When was artificial surfactant invented




















If gas exchange does not occur at the alveoli, oxygen will not reach the bloodstream or tissues throughout the body, including the brain and other organs. The second role surfactant plays in the lungs is that it increases the compliance, or expandability, of the lungs. Lungs expand during respiration as they take in oxygen-rich air from the atmosphere.

Without that expandability, the lungs do not take in enough oxygen. Infants born before thirty-five weeks gestation are at risk for respiratory distress syndrome because their Type II alveolar cells are not producing enough surfactant for sufficient breathing. When a premature infant whose lungs are not producing enough surfactant is born, those lungs are unable to provide the infant with enough oxygen, which results in respiratory distress syndrome.

Rarely, some very premature infants are unable to take a first breath because their lungs are stiff and unable to expand and contract as needed to breathe. Usually, however, affected infants can breathe, but display obvious signs of distress, such as flared nostrils during inhalation and grunting during exhalation. After a few hours, whatever small amount of surfactant present in the lungs at birth gets used up, making treatment necessary. Because labored breathing can be caused by conditions other than respiratory distress syndrome , physicians must first diagnose respiratory distress syndrome before deciding on a treatment plan.

Physicians diagnose respiratory distress syndrome using chest x-rays, blood tests, and echocardiography. If the infant has respiratory distress syndrome , their chest x-ray will show a bell-shaped thorax, or chest cavity, and small, underdeveloped lungs. Physicians use blood tests and echocardiography to rule out other diagnoses. Once physicians diagnose an infant with respiratory distress syndrome, they can treat the infant by administering artificial surfactant.

In the US, artificial surfactant used for surfactant replacement therapy is extracted from the lung of a cow or a pig. Physicians use two strategies for administering surfactant. First, using a preventative strategy, physicians administer artificial surfactant to premature infants who are at risk for developing respiratory distress.

Second, using a therapeutic strategy, physicians administer surfactant to infants who have been ventilated after their respiratory distress syndrome has been diagnosed. Physicians can choose to administer one or two doses of surfactant. In infants with respiratory distress syndrome, excess pressure is exerted on the alveoli by attempts to open them during respiration. The excess pressure ruptures the alveoli, allowing air to flood out of the lungs into the surrounding chest.

However, the risk of rupture decreases if a physician uses two doses of surfactant rather than one dose. Using two doses can also decrease the risk of sepsis, or bloodstream infection, and infant death. Generally, physicians do not administer more than two doses of surfactant. In the first decade of the twenty-first century, cases of neonatal respiratory distress syndrome grew because of an increase in pre-term deliveries.

However, the mortality rate of neonatal respiratory distress syndrome has decreased due to surfactant replacement therapy. However, as they are more resistant to inactivation they may have a role in treatment of adult or acute RDS. The last 25 years have seen a large increase in basic science research on surfactants with determination of the structure and function of the four surfactant proteins probably being the most important advances.

Future studies will focus on widening the indications for surfactant treatment, developing non-invasive means of administration and assessing the role of the newer synthetic surfactants. Abstract The first successful trial of surfactant treatment for respiratory distress syndrome RDS was reported in The first multicenter trial of poractant alfa published in showed reduced pulmonary air leaks and neonatal mortality in preterm infants with severe RDS A second trial, by Speer et al.

Subsequent trials of poractant alfa showed that early treatment was more effective than later administration 37 , 38 , Six randomized clinical trials comparing poractant alfa and beractant have been published 40 , 41 , 42 , 43 , 44 , In a systematic review and meta-analysis by Singh et al. None of the trials studied surfactant prophylaxis, and none compared poractant alfa with calfactant. The test of heterogeneity yielded positive results for the latter two outcomes.

The difference remained statistically significant for deaths and the need for redosing with high-dose poractant alfa but not for low-dose poractant alfa.

Another meta-analysis by Fox and Sothinathan 47 concluded that results of randomized, controlled trials of different preparations of animal derived surfactants suggest that poractant alfa reduces the need for repeat dosing, associated with fewer complications of administration, leads to better short-term oxygenation and may reduce the risk of mortality compared to beractant.

Similar results were also reported in the meta-analysis by Halliday The difference in these outcomes was limited to studies using a higher initial dose of poractant alfa. Although these studies suggest that the differences observed between poractant and beractant are related to the higher phospholipid dosage of the former, one cannot exclude that other factors such as animal source porcine vs. Current literature lack dose-equivalent comparison groups with appropriate sample size.

In a large retrospective study, Ramanathan et al. Overall mortality tended to be lower in infants treated with poractant alfa 3.

A third retrospective study evaluating comparative effectiveness between these three surfactants in 51, infants showed no differences in mortality In addition, the authors did not account for all known confounders. Third-generation synthetic surfactant containing DPPC, 1-palmitoyloleoyl-PG POPG and SP-B and SP-C analogs has been shown to be superior, when compared to calfactant in an animal model of acute RDS and is better equipped to handle surfactant inactivation in chemical acute lung injury than a synthetic surfactant with only a single surfactant peptide or animal-derived surfactant For the first time in an in-vivo model, a synthetic surfactant containing both SP-B and SP-C analogues CHF resisted inactivation better than poractant alfa in preterm lambs However, with increasing use of antenatal corticosteroids and routine use of continuous positive airway pressure CPAP during delivery room stabilization, prophylactic surfactant therapy is associated with more risk of death or BPD relative risk 1.

In a population with a high usage of antenatal steroids and routine use of NCPAP in the delivery room, prophylactic surfactant therapy is no longer recommended. In , Verder et al. Ten years later, in , a similar trial published from Colombia, South America demonstrated significantly less need for intubation and less air leaks with early rescue treatment Reduction in the need for mechanical ventilation is an important outcome when medical resources are limited and may result in less BPD in both developed and low resource areas.

Late surfactant treatment beyond the first week of life was recently evaluated in two RCTs 58 , Ballard RA et al. Exact timing for administering surfactant is still under debate, especially in infants receiving noninvasive ventilation NIV. Supplemental oxygen needs may be different based on the pressures used during NIV. Studies evaluating the timing based on oxygen requirement while on NIV are being evaluated.

Future research should focus on optimizing timing for individual patients with not only oxygen requirement but also taking into the consideration of pressures, gas exchange, clinical condition and radiologic findings. In the past, surfactant was given to preterm infants who were on mechanical ventilation due to respiratory failure from RDS. Adverse pulmonary and nonpulmonary outcomes directly correlated with the duration of invasive mechanical ventilation. INSURE procedure involves intubation and surfactant administration using an endotracheal tube and extubation after a brief period of mechanical ventilation.

Often, premedication with opioids are used during this procedure. Failure or reluctance to extubate following surfactant administration is common even with reversal of sedation using opioid antagonists. In premature infants with RDS, strategies to avoid intubation and invasive positive pressure and mechanical ventilation are being sought. Tracheal intubation may damage the larynx or trachea and requires the use of sedatives and pain medications that have undesirable side effects.

Also, positive pressure and mechanical ventilation can damage the preterm lung and its avoidance may decrease the incidence of chronic lung disease CLD. Leone et al. There is concern that even a brief period of ventilation can induce lung injury in the vulnerable preterm population. Furthermore, surfactant distribution may be suboptimal when surfactant is given using positive pressure ventilation. Surfactant administration via laryngeal mask airway LMA has been described in several small studies demonstrating safety and feasibility in larger preterm infants In a randomized trial of LMA vs.

This technique is a very good option in low-income countries with limited resources to administer surfactant, especially, in moderately preterm infants with RDS This technique involves surfactant administration using a feeding tube, umbilical catheter, or a small angiocatheter while the patient is breathing spontaneously and receiving noninvasive respiratory support.

In a retrospective study by Klebermass-Schrehof et al. They found significantly higher survival rates In a similar study, Krajewski et al.

In addition, better pulmonary outcomes were seen with the new method of surfactant replacement. BPD in the study group was significantly lower Further studies are needed to refine instillation techniques, use of sedation or analgesia, choosing optimal surfactant dose and selection of preterm infants who would benefit most. Potential advantages of administering aerosolized surfactant include avoidance of hypoxemia, more homogenous distribution, less need for airway as well as mechanical ventilation, and less volume.

Even though the animal studies have demonstrated promising results there have been a limited clinical studies demonstrating efficacy of this route. Finer NN et al. Chronic lung injury is primarily due to persistent inflammation, triggered by infection, mechanical ventilation, and or oxygen. Release off proinflammatory cytokines leads to aberrant repair of the developing lung in preterm infants. Lung inflammation plays a crucial role in the pathogenesis of BPD and glucocorticoid is one potential therapy to prevent BPD.

In a pilot study by Yeh et al. No clinically significant adverse effects were observed during the study and at the time of the follow-up assessment at 2—3 y of age. Recently, same investigators reported results from a randomized multicenter study of using surfactant with budesonide in very-low-birth-weight infants More studies are needed using this technique as both these studies had high BPD rates in the control population.

In the future, intratracheal instillation of budesonide using surfactant as a vehicle may play a role in the prevention of BPD in extremely-low-birth-weight infants. Club Cell protein CC is one of the most abundant protein produced endogenously by airway epithelial cells and plays a significant role in airway epithelial repair, airway immunomodulation, and inhibits NF-kB pathway in the airways.

A phase II trial evaluating intratracheal use of rhCC in surfactant treated preterm infants has been completed and results are pending NCT In summary, understanding surfactant composition, function, and therapeutic usefulness has increased exponentially over the last 50 y.

Exogenous surfactant therapy has become one of the most common procedures performed for the treatment of RDS in preterm infants globally. Composition, timing, and techniques of administering surfactant have been evolving over time Table 3. Prophylactic surfactant therapy may only have a limited role where antenatal corticosteroid administration rates are low.

At present, animal-derived surfactants are the standard of care for RDS. Several national guidelines based on local incidence of RDS or local practices have been published 75 , Future research of surfactant therapy should focus on using surfactant as a vehicle to deliver anti-inflammatory molecules, and less invasive or noninvasive modes of surfactant administration. He donates all honorarium received when giving talks on behalf of any company in the USA or outside to charity organizations to help mothers, newborn infants and children around the world.

The authors have no financial relationship relevant to this article to disclose. Core concepts: respiratory distress syndrome.

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