Surfactant

The development of surfactant therapy is one of the greatest success stories in modern neonatology, transforming Respiratory Distress Syndrome (RDS) — historically known as hyaline membrane disease —from a leading cause of neonatal mortality into a manageable condition. It is in fact the first an only drug that has been developed solely for use in neonates. But the story of surfactant therapy spans decades, as researchers and clinicians from many different specialties slowly pieced together a puzzle that would eventually save millions of premature babies.

Our story begins in 1929 with Kurt von Neergaard, a Swiss physiologist, who experimented with porcine lungs. At the time, doctors thought of lungs simply as elastic balloons. But von Neergaard realized there was a hidden force at play: surface tension. The microscopic air sacs in the lungs (alveoli) are lined with fluid. Basic physics dictates that the water molecules in this fluid should attract each other, creating a high surface tension that would force the tiny air sacs to collapse. He theorized there had to be something lowering that tension, or respiration would be impossible, but he did not investigate it further. Peter Gruenwald, a pathologist in New York, repeated von Neergaard’s experiments in 1947 and showed that surface active substances could reduce the pressure needed for aeration.

In 1955, a British researcher named Richard Pattle was studying lung edema when he noticed something strange: the foam from the lung fluid consisted of tiny bubbles that refused to pop. They were far too stable for normal water, leading Pattle to suspect the presence of a unique, surface-tension-lowering substance. Two years later, John A. Clements, a physiologist working for the U.S. Army, followed up on this observation. Using a makeshift device called a modified Wilhelmy balance — famously cobbled together with a rubber band, a platinum slide, and a tray of lung extract — Clements meticulously measured the physical properties of this mystery substance. He proved that this “pulmonary surfactant” dynamically lowered surface tension as the lung’s volume decreased. It was the biological coating that kept lungs open during exhalation.

The pivotal connection was made by Mary Ellen Avery, a young pediatrician and researcher working in Boston. She was intimately familiar with the tragedy of hyaline membrane disease and was searching for a cause. When she learned about Clements’ work on surface tension, she hypothesized that perhaps premature babies weren’t dying from a physical blockage or an infection, but because they were born before their bodies could manufacture this crucial surfactant. In 1959, along with physiologist Jere Mead, she extracted lung fluid from infants who had died of the disease and tested it. The results were undeniable: the surfactant was completely missing. The babies were literally fighting to pry open stuck, collapsed lungs with every single breath.

Knowing the cause was a monumental accomplishment, but turning it into a treatment was another massive hurdle. You couldn’t just inject surfactant; you had to figure out how to deliver it into the delicate lungs of a tiny infant. In the 1970s, researchers Göran Enhörning and Bengt Robertson took up the challenge. Working with premature rabbit models, they developed a technique to instill natural surfactant directly into the trachea before the first breath. The results were spectacular. The treated rabbits breathed easily and survived, proving that exogenous (externally administered) surfactant could effectively replace what the premature body lacked.

The successful translation from animal research to infants was made by Japanese physician Tetsuro Fujiwara. Early attempts by others to treat infants using synthetic aerosols had failed because the mixtures lacked crucial proteins found in natural lung fluid. Fujiwara ingeniously formulated an enriched, modified surfactant derived from cow lungs (bovine extract). In 1980, he published the results of the first successful human trial. He administered his bovine surfactant to ten premature, critically ill babies who were on maximum life support and failing. The change was rapid and dramatic. Babies who were blue and dying suddenly turned pink as their lungs opened up and oxygen flooded their bloodstreams. Eight of the ten infants survived.

Fujiwara’s success triggered a shockwave through the medical community. Throughout the 1980s, massive randomized controlled trials with many different synthetic and natural surfactant preparations were conducted, and validated Fujiwara’s findings. By 1990, the FDA approved the first commercial surfactant preparations. What was once an often-fatal diagnosis became a highly treatable condition, revolutionizing the practice of neonatology. Today, exogenous surfactant therapy is the global standard of care for premature infants suffering from or at high risk for RDS. It has saved millions of lives and significantly reduced neonatal morbidity.

In the years since 1990, the use of surfactant has continued to evolve. The original synthetic surfactants fell out of favor, while natural, animal-derived surfactants (porcine or bovine, such as Curosurf and Survanta) became preferred because they contain crucial surfactant proteins (SP-B and SP-C) that the older synthetics lacked. Research is ongoing with newer synthetic surfactants that include attempts to mimic the action of the missing “natural” surfactant proteins. At the same time, the field has shifted away from aggressive mechanical ventilation. Techniques like LISA (Less Invasive Surfactant Administration) and MIST (Minimally Invasive Surfactant Therapy) are now used whenever possible. These involve instilling surfactant through a thin catheter while the infant remains on non-invasive continuous positive airway pressure (CPAP), protecting the fragile premature lungs from ventilator-induced injury.

Further Reading

1. Avery, M. E., & Mead, J. (1959). Surface properties in relation to atelectasis and hyaline membrane disease. AMA Journal of Diseases of Children, 97(5), 517–523. (The foundational paper linking RDS to surfactant deficiency).
2. Fujiwara, T., et al. (1980). Artificial surfactant therapy in hyaline-membrane disease. The Lancet, 1(8159), 55–59. (The first successful human trial).
3. Halliday, HL (2008): Surfactants, Past, Present, and Future. Journal of Perinatology 28, S47-S56.
4. Engle, W. A., & American Academy of Pediatrics Committee on Fetus and Newborn. (2014). Surfactant-replacement therapy for respiratory distress in the preterm and term neonate. Pediatrics, 133(1), 156-163. (Clinical guidelines).

Last Updated on 02/25/26