Table of Contents - PDF document

Table of Contents Page No. 1. Synopsis 3 2. Summary statement of the proposal 4 3. Name of the organization(s) consulted and/or supporting the application 4 4. Examples of surfactant preparations by generic names 4 5. Formulation proposed for inclusion 4 6. Whether listing is requested as an individual preparation or as a group 4 7. Definition of respiratory distress syndrome (RDS) 4 8. RDS: epidemiological information on disease burden 5 9. Surfactant composition and function 6 10. Commercially available surfactant preparations 7 11. Summary of comparative effectiveness 8 11.1 Surfactant replacement for RDS 8 11.1.1 Prophylactic versus rescue surfactant 8 11.1.2 Natural versus synthetic surfactant 10 11.1.3 Surfactant administration 10 11.2 Surfactant replacement for respiratory disorders 12 other than RDS 11.2.1 Persistent pulmonary hypertension of the newborn (PPHN) 12 11.2.2 Meconium aspiration syndrome (MAS) 12 11.2.3 Neonatal pneumonia and sepsis 12 11.2.4 Congenital diaphragmatic hernia (CDH) 13 11.2.5 Neonatal pulmonary hemorrhage 13 11.2.6 Acute lung injury and acute 13 respiratory distress syndrome (ARDS) in adults 12. Methodological quality of surfactant studies 14 12.1 Prophylaxis studies 14 12.2 Treatment studies 14 13. Cost effectiveness of prevention and treatment of RDS 14 with exogenous surfactant 14. List of abbreviations 16 15. References 17 2 1. Synopsis Surfactant is proposed for the care of the newborn infant. It is specifically proposed for the prophylaxis and/or treatment of respiratory distress syndrome (RDS) since there is robust evidence that surfactant reduces mortality and pulmonary air leaks in preterm infants with or at high risk for RDS. Surfactant may also be considered for infants with hypoxic respiratory failure attributable to secondary surfactant deficiency (eg. meconium aspiration syndrome, sepsis/pneumonia, and pulmonary hemorrhage). Some differences between natural and synthetic surfactant have been highlighted, for example a difference in terms of reduction in the risk of death and pneumothorax, favoring the former. However, both animal-derived and synthetic surfactants are beneficial for prophylaxis and rescue treatment of RDS in preterm infants and therefore listing in the World Health Organization (WHO) Model List of Essential Medicines is requested as a group and not as an individual preparation. At present, neither early nasal continuous positive airway pressure (nCPAP) nor mechanical ventilation and surfactant can be said to be superior for the prevention of death or bronchopulmonary dysplasia (BPD) in very preterm infants. The methods complement each other but the question regarding an optimal approach remains yet to be answered in future studies. The ability to administer surfactant during nCPAP appears to be important in Extremely Low Birth Weight (ELBW) infants and more mature infants with established RDS. New modalities of surfactant administration (e.g. aerosolized surfactant; surfactant via nasogastric tube) may in the future help to combine nCPAP and surfactant therapy more effectively and safely. 3 To optimize surfactant administration, controlled trials have compared different treatment procedures (bolus, infusion, multiple lumen endotracheal tube (ETT), side-hole adapter and number of doses). Bolus versus infusion Surfactant has been administered through an endotracheal tube either by bolus/fairly rapid installation or slow infusion. In animal studies bolus administration has been shown to be superior and lead to a more uniform distribution compared to infusion over 5, 30 or 45 minutes (Segerer 1996, Segerer 1993 Ueda 1994). Human data on this issue are sparse. A small clnical trial enrolling 299 infants showed no significant differences in outcome measures of fractional inspired oxygen, mean airway pressure, and arterial-alveolar ratio of partial pressure of oxygen at 72 hours of life, or in the incidences of air leaks, pulmonary interstitial emphysema, or death through 72 hours of life (Zola 1993). However, oxygen desaturation occurred more often when bolus administration was used, whereas reflux into the ETT occurred more often when the infusion technique was used. Single lumen ETT bolus installation vs. dual-lumen ETT An RCT including one hundred ninety-eight infants (birth weight 600-2000 g) with RDS needing mechanical ventilation with a fraction of inspired oxygen (FIO2) of 0.40 comparing 200 mg/kg of Curosurf, either by bolus instillation or by a simplified dosing technique (giving the full dose in 1 minute via a dual-lumen endotracheal tube without positioning, interruption of mechanical ventilation, or bagging) found fewer episodes of hypoxia and a smaller decrease in heart rate and oxygen saturation in the dual-lumen group. Infants in the dual-lumen group also had a lower total time exposure to supplemental oxygen but no difference in patient relevant long term outcomes was found ( Valls-i-Sole r 1998). Bolus vs. 1-minute infusion through a side-hole adapter Another RCT that compared the incidence of transient hypoxia and bradycardia, gas exchange, ventilatory requirements and 28 day outcomes of two different surfactant dosing procedures (bolus vs. surfactant given in 1 min via a catheter introduced through a side-hole in the tracheal tube adaptor) in infants with RDS found no differences between the two procedures ( Valls-i-Soler 1997). Repeated doses Most RCTs evaluating the effectiveness of surfactant used single doses. Since surfactant was introduced in neonatal care, physicians have noted that some neonates respond only transiently to surfactant therapy and the question arose whether multiple doses of surfactant 11 might be more effective than a single dose. Individual trials have shown that repeated doses of surfactant (both natural and synthetic) given at intervals for predetermined indications have decreased mortality and morbidity compared with single surfactant doses or placebo (Hoeckstra 1991, Liechty 1991, Dunn 1990, Corbet 1995, Speer 1992). A systematic review from the Cochrane Collaboration that compared multiple versus single dose natural surfactant extract for severe neonatal RDS identified two RCTs (Dunn 1990, Speer 1992) including 394 patients. Meta-analysis of these trials suggests a reduction in the risk of pneumothorax (RR 0,51; 95% CI 0,3-0,88) and a trend towards a reduction in mortality (RR 0,63; 95% CI 0,39-1,02) (Soll 1999). At present there is insufficient evidence to recommend the optimal number of fractional doses of surfactant (Zola 1993), however, the OSIRIS trial, a large factorial RCT provided no evidence that a regimen including the option of a third and fourth dose of a synthetic surfactant when signs of RDS persisted or recured was clinically superior to a regimen of two doses (OSIRIS Collaborative Group 1992). The optimal method of surfactant administration remains yet to be clearly proven. New methods such as aerosolized surfactant and surfactant administered via a nasogastric tube need testing in future controlled trials. 11.2 Surfactant replacement for respiratory disorders other than RDS 11.2.1 Persistent pulmonary hypertension of the newborn (PPHN) PPHN is the result of a failed normal circulatory transition after birth. It is a syndrome characterized by marked pulmonary hypertension that causes hypoxemia and right-to-left extrapulmonary shunting of blood. With inadequate pulmonary perfusion, neonates develop refractory hypoxemia, respiratory distress, and acidosis. PPHN is caused by a number of medical conditions, including meconium aspiration syndrome (MAS), pneumonia and sepsis and congenital diaphragmatic hernia (CDH). In some of these conditions surfactant has been shown in controlled trials to be beneficial. 11.2.2 Meconium aspiration syndrome (MAS) The aspiration of meconium stained amniotic fluid before, during, and after birth can lead to unfavorable pulmonary symptoms in the neonate, a condition that is called meconium aspiration syndrome (MAS). Several constituents of meconium, especially the free fatty acids (eg, palmitic, stearic, oleic), have a higher minimal surface tension than surfactant and strip it from the alveolar surface. Thus MAS may lead to severe respiratory failure and secondary surfactant insufficiency. 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