Four Ways to Give a Premature Baby the Medicine That Opens the Lungs

A large review of 36 studies and 4,035 babies compares breathing tubes, thin tubes, small airway masks, and mist

Premature babies often cannot make enough of a natural substance called surfactant, which keeps the tiny air sacs in the lungs from collapsing. Giving surfactant as a medicine saves lives, but it has to reach the lungs somehow. A large 2024 review compared four different ways of getting it there, and found that a very thin soft tube passed briefly into the windpipe still works best overall — with a small airway mask a close and gentler second.

That review pooled the results of 36 separate randomised studies involving 4,035 babies, which makes it one of the most complete comparisons of surfactant delivery methods published to date [1]. Understanding why the question matters takes a short step back in time.

The Problem That Started All of This

Around 13.4 million babies are born too early each year worldwide [2]. The more premature a baby is, the less surfactant their lungs have made. Without it, each breath out lets the air sacs collapse, and the next breath in has to reopen them — exhausting work for a newborn who may weigh less than a bag of sugar. Doctors call this respiratory distress syndrome, or RDS.

Before the 1980s there was very little to offer beyond oxygen and a ventilator. Then, in 1980, a Japanese team gave manufactured surfactant directly into the lungs of premature babies, and the results were dramatic enough that within about ten years the treatment had spread across the world and become standard care. Fewer babies died, and fewer suffered burst air pockets in the lung [3].

But there was a catch, and it is the catch this whole field has been wrestling with ever since. Surfactant is a liquid. To get it into the lungs, doctors traditionally had to place a breathing tube down the baby's windpipe, squirt the medicine in, give a few breaths by machine, and then take the tube out. This is called intubation-surfactant-extubation, or the InSurE method. The problem is that even a short time on a ventilator can injure a very immature lung. In the United States, around 40 out of every 100 babies treated this way still go on to develop bronchopulmonary dysplasia, a form of chronic lung damage that can mean months of extra oxygen and repeated hospital stays [4].

So the question became: can we give the medicine without the breathing tube?

Four Answers, and How They Differ

The thin catheter. In the early 2000s, doctors in Cologne, Germany, tried something simple. Instead of a breathing tube, they slipped a very fine, soft catheter — thinner than a drinking straw — between the vocal cords of a baby who was breathing on their own with gentle pressure support through the nose. The surfactant trickled down while the baby kept breathing. It worked, even in extremely premature infants [5]. This approach is now known as LISA (less invasive surfactant administration) or MIST (minimally invasive surfactant therapy), and European guidelines recommend it as the preferred method for babies who are breathing on their own [6]. A German multicentre trial confirmed the benefit in a randomised comparison [7], and a follow-up consensus guideline set out how to do it consistently [8].

The laryngeal mask. A thin catheter still requires the doctor to look at the vocal cords using a lighted instrument, which is a skill that takes practice and can briefly stress the baby. A laryngeal mask avoids that. It is a small soft cup that sits over the entrance to the windpipe without going into it, and it can be placed by feel, without the lighted instrument and without sedative medicines. Studies in the United States tested giving surfactant this way, comparing it both to leaving babies on breathing support alone [9] and to a brief breathing tube — the latter in 93 babies, 51 given the mask and 42 the tube, with the mask holding its own [10].

Mist. The gentlest option of all is to turn the surfactant into a fine mist that the baby simply breathes in through their nose. Nothing enters the airway at all.

The traditional breathing tube, still used when a baby needs one for other reasons.

What the Review Found

The babies in these 36 studies were mostly born between 25 and 36 weeks of pregnancy, with an average of about 31 weeks. Just over half were treated in Asia, with the rest split fairly evenly between North America and Europe. Almost all received treatment within 12 hours of birth [1].

The clearest finding concerned whether a baby ended up needing a full breathing tube and ventilator in the first week of life. Both the thin catheter and the laryngeal mask cut that risk substantially compared with waiting and treating only if necessary — the odds fell by roughly 80% with each. The traditional tube method also helped, but less. Crucially, the mask and the catheter were not meaningfully different from each other on this measure.

Mist was the disappointment. Babies given misted surfactant were about three times more likely to need a breathing tube than those given it by catheter or mask, were the most likely to need a second dose, and had somewhat higher rates of a collapsed lung and of a heart-vessel problem called patent ductus arteriosus. The likely reason is not that the medicine is different, but that far less of it actually lands in the lungs when inhaled as a mist. Newer mist devices are improving on this in laboratory testing [11], but they are not there yet.

There was one unexpected result. Babies who received surfactant through the laryngeal mask had higher rates of chronic lung damage than those who received it by thin catheter. This surprised the researchers, because the mask is the gentler procedure. They are careful to say the finding rests on a small number of studies and may not hold up — but it is a reason to keep watching.

Both the mask and the mist had the fewest problems during the procedure itself: less gagging, less vomiting, fewer drops in heart rate.

What This Means for Families

If your baby is given surfactant, the choice your team makes between a thin catheter, a mask, or a brief breathing tube is a choice about the route, not the medicine. The surfactant itself is the same.

On current evidence, most units will reach first for the thin catheter, because it has the strongest track record. The laryngeal mask is a reasonable and gentler alternative for babies born at around 30 weeks or later — masks small enough for the tiniest babies do not yet exist. That is also why this research cannot yet answer the question for extremely premature infants: almost none of the studies comparing these methods included them.

Whichever route is chosen, the procedure itself is brief — usually a few minutes — and your baby stays on their usual breathing support throughout with the thin catheter and the mask. You may hear the team describe crackles in the chest afterwards; this is expected, and simply reflects the liquid spreading through the lungs. Improvement in oxygen levels is often visible on the monitor within minutes to hours. Some babies need a second dose, which is a normal part of treatment rather than a sign that the first dose failed.

It is fair to ask your team which method they use and why. It is equally fair to know that these are all good options, and that the difference between them is smaller than the difference between having surfactant and not having it.

What Researchers Are Working On Next

Three things. First, whether babies should be given pain or sedative medicine before a thin catheter is passed — practice varies, and there is no agreement yet. Second, whether laryngeal masks can be made small enough for the most premature babies, and whether the chronic lung finding is real. Third, whether misted surfactant can be improved enough — by changing the device, the airflow, or the concentration — to become genuinely competitive.

The research community has been circling this question for years. An earlier 2016 review could find only one study each on masks and mist [12], and a 2021 review was still weighted heavily toward the thin catheter [13]. One of the largest and most rigorous trials of the thin catheter method, known as OPTIMIST-A, compared it against a dummy procedure across many hospitals internationally and helped clarify both its strengths and its limits [14]. The 2024 review is the first with enough evidence to place all four routes side by side — a meaningful step, even if the final answer is still some years away.

References

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  2. Ohuma EO, Moller A-B, Bradley E, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. The Lancet. 2023;402(10409):1261–1271. doi:10.1016/S0140-6736(23)00878-400878-4) ↩
  3. Stevens TP, Sinkin RA. Surfactant replacement therapy. Chest. 2007;131(5):1577–1582. doi:10.1378/chest.06-2371 ↩
  4. Donda K, Vijayakanthi N, Dapaah-Siakwan F, Bhatt P, Rastogi D, Rastogi S. Trends in epidemiology and outcomes of respiratory distress syndrome in the United States. Pediatric Pulmonology. 2019;54(4):405–414. doi:10.1002/ppul.24241 ↩
  5. Kribs A, Pillekamp F, Huenseler C, Vierzig A, Roth B. Early administration of surfactant in spontaneous breathing with nCPAP: feasibility and outcome in extremely premature infants (postmenstrual age ≤27 weeks). Pediatric Anesthesia. 2007;17(4):364–369. doi:10.1111/j.1460-9592.2006.02126.x ↩
  6. Sweet DG, Carnielli V, Greisen G, et al. European consensus guidelines on the management of respiratory distress syndrome – 2019 update. Neonatology. 2019;115(4):432–450. doi:10.1159/000499361 ↩
  7. Kribs A, Roll C, Göpel W, et al. Nonintubated surfactant application vs conventional therapy in extremely preterm infants: a randomized clinical trial. JAMA Pediatrics. 2015;169(8):723–730. doi:10.1001/jamapediatrics.2015.0504 ↩
  8. Reynolds P, Bustani P, Darby C, et al. Less-invasive surfactant administration for neonatal respiratory distress syndrome: a consensus guideline. Neonatology. 2021;118(5):586–592. doi:10.1159/000518396 ↩
  9. Roberts KD, Brown R, Lampland AL, et al. Laryngeal mask airway for surfactant administration in neonates: a randomized, controlled trial. The Journal of Pediatrics. 2018;193:40–46.e1. doi:10.1016/j.jpeds.2017.09.068 ↩
  10. 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. The Journal of Pediatrics. 2023;254:17–24.e2. doi:10.1016/j.jpeds.2022.10.009 ↩
  11. Bianco F, Pasini E, Nutini M, et al. In vitro performance of an investigational vibrating-membrane nebulizer with surfactant under simulated, non-invasive neonatal ventilation conditions. Pharmaceutics. 2020;12(3):257. doi:10.3390/pharmaceutics12030257 ↩
  12. Isayama T, Iwami H, McDonald S, Beyene J. Association of noninvasive ventilation strategies with mortality and bronchopulmonary dysplasia among preterm infants: a systematic review and meta-analysis. JAMA. 2016;316(6):611–624. doi:10.1001/jama.2016.10708 ↩
  13. Bellos I, Fitrou G, Panza R, Pandita A. Comparative efficacy of methods for surfactant administration: a network meta-analysis. Archives of Disease in Childhood — Fetal and Neonatal Edition. 2021;106(5):474–487. doi:10.1136/archdischild-2020-319763 ↩
  14. Dargaville PA, Kamlin COF, Orsini F, 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;326(24):2478–2487. doi:10.1001/jama.2021.21892 ↩