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Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome

RHL Commentary by Velaphi S

1. INTRODUCTION

In developing countries, neonatal deaths account for more than one third of all deaths in children under the age of 5 years (1). Mortality rates are very high in the early neonatal period with 25%–45% occurring in the first 24 hours of life, and about 75% occurring during the first week after birth (1, 2).

Respiratory distress syndrome (RDS), or hyaline membrane disease (HMD), has been recognized as the most common complication of prematurity, with more than half of those with a birth weight of between 501 grams and 1500 grams showing signs of RDS (3, 4,). In infants with RDS, exogenous surfactant has been shown to reduce mortality and any form of pulmonary air leaks by about 30% and 50%, respectively (5). The timing of administration of exogenous surfactant appears to be critical as it has been shown that infants who are given prophylactic surfactant (administered soon after delivery before the infant develops respiratory distress) have better outcomes than those given rescue surfactant (given only to those who develop respiratory distress) (6).

In under-resourced settings, prophylactic use of surfactant is unaffordable owing to its high cost. Hence, it is important to know if the timing of surfactant administration as a rescue therapy (i.e. its use in infants with signs of respiratory distress) makes a difference in neonatal mortality and morbidity. The aim of this Cochrane review (7) is to present a summary of the findings of a meta-analysis of studies that have compared early versus late administration of surfactant in preterm infants with a diagnosis of RDS and requiring mechanical ventilation. The review also aims to assess if the studies reviewed are relevant and whether the intervention (early use of surfactant in RDS) can be used by health-care providers in under-resourced areas.

2. METHODS OF THE REVIEW

The review author performed a wide literature search of different databases, which included the Oxford Database of Perinatal Trials, Medline, and PubMed. He also searched abstracts from conferences and proceedings of symposia and did hand-searching of English-language journals in addition to seeking the help of expert informants. The inclusion criteria for the review were prospective randomized controlled trials comparing early selective surfactant administration (surfactant administered within two hours of life) versus delayed surfactant administration (surfactant administered beyond two hours of life) in premature infants who were intubated for RDS. There is no comment in the review on whether there were studies that were excluded and, if so, what criteria were used to exclude them. The quality of the studies was assessed by looking at randomization, blinding of randomization, blinding of intervention, and blinding of outcome assessment and follow-up. Analysis of the outcomes was done on an intention-to-treat basis – i.e. all patients were included in the analysis based on which group they were randomized to, irrespective of whether the surfactant was administered early or later. The outcomes studied included mortality at discharge from hospital, mortality within the first 28 days of life (neonatal mortality), mortality and/or bronchopulmonary dysplasia, mortality and/or chronic lung disease and other morbidities, including pulmonary air leaks (pneumothorax and pulmonary interstitial emphysema), pulmonary haemorrhage, patent ductus arteriosus, necrotizing enterocolitis, retinopathy of prematurity, intraventricular haemorrhage, bronchopulmonary dysplasia and chronic lung disease. The search was done for studies published up to 1998. Hence, the author may have missed studies done after 1998. Also, some databases like Embase were not searched. The assessment of the quality of the studies is appropriate. The data are clearly presented in both the tables and in the text.

3. RESULTS OF THE REVIEW

In the final analysis, four studies were included. Two studies each reported on artificial and natural surfactants, respectively. A total of 3459 preterm infants (gestational age between 26 and 32 weeks and/or weighing between 500 grams and 1500 grams) were enrolled in the four studies, with the majority (n=3110) receiving artificial surfactant, Exosurf; the remaining received bovine surfactant (n=317) or surfactant TA (n=32). In 1726 infants, surfactant was administered early within the first two hours of life and these infants were compared with 1733 infants in whom surfactant administration was delayed (administered after two hours of life).

The meta-analysis revealed that in preterm infants who are intubated for RDS or HMD, administration of surfactant within the first two hours of life, compared with those who are given surfactant beyond two hours of life, results in a reduction in: pneumothoraces by 30% [relative risk (RR) 0.70; 95% confidence interval (CI) 0.59–0.82]; pulmonary interstitial emphysema by 37% (RR 0.63; 95% CI 0.43–0.93); neonatal mortality rate by 13% (RR 0.87; 95% CI 0.77–0.99); chronic lung disease by 30% (RR 0.77; 95% CI 0.55–0.88) and combined outcome of death or chronic lung disease by 16% (RR 0.84; 95% CI 0.75–0.93). Early administration of surfactant has no effect on other common conditions associated with prematurity, namely pulmonary haemorrhage, patent ductus arteriosus, necrotizing enterocolitis, retinopathy of prematurity, intraventricular haemorrhage, bronchopulmonary dysplasia. There were no data on whether there was a difference in the duration of stay in a neonatal intensive care unit or for the use of mechanical ventilation between early and delayed administration of surfactant.

4. DISCUSSION

4.1 APPLICABILITY OF THE RESULTS

In preterm infants, compared with placebo or administering nothing, irrespective of timing, the administration of surfactant significantly reduces mortality due to respiratory distress syndrome (5). Hence, surfactant use in RDS should always be encouraged. The review specifically concludes that early (within two hours of life) administration of surfactant results in reduction in neonatal mortality rate and in incidence of complications associated with RDS in infants requiring ventilation, namely pulmonary air-leaks and chronic lung disease.

In this review, the majority of patients were given synthetic surfactant. Although in the meta-analysis the above differences were noted, in the subgroup analysis of the natural surfactants there were no differences in any of the outcomes studied between early and delayed treatment groups. This is most likely due to small numbers in the group of patients that were given natural surfactants compared with those given synthetic surfactants as there is no expected physiological explanation for this difference. The included studies were conducted before non-invasive ventilation methods such as continuous positive airway pressure (CPAP) began to be widely used. Therefore, some of the infants who were intubated in these studies would most likely be put on CPAP nowadays. Then the question then arises: does early administration of surfactant in infants with RDS on CPAP results in better outcomes when compared to delayed administration? Studies that have compared the use of CPAP with or without selective use of surfactant to intubation for mechanical ventilation and surfactant in very preterm infants have reported that there was no significant difference in the rate of death and need for supplemental oxygen by 36 weeks (8, 9). This suggests that in under-resourced settings, where mechanical ventilator machines may not be easily accessible, the use of CPAP with or without surfactant might result in improvement in mortality rates and chronic lung disease. There are no randomized clinical trials that have used CPAP for respiratory distress syndrome and studied whether the timing of administration of surfactant affects the outcomes (i.e. comparison of early versus delayed selective use of surfactant in infants treated with CPAP).

High cost of surfactants and limited intensive care beds for mechanical ventilation can adversely affect the applicability of this intervention in under-resourced settings. Shortages of surfactant might result in the drug being administered only in those who are very sick and who require intubation, as it is the case in the studies included in this review. The limited intensive care beds might result in delays in infants getting access to mechanical ventilation and therefore delays in administering surfactant. Therefore, administering surfactant within two hours of life might not always be possible, resulting in poor outcomes of infants with RDS in developing countries.

4.2. IMPLEMENTATION OF THE INTERVETNION

While early administration of surfactant should be preferred in all settings, in settings where its use within the first two hours of life is not be possible, use of surfactant in RDS requiring mechanical ventilation should be encouraged irrespective of timing.

Infections have been shown to impair the effectiveness of surfactant therapy in infants with RDS (10,11,12). Since the incidence of infections is high in developing countries, surfactant therapy may be less effective in those countries. In under-resourced settings, severely preterm infants, who might benefit the most from early administration of surfactant, are often not offered mechanical ventilation. In view of the limited resources and impact of infections on the effectiveness of surfactant therapy, it might be appropriate to limit the use of early administration of surfactant to those with a better chance of survival – i.e. those weighing between 750 grams and 1000 grams and with no overt signs of infection. Also, in under-resourced settings, the numbers needed to treat to see improved outcomes may be higher due to: (i) the effects of infection; (ii) surfactant being used in infants with severe disease; and (iii) non-use of surfactant in extremely low-birth-weight infants, who might benefit the most from it.

In infants who are on CPAP and are not weaning off oxygen, an approach of intubation to administer surfactant and extubation soon afterwards should be encouraged. This should be done at both secondary and tertiary levels of care. Primary care centres should transfer mothers in preterm labour as soon as possible to higher levels of care, and where this is not possible, preterm infants and their mothers should be immediately referred to higher-level facilities. The infants must be put on CPAP during transportation or while waiting for transport.

4.3. IMPLICATIONS FOR RESEARCH

One question for research is to evaluate whether early administration of surfactant in infants with RDS on CPAP result in better outcomes compared with delayed administration of surfactant. It is also important to determine if there is a time point beyond which administration of surfactant offers no benefit. There is need to develop low-cost genetically engineered surfactant. Finally, in the interest of cost-saving, it may be useful to determine if there exists a cut-off weight or gestational age beyond which surfactant should automatically be made available to preterm infants.

References

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• Zupan J, Aahman E. Perinatal mortality for the year 2000: estimates developed by WHO. Geneva: World Health Organization, 2005.
• Hack M, Fanaroff AA. Outcomes of extremely-low-birth-weight infants between 1982 and 1988. New England Journal of Medicine 1989;321:1642-1647.
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• Segerer H, Stevens P, Schadow B, Maier R, Kattner E, Schwarz H, Curstedt T, Robertson B, Obladen M. Surfactant substitution in ventilated very low birth weight infants: factors related to response types. Pediatrics Research 1991;30:591-596.
• Herting E, Gefeller O, Land M, van Sonderen L, Harms K, Robertson B. Surfactant treatment of neonates with respiratory distress failure and group B streptococcal infection. Members of the Collaborative European Multicenter Study Group. Pediatrics 2000;106:957-964.
• Shima Y, Takemura T, Akamatsu H, Kawakami T, Yoda H. Clinicopathological analysis of premature infants treated with artificial surfactant. Journal of Nippon Medical School 2000;67:330-4.

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This document should be cited as: Velaphi S. Early versus delayed selective surfactant treatment for neonatal respiratory distress syndrome: RHL commentary (last revised: 1 September 2010). The WHO Reproductive Health Library; Geneva: World Health Organization.

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