Dr. Sanjay Akangire (Host): Hello, everyone. This is Dr. Akangire. Welcome back to another edition of our podcast, Neonatology Review: Isolette to Crib. Today, I'm your host. The purpose of this podcast is to review high-yield common topics in Neonatology. While our focus is geared towards the neonatology, perinatology boards, anyone learning or studying neonatology will find this podcast helpful. For this episode, we have Dr. Sharma as our guest. Tell everyone hi, Dr. Sharma.

Dr. Joti Sharma: Hi, everyone. Yes, today I'm here as a guest and happy to be here as always.

Host: In our last podcast, we discussed fetal lung and surfactant physiology. And in today's podcast, Dr. Sharma will cover the topic of exogenous surfactant, again a very important topic from the board standpoint. So, we will discuss available exogenous surfactant, their properties, and indications for use.

With advancements in neonatal care and improved non-invasive ventilation techniques, the use of exogenous surfactant in preterm infants has decreased, as you know, especially prophylactic surfactant replacement. Exogenous surfactant still remains an important aspect of respiratory therapy in neonates.

Dr. Sharma, before we discuss the properties of exogenous surfactant, I think we do need to talk about the history of surfactant development, because it was one of the most important advancements in neonatal care.

Dr. Joti Sharma: Dr. Akingire, you are correct. Surfactant replacement therapy is one of the major advances in Neonatal Medicine in the last 50 years. Actually, in some aspects, the history of surfactant research and development is also the history of neonatology.

Host: I agree, Dr. Sharma. So, the journey from identification of surfactant deficiency as cause of respiratory distress syndrome or RDS to the development of testing of surfactant preparations was the result of decades of research.

Dr. Joti Sharma: Yes. For the history of surfactant, we need to go back to 1957 when actually a physiologist, John Clements, recognized that some uncounted forces of surface tension would lead to alveolar collapse. After developing some special tools to measure surface tension, he actually identified pulmonary surfactant. At that time, he called it anti-atelectasis factor.

Then, in late 1950s, Mary Ellen Avery and Jerry Mead made the discovery, a very important discovery, that surfactant was absent from the lungs of infants who died from RDS, but present in infants who died without pulmonary disease. Their hypothesis was that immaturity of the lung with respect to the capability to synthesize surfactant could lead to atelactasis.

In 1963, President Kennedy's son, Patrick Kennedy, was born at 34 weeks. He died two days later from RDS. It's interesting. This day and age, we have 34-week gestation infants born and they are discharged home within two or three weeks. But 1963, that was not the case. President Kennedy actually brought about funding for research into the cause and treatment of RDS, which actually led to regionalized neonatal intensive care units.

Host: So, it looks like it took almost 20 years from initial research on development of exogenous surfactant to clinical trials using exogenous surfactant, right?

Dr. Joti Sharma: Yes, that is correct. Most research started in the late '60s. And in 1980, Fujiwara and his colleagues published a paper in Lancet where they successfully treated premature infants with RDS using surfactant prepared from cow lungs. More research took place in the 1980s and Dr. John Clements at that time invented Exosurf, the first or the original synthetic surfactant, which was phospholipid-based.

In 1990, actually in August 1990, FDA approved the first exogenous surfactant, which was Exosurf. Since 1990, we have actually moved from synthetic to animal-derived surfactant or natural-derived surfactant. And now, research is actually ongoing on synthetic surfactant with proteins. Remember, the first surfactant Exosurf only contained phospholipids.

So in the 1990s, virtually all NICUs in the U.S. and the developed world quickly adopted surfactant for the treatment of RDS, and death rates for premature infants fell. For infants born between 24 to 32 weeks' gestation, the mortality dropped by 30-45% after the widespread use of surfactant.

Host: Compared to no surfactant, what did the early surfactant trials show?

Dr. Joti Sharma: The early surfactant trials, remember most of these trials initially involve the synthetic phospholipid-based surfactant, showed that infants who received exogenous surfactant had decreased risk of pneumothorax, pulmonary interstitial emphysema, intraventricular hemorrhage, neonatal mortality. And even the neonatal mortality prior to hospital discharge and at one year of age was decreased. What's important to note is that most of these studies were in the era of low use of antenatal steroids. And at that time, non-invasive ventilation had not advanced as it is now.

Host: Let's discuss the available exogenous surfactant. It helps to discuss exogenous surfactant as synthetic and natural. Can you talk about synthetic surfactant first, Dr. Sharma? 

Dr. Joti Sharma: Exogenous surfactant can be divided into synthetic or artificial, and natural based on their origin and their surfactant properties. So, with regards to synthetic surfactant, we can further categorize them as original synthetic surfactant and the newer synthetic surfactant.

So, when we say the original synthetic surfactant, it's also known as the non-protein synthetic surfactant or the phospholipid-based surfactant, which contained DPPC and PG. the most common early synthetic surfactant was Exosurf. 

Host: Okay. So, I understand these early synthetic surfactants are not available or used in clinical practice anymore, right?

Dr. Joti Sharma: Yes. Dr. Akingire, you are correct. But essentially, the early synthetic surfactants have been replaced by the natural surfactants for clinical use, which we will discuss soon. But first, I just want to mention some of the newer generation synthetic surfactants. These are still mainly used in clinical trials.

The newer generation synthetic surfactants are also called peptide-containing synthetic surfactants. They contain both phospholipids and peptide, which resembles the natural surfactant protein B. One of these, Surfaxin, is actually FDA approved, but it's not used much in clinical practice. There is another one, which is known as CHF5633. It's the first synthetic surfactant that is undergoing clinical trials, and it contains the analogs of both the surfactant protein B and surfactant protein C. As I mentioned, these are all mostly used for clinical trials at the moment.

Host: That's a great summary, Dr. Sharma, about artificial and natural surfactants. Let's now focus on the natural exogenous surfactant. In clinical practice, the naturally derived surfactant is the one utilized. I know there are differences in composition in early synthetic surfactant and natural, which I hope you will discuss. Were there any differences noticed in clinical trials? 

Dr. Joti Sharma: So, in clinical trials, the benefits of natural surfactant over Exosurf included faster weaning on the ventilator and decreased pneumothorax in patients that received natural surfactant as compared to the synthetic surfactant.

Host: Can you discuss the main differences between the natural and early synthetic surfactants?

Dr. Joti Sharma: The main difference from the early synthetic surfactant is that the natural surfactants also contain surfactant-specific proteins together with phospholipids. So, the natural surfactants have both phospholipids and surfactant proteins, the natural exogenous surfactants are derived from animal lung.

The surfactant proteins, which we did discuss in the last podcast, are specifically SP-B and SP-C, play a key role in its ability to lower surface tension at the air-fluid interface of the alveolar surface. These surfactant surfactant proteins also aid in surfactant absorption, and resist surfactant inactivation. This leads to rapid onset of action, allowing the ventilator settings and FiO2 to be decreased quickly.

Host: There are a few natural surfactants, it looks like, but it appears only one is most often used in the clinical practice, right, Dr. Sharma? 

Dr. Joti Sharma: Most of the natural surfactant trials happened in late '80s and '90s. And the three commonly naturally derived surfactants that were used in the clinical trials were Curosurf, which is actually derived from the porcine or pig lung tissue; Infasurf, derived from the bovine or calf lung, but through a bronchoalveolar lavage. And then, the last one is Survanta, which is also bovine-derived lung tissue. 

Host: So, Survanta was more common in the past. But for the last 10 to 15 years, it seems most Neonatal Intensive Care units use Curosurf for surfactant replacement. I wonder why the change?

Dr. Joti Sharma: Most Neonatal Units made this switch based on the exogenous surfactant properties. Curosurf actually contains more phospholipids compared to both Infasurf and Survanta. With regards to surfactant protein B and surfactant protein C, Curosurf and Infasurf contain greater amounts of SP-B and SP-C compared to Survanta.

In terms of the volume of surfactant administered endotracheally, and the frequency of repeat dose, Curosurf is a smaller volume, and repeat dose is in 12 hours as compared to Survanta, which is a larger volume, and the repeat dosing is usually six to eight hours. Therefore, based on these factors and clinical studies, most centers now use Curosurf as their surfactant of choice.

Host: Having covered the development of surfactant, the types of surfactant, can we discuss its use in current clinical practice, especially with advances in non-invasive ventilatory support to avoid ventilator-induced lung injury?

Dr. Joti Sharma: Our practice with regards to management of RDS in premature infants has evolved. early surfactant replacement therapy was in two forms: prophylactic, usually given in the delivery room once the patient was intubated, and then rescue, which surfactant was given later based on worsening respiratory status.

But as you have mentioned with advances in not only non-invasive ventilatory support, but overall neonatal prenatal care and results of randomized trials, the current recommendation is prophylactic surfactant replacement may no longer be beneficial in preventing deaths and air leaks. And most have moved to using surfactant replacement therapy as rescue treatment rather than as prophylaxis.

Host: As neonatologists, we still worry about ventilator-induced lung injury, which contributes to chronic lung disease and giving endotracheal surfactant requires intubation and mechanical ventilation. Are there any advances in this area? 

Dr. Joti Sharma: There has actually been significant advances with regards to giving surfactant without continued mechanical invasive ventilation. So, let's talk about INSURE, which is I-N-S-U-RE. It stands for intubate, I-N; surfactant, S-U-R, and then extubate, EX. The INSURE procedure comprises of intubation followed by administration of a surfactant, early extubation either to CPAP or other non-invasive ventilation.

While INSURE might help minimize the complications associated with mechanical ventilation, its success rate is not very high. INSURE was successful in approximately 30% of infants less than 32 weeks. And those who failed INSURE required longer periods of ventilation or reintubation. One of the other factors is that sedation is required during INSURE with placement of an endotracheal tube, which may result in extubation not happening earlier than anticipated. A systemic review reported that failure of INSURE was more common in extremely low-birth-weight infants, infants of lower gestational age, and those with severe RDS.

Host: INSURE still requires intubation with endotracheal tube placement. And since sedation is used, some of these infants may not be able to really extubate. With that in mind, are there other procedures in giving surfactant therapy without the need for intubation?

Dr. Joti Sharma: We have had some significant advances, I would say, just in the last three, four years in that area. You have probably heard of LISA. LISA, which stands for Less Invasive Surfactant Administration. It's also called MIST, Minimal Invasive Surfactant Administration. So, LISA aims to introduce an adequate amount of surfactant into the trachea where a small diameter catheter placed orally or nasally beyond the vocal cord. LISA allows infants to breathe spontaneously during the delivery of the surfactant.

Early respiratory support using CPAP or other forms of non-invasive ventilation and rescue surfactant administration using LISA are recommended for spontaneous breathing of preterm infants at risk of RDS. A meta-analysis reported that infants treated with LISA showed decreased rates of BPD or bronchopulmonary dysplasia decreased need and duration of respiratory support and lower rates of CPAP failure when compared to other methods of surfactant delivery.

In another study with a two-year follow up, LISA did not exhibit negative effects on body length, body weight, and neurodevelopment of preterm infants. LISA will likely become a more common method of surfactant therapy to minimize long-term ventilation and high oxygen exposure, both of which actually contribute to BPD.

Host: Has surfactant been useful or recommended for other neonatal conditions or diseases?

Dr. Joti Sharma: Overall, the use of exogenous surfactant therapy outside of respiratory distress syndrome is unlikely to alter the clinical outcomes. But it may show a transient improvement in oxygen in infants with pneumonia and pulmonary hemorrhage.

Host: Okay. So in these conditions, it is considered due to the concern that endogenous surfactant is inactivated by inflammatory mediators.  

Dr. Joti Sharma: Yes, that is correct. But as noted, the improvement is only transient. Therefore, it should be used cautiously in neonatal pneumonia and pulmonary hemorrhage. With regards to congenital diaphragmatic hernia, surfactant therapy is not recommended for infants with CDH unless the infant has surfactant deficiency secondary to RDS, in which the patient most likely is going to be premature.

There is some evidence that surfactant therapy can reduce the need for ECMO in newborns with meconium aspiration syndrome. And again, it can be used in meconium aspiration syndrome, but most would suggest that we have to do it cautiously and be prepared to place the patient on ECMO if needed. So, most of us would give surfactant in meconium aspiration syndrome in an ECMO center. 

Host: This is a detailed review of surfactant replacement therapy. Could you summarize some take-home points?

Dr. Joti Sharma: So in summary, the discovery of surfactant advanced neonatal care dramatically. The exogenous surfactant used now in clinical practice is naturally derived and contains both phospholipids and surfactant proteins B and C. With advances in neonatal care, it is now recommended to give surfactant replacement therapy as rescue treatment rather than prophylactically.

Newer method of surfactant administration, such as LISA, is becoming more common in clinical practice as neonatologists try to decrease the burden of ventilator-induced lung injury to help prevent BPD.

Host: We are almost close to the end of our podcast, Dr. Sharma. So, do you have any questions for our listeners?

Dr. Joti Sharma: Yes, I do have one question concerning exogenous surfactant. What is the main difference? The composition of early synthetic surfactant, and naturally derived surfactant. A, DPPC; B, phosphatidylglycerol; C, surfactant protein B; D, phospholipids. What do you think is the answer?

Host: So DPPC, PG, and phospholipids, they are all lipids. And SP-B, it's a surfactant protein. So, I think that the answer is SP-B.  

Dr. Joti Sharma: You are correct. The main difference is SP-B. Naturally derived proteins contain surfactant protein. Both contain phospholipids. Only naturally derived ones contain SP-B.

Host: Thank you very much, Dr. Sharma, for the great review on surfactant replacement therapy. Hopefully, this information will give you a better understanding of surfactant physiology. Until next time, this is Neonatology Review: Isolette to Crib. I am Dr. Sanjay Akangire. Thank you very much for listening.