt to impact neurodevelopmental outcomes. Standard practice in their unit is to give that loading dose of 20 mgs per kilo for less than 34 weeks, followed by a maintenance dose of five mgs per kilo per day until 34 weeks. In the last five years of this cohort, there was a shift in practice to increase the maintenance dose to a range of 7.5 to 10 mgs per kilo per day for infants born at less than or equal to 28 weeks gestation. Infants were assigned to low dose based on what they were already getting in clinical practice. 62 infants were in the low-dose group.

Ben Courchia MD (05:17.538) Mm-hmm.

Daphna Yasova Barbeau MD (05:23.501) They considered low dose as an average daily dose of less than or equal to six mgs per kilo per day, which would encompass those babies getting the five mgs per kilo per day regimen. High-dose infants were 111 of those babies that still got a 20 mgs per kilo bolus, but received an average daily dose of greater than six mgs per kilo per day. The primary objective was to compare rates and severity of BPD in the infants who received low versus high daily caffeine doses. A secondary objective was to compare neurodevelopmental outcomes using the Bayley scores. Most infants were followed up at their outpatient clinic at 6, 12, 18, and 24 months. There were some differences. Birth length and five-minute Apgars were lower in the low-dose group. Rates of maternal chorioamnionitis, which we know is linked to BPD, were higher in the low-dose group. So they had smaller birth lengths, lower five-minute Apgars, but they also had higher rates of maternal chorioamnionitis in the low-dose group. I think that is potentially important for us. The average daily dose of caffeine in the low-dose group was 5.15 mgs per kilo per day, while the average daily dose in the high-dose group was 8.18 mgs per kilo per day. There was no statistically significant difference in the duration of treatment or the need to decrease the dose secondary to adverse effects such as tachycardia. There were significantly higher rates of surgically treated PDA, number of packed red blood cell transfusions given prior to 36 weeks, duration of invasive ventilation, as well as patients discharged home on respiratory support seen in the low-dose group. Conversely, the duration of non-invasive ventilation was longer in the high-dose group. When looking at the BPD outcomes, there was no significant difference between the rates of BPD overall. However, there was a statistically significant difference in the severity of BPD between the two groups.

Daphna Yasova Barbeau MD (07:48.638) The low-dose caffeine group had grade one or mild BPD in 30% of patients compared to nearly 36% of patients in the high-dose group. Grade two or moderate BPD was 35% of patients in the low-dose group compared to 60% of patients in the high-dose caffeine group. Grade three was 35% in the low-dose caffeine group compared to 7%. Again, it's only six patients, but 7% in the high-dose caffeine group. When evaluating the Bayley scores at 6, 12, 18, and 24 months, there was a difference in cognitive scores at six months. This was not seen at subsequent follow-up. Looking for confounding variables, they used a logistic regression and linear regression for BPD outcomes and the six-month Bayley cognitive score. There continued to be a significant difference between the two groups, with the higher caffeine group having improved outcomes. So, less severe BPD and better cognitive scores. Variables such as gestational age, birth weight, and sepsis were also significant predictors of severe BPD rates. We know that from previous studies. Severe BPD itself was a significant predictor of worse Bayley cognitive scores at six-month follow-up. They conclude that the study adds to the data that may support a higher maintenance dose in this population of less than or equal to 28 weeks. There was a significant reduction in the rate of severe BPD and an improvement in the Bayley cognitive score at six months. Importantly, there were no differences in adverse outcomes noted between the two groups, such that caffeine at higher doses may be safe and may confer some additional protection for these babies. Thoughts? I love caffeine. My thoughts are... Go ahead, you go.

Ben Courchia MD (09:48.322) What are your thoughts? You love caffeine. It's interesting because I was going to mention the discussion we had after our On with VON episode with Dr. White. You are a neurodevelopmental expert, and you said, "Can we retime our caffeine to morning time caffeine?" Everybody was on board, and then the question came up: What if you give a loading dose too close to the morning dose of caffeine? Do you give it the next morning or do you wait another day? And you were like, "No, it's fine. More caffeine, there's no issue."

Daphna Yasova Barbeau MD (10:00.627) That's right.

Daphna Yasova Barbeau MD (10:06.27) Mm-hmm.

Daphna Yasova Barbeau MD (10:13.598) See, it's fine.

Ben Courchia MD (10:21.006) So I know you advocate for more caffeine. I'm just wondering what your thoughts are.

Daphna Yasova Barbeau MD (10:27.496) Well, I myself have experienced adverse effects of caffeine. So I know that I had to cut back on my caffeine. When I moved to South Florida, I realized that I was getting cafecitos five or six times a day passed in the unit. That is not something I had been drinking in Gainesville, Florida. Anyways, I think that caffeine is...

Ben Courchia MD (10:40.494) Yeah. Yeah.

Daphna Yasova Barbeau MD (10:56.068) ...one of the few interventions that we have good data for in the NICU. Could we go higher on caffeine? I don't know. We have lots of babies in our unit where I feel like we are reducing caffeine quite a bit for tachycardia. Does it always fix the tachycardia? No, it usually doesn't in those babies that just stay tachycardic. But I think there's a lot of discussion about how we use caffeine. What's the timing for caffeine? In every unit that I've been in, we've done things differently. In one unit, we started a dose, we never checked it, and we never increased the dose. In one unit, we checked the levels and we increased the dose based on the levels. In our current unit, we weight-base the dose weekly. We don't really have good data for any of those practices. So I think for young...

Ben Courchia MD (11:32.546) Really.

Ben Courchia MD (11:50.583) Interesting.

Daphna Yasova Barbeau MD (11:51.504) ...early neonatal professionals, I think people think caffeine is solved, but I think there's still work to be done.

Ben Courchia MD (11:59.564) I was not very impressed with that particular paper from the standpoint that I don't know how much stake I place on a six months' Bayley.

Daphna Yasova Barbeau MD (12:10.766) Sure, yes. I mean, the CAP trial showed improvements at school age, but that didn't bear out into adolescence.

Ben Courchia MD (12:19.47) But the point of this paper is like, could I give more caffeine basically? It doesn't seem to be causing harm. That's first; I think that this is quite good. Am I going to be prompted to increase the dose of caffeine on babies because a retrospective study shows that at six months Bayley, the cognitive outcomes are marginally better? I don't know.

Daphna Yasova Barbeau MD (12:44.83) Yeah, I 100% agree with you, but a reduction in severe BPD is no small thing. That means, with this criteria, invasive mechanical ventilation at 36 weeks.

Ben Courchia MD (12:59.042) Yeah, it's a small group and it is... yeah, the BPD outcomes are...

Daphna Yasova Barbeau MD (13:01.286) It's a small group, obviously, but...

Daphna Yasova Barbeau MD (13:10.119) Hmm.

Daphna Yasova Barbeau MD (13:17.576) I also think the average caffeine doses weren't that different, six and eight overall. Most everywhere I've worked, we've been doing 10 per kilo.

Ben Courchia MD (13:21.802) Yeah.

Ben Courchia MD (13:31.02) Yeah. Okay. All right, buddy. I will see you next week. Tomorrow is Neo News. Stay tuned for that, and then I'll see you Monday.

Daphna Yasova Barbeau MD (13:37.95) Sounds good.