Current research is showing that surfactant supports many other functions besides reducing surface tension

Gene BG.jpg (5048 bytes)Pulmonary surfactant is a complex and still incompletely understood material composed of lipids and proteins, including the critical surfactant proteins SP-A, SP-B, SP-C, and SP-D. It is found in the fluid lining the alveolar surfaces of the lung. Part of its function is to decrease the surface tension at the pulmonary alveolar air-fluid interface and prevent the total collapse of the alveoli at the end of a breath. Hence problems with surfactant lead to ventilation-perfusion mismatch and respiratory distress.

In 1990, the United States Food and Drug Administration released an exogenous surfactant, colfosceril palmitate, for clinical use with preterm infants. Surfactant therapy had an immediate and significant effect in reducing the morbidity and mortality of preterm infants. To date, surfactant replacement therapy is clinically indicated only for the treatment of neonatal respiratory distress syndrome (RDS); however, research into the use of surfactant in cases of pediatric and adult acute RDS (ARDS), and other conditions is continuing.1

Production of Surfactant
The alveolus is lined with thin Type I cells and larger Type II cells, called pneumocytes, along with other types of intracellular structures and cells. Type II cells secrete the components making up pulmonary surfactant. If these cells are damaged, they divide into Type I cells.

Surfactant is composed of lipids and proteins, more specifically, the long-chain dipalmitoylphosphatidylcholine (DPPC), four surfactant proteins, and other proteins that seem to play roles in other functions. Two of these surfactant proteins, SP-B and SP-C, appear to be particularly important in the effective functioning of surfactant in the lung.2

“SP-B is unique among the body’s proteins, in that it is extraordinarily hydrophobic,” says Robert Capetola, PhD, and CEO of a company researching and producing surfactant. “The protein binds to the side-chains of DPPC. Once the surfactant lines the inside surface of the alveolus, the proteins prevent the collapse of DPPC into little liposomal balls. Any lipid would work, but only for a few seconds. SP-B allows DPPC to work for up to 50 hours.” Hence, lack of the gene for production of SP-B is fatal at birth.

Although SP-B may be the star of the show for now, a recent report by Ramet et al,3 shows that the SP-A gene locus may play a more important role than previously believed. The researchers found that over or under representation of one of the alleles in the SP-A gene locus was an important determinant for the predisposition of the neonate to RDS. Further study of the genetic makeup and function of pulmonary surfactant proteins is under way.

SP-D, as well as other components of surfactant, are now thought by some researchers to play a role in the control of infection. Besides its pivotal purpose in decreasing alveolar surface tension, surfactant is now thought to play additional significant roles in the lung.

Loss or dysfunction of pulmonary surfactant
The first role of surfactant was in the treatment of preterm infants with RDS and hyaline membrane disease. Neonates may have insufficient surfactant due to immaturity of the Type II cells. Additionally, these infants may at first seem to be ventilating properly, indicating sufficient surfactant, but may develop RDS after several hours. Initial ventilation or overventilation may damage Type II cells, and, because surfactant has a half-life of about 10 hours, the infant may develop RDS due to damaged or insufficiently developed Type II cells, leading to insufficient pulmonary surfactant.

Corticosteroids speed maturation of the Type II alveolar cells and help to speed up the production of surfactant. For these reasons, the protocol in many hospitals is to administer antenatal corticosteroids at least 24 hours before birth, if time allows, followed by early administration of surfactant to the neonate, if symptoms indicate the need.

Not all preterm infants are in need of surfactant therapy, and not all so-called full-term infants are free of the risk of surfactant deficiency. According to clinical observations,4 the incidence of infant RDS seems related more to lung immaturity than to the infant’s gestational age. It is still not clear at what gestational age an infant can be said to be free of the risk of surfactant deficiency.

Surfactant and Treating MAS
Meconium aspiration syndrome (MAS) is a frequent cause of full-term infant respiratory distress. Meconium has been demonstrated to be very damaging to surfactant. Early tracheobronchial lavage with diluted surfactant, both to physically wash out the meconium from the infant’s lung, and to treat with surfactant, appears to be a safe and effective method of surfactant therapy.5

Another study6 examined partial liquid ventilation after lavage with surfactant, in an animal model of MAS. The researchers again concluded that bronchial lavage with exogenous surfactant seemed to improve the effectiveness of ventilation and ultimate outcomes.

Natural, synthetic, and modified natural surfactants
Debate continues to rage about the benefits of natural versus synthetic surfactants. The crucial issue appears to be the presence, absence, or addition of the proteins critical to the effective function of surfactant.

Natural surfactant such as calfactant is produced by rinsing out the lungs of freshly slaughtered calves, and treating the resulting liquid to an organic or chemical extraction to purify it. The synthetic surfactant colfosceril palmitate is made in the laboratory, and was initially the best-known product for surfactant therapy.

The third type, known as beractant, which some researchers term a modified natural surfactant, is produced by mincing the entire lung of the adult cow and removing the contaminants. To this point, the process is similar to the production of natural exogenous surfactant. However, the manufacturer adds back DPPC, as well as surface active and spreading agents, such as palmitic acid, to produce a more “natural”-acting surfactant.

James Cummings, MD, professor of pediatrics and physiology at East Carolina University School of Medicine, Greenville, NC, favors the more natural surfactant. “There is a growing body of clinical and pre-clinical data that suggest that the closer you approach natural surfactant compositionally, the more effective a surfactant product you have. By any parameters—onset, duration, or extent of activity—those surfactants that most closely approach natural surfactant seem to function the best.”

One survey of the literature7 concluded that neonates receiving natural surfactant showed greater early improvement in the need for ventilatory support, and fewer complications such as pneumothoraces. It was suggested that natural surfactant is clinically the preferred choice.

The difference seems to lie in the proteins. Colfosceril palmitate lacks these proteins entirely; beractant adds the surfactant proteins back in; and calfactant, by virtue of its derivation from calf lungs, already contains at least some of the proteins.

“In fact,” Cummings adds, “in preclinical studies in animals, if SP-B is added to beractant, it comes very close in function to calfactant.”

Porcine surfactant, another modified natural surfactant, also starts with a lung mince. However, it is purified through a two-dimensional gel electrophoresis, to such an extent that the end product has almost twice the DPPC as any other surfactant. Although manufacturers suggest that only half the regular dose is needed, no data support the idea that giving less volume provides a better treatment. In fact, the opposite is true, with practical limitations.

There has been speculation that natural or modified natural surfactants may increase the infection rate in treated patients. One study8 examined the rescue use of colfosceril palmitate versus porcine surfactant. Researchers concluded that, other than a more effective initial response, the porcine surfactant offered no advantage over colfosceril palmitate, and that in fact the porcine surfactant appeared to increase the rate of infection. Further study of the structure and function of natural, modified natural, and synthetic surfactants is needed in order to clarify this issue.

The next trend in surfactants may be toward a fully synthetic product that is optimized in terms of composition, DPPC, and surfactant proteins. “The goal,” Capetola says, “is to provide a humanized version of SP-B and to make it by modern pharmaceutical standards, in order to supplant the animal proteins that may be causing other problems, such as an increased risk of infection or allergic reactions.”

The refinement involves biotechnology and recombinant proteins—proteins developed in vitro using bacteria, and which are designed to mimic the action of SP-B. The mimic, called KL-4, is synthetic and is now produced more cost-effectively by using liquid and solid phase synthesis. It shares a homology, or similarity, with SP-B. Lucinactant, a surfactant containing KL-4, is currently in various stages of clinical trials in the United States.

Capetola adds that once manufacture of lucinactant is possible in unlimited quantities and to pharmaceutical standards of purity and consistency, then it should be possible to expand its usage to other indications where surfactant replacement therapy makes sense. These uses may include the treatment of ARDS via segmental bronchoscopic lavage of the lung with a diluted surfactant preparation; as a spray to treat asthma; and as a lavage for lungs harvested for transplant purposes.

This is a bit of a catch-22 situation. At this time, pharmaceutical companies simply do not find it very interesting to put significant resources into surfactant drug development, because the only approved usage is in the treatment of neonatal RDS. This represents a very small market, and pharmaceutical companies must recoup their research and development expenses if they are to remain in business. However, if the door can be cracked open toward other uses, especially for the treatment of ARDS, then the resources will likely follow.
Another point in favor of the use of improved synthetic surfactants may be argued on religious grounds. Surfactants derived from cow or pig tissues will be unacceptable to some groups. Synthesizing the exogenous surfactant would eliminate this issue.

Routes of Delivery
Exogenous surfactant continues to be delivered primarily in bolus doses via the endotracheal tube. Although administration via aerosol has long been an attractive idea, the fatty lipid nature of surfactant results in the production of large molecules upon aerosolization; the surfactant tends to precipitate before reaching the target area of the lung.

Research continues into aerosolized delivery of surfactant. Endotracheal surfactant atomization may be an alternative to instillation directly into the endotracheal tube. Wagner et al9 in Germany treated 15 surfactant-deprived rabbits with surfactant either as a bolus or by intratracheal surfactant fog. Their findings indicated that endotracheal surfactant fog application may be as effective as bolus installation, and may play a role in the treatment of ARDS.

In a similar pilot study,10 34 neonates requiring nasal continuous positive airway pressure (CPAP) were divided into two groups. One group received aerosolized surfactant; the other group acted as the control. All neonates remained on nasal CPAP. The researchers found that, contrary to results in animal studies, there were no beneficial effects of aerosolized surfactant. They suggested that this may be due to differences in the administration techniques, but that further work is needed.

Expanded usage of surfactant
Increased research and development into the properties of surfactant are leading to improved synthetic surfactants. As the development and refinement of surfactant continue, there is increasing data11 to suggest that variations of improved surfactant may be useful in conditions other than premature lung disease. Among these potential conditions are pediatric respiratory distress, respiratory failure in burned patients, and adult asthma.

In one study,12 42 pediatric intensive care unit (PICU) patients with acute hypoxemic respiratory failure received instillations of intratracheal surfactant. The patients who received surfactant were extubated 32% sooner and spent 30% less time in the PICU. The researchers suggested that, while the results were very promising, further study is required before beginning routine treatment in the PICU with surfactant. Treatment with surfactant allowed faster weaning from the ventilator and fewer days in the PICU.

Another study13 involved the use of surfactant in a burned infant with severe respiratory failure, with a repeat dose after 12 hours. The infant was successfully weaned from mechanical ventilation in a few weeks, despite a plethora of other complications. The study suggests that surfactant therapy may improve the outcome of burned patients with respiratory insufficiency.

Surfactant lines not only the alveoli, but the narrow conducting airways of the tracheobronchial passages as well. Surfactant’s role in the airways and in mucociliary clearance suggests that it may be useful in the treatment of chronic obstructive airway diseases, such as asthma, chronic bronchitis, and the respiratory aspects of cystic fibrosis. Some researchers14 are suggesting that the next step is to formulate surfactants targeted toward general or specific clinical conditions. This will require continued study of the properties of both natural and synthetic surfactants.

One factor preventing the effective use of surfactant in ARDS has been the inactivation of surfactant in the course of the disease. Until recently, inactivation may have been a key reason why surfactant was not widely used in ARDS. New directions in research15 point toward the development of surfactants that are less prone to inactivation. These new formulations may reintroduce surfactant therapy into the treatment of ARDS.

Cummings notes, again, the apparent advantages of natural over synthetic surfactant with regard to inactivation. “Inactivation really isn’t a new topic, but it’s come up again recently. Many conditions, such as MAS or birth asphyxia, may result in the leakage of serum proteins and fluids into the lung. In animal models this has inactivated native surfactant; if you add it back, then theoretically you can overcome the inactivation to some extent. And a more natural surfactant should be less inactivated.”

Antenatal steroids followed by surfactant
Evidence continues to indicate that administration of antenatal steroids less than 24 hours before delivery reduces infant mortality and respiratory distress. It appears that in infants born at 24-28 weeks gestation, steroids may not prevent RDS, but they do seem to reduce its severity. Surfactant therapy then seems to work well when used in conjunction with antenatal steroid therapy. The preference is generally to give steroids if there is time, and to treat the neonate with exogenous surfactant therapy early after birth.

Prophylactic vs early or rescue administration
The debate continues over whether to administer surfactant prophylactically or in early or rescue administration. Current research seems to indicate that the greatest benefit may come from the earliest care. However, should relatively mild cases be exposed to the potential risks and costs of surfactant therapy?

“Studies show that early treatment is preferable to prophylactic treatment,” says Martin Keszler, MD, of Georgetown University Medical Center, Washington DC. “This is an ongoing controversy, but if the baby shows the need for surfactant, it’s best to give it early, rather than waiting several hours. We know that lung injury occurs rapidly, in a matter of a couple of hours.”

Prophylactic treatment during the first 15 minutes of life appears to be more effective, but may lead to some infants being treated, and possibly being exposed to adverse effects, unnecessarily.16 Not all infants that would appear to be at risk of developing RDS, for example due to gestational age, actually develop the condition. Nevertheless, prophylactic administration of surfactant to all neonates deemed at high risk for RDS does appear to reduce the risk of pneumothorax, pulmonary interstitial emphysema (PIE), and death. Better identification of the at-risk neonate would improve the selection criteria and the ultimate outcome of surfactant therapy.

Research continues to explore the benefits of single-dose versus multiple-dose treatment of neonates. Two studies18 using natural surfactant extract looked at the effect of single and multiple doses. No adverse effects of multiple dosing were reported in the trials. The reviewer concluded that multiple-dose therapy given to infants with confirmed RDS resulted in improved clinical outcome.

Immunological and surfactant
Another article suggests that surfactant may be closely involved in the protection of the lungs from injury and infection; harvesting of surfactant by pulmonary lavage may disrupt its existing micro-organization, a consideration that the researcher suggests should be kept in mind when interpreting clinical studies. Further study is needed; much more is known about surfactant than was known a decade ago, but far more work remains to be done.19 Careful laboratory and clinical study is likely to result in the successful use of specific types of surfactant outside of the neonatal ICU.

“There are two reasons why the surfactant given to neonates does not contain the major surfactant proteins, which may also be the proteins that play an immunological role. One is that these proteins have little to do with the surface-active properties of surfactant. The other is that once treatment starts to involve putting large proteins from animals into babies, there is the risk of causing allergic responses,” Cummings says.

Will surfactant eventually be condition-specific? “We’re gathering information and experience, and continuing to learn the differences between the various surfactants,” Keszler adds. “We may someday be able to choose the most appropriate surfactant, given the patient’s particular clinical condition.” For example, perhaps an infant suffering from MAS could be treated with a surfactant that is particularly resistant to degradation by meconium.

Some researchers believe that surfactant has been misnamed, in that the medical community is now starting to realize that surfactant supports many other functions besides reducing surface tension. But the first application of the fluid was for the treatment of surface-active deficiency conditions, and the name “surfactant” stuck.

The respiratory care practitioner would do well to look beyond the implications of the name, and to bear in mind its other functions, both proven and predicted. In all likelihood, the next 3 to 5 years will see surfactant formulations finding use in several conditions other than neonatal RDS.

Valerie Kellogg, RRT, AAS, MA, MBA, is a contributing writer for RT Magazine

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