Evidence for the effectiveness of exogenous surfactant has been accumulating since 1980. It is now widely used in most countries where neonatal intensive care is available. Synthetic surfactant was registered in Malaysia in 1993 and became available in Government Hospitals in 1994. Subsequently natural surfactant has also become available.

Surfactant is expensive, however evidence for its effectiveness is very strong. Therefore it is important that a guideline be made available allowing for optimum usage at minimal expense. The guideline is for the benefit of those who care for neonates.

The aim of this guideline is to:

Discuss the types of surfactant available
Its administration
The evidence for its effectiveness
Long term benefits
Its cost-effectiveness

Types of Surfactant

There are 2 types of surfactant, synthetic and natural. Synthetic surfactant has no protein but has added spreading agents, hexadecanol (an alcohol) and tyloxapol (a non-ionic surfactant). Natural surfactants are made from animal lung extracts. Both types of surfactant are available in Malaysia.

Administration

Surfactant is administered by one of 2 approaches i.e. the prophylactic or treatment strategy. The treatment strategy is also known as rescue treatment. In prophylactic administration, high-risk infants below a specified weight or gestation are given surfactant within 15 minutes birth. Prophylactic administration allows surfactant to be administered before the hyaline membrane begins to develop and before the lungs are subjected to the traumatic effects of mechanical ventilation. This may reduce barotrauma. However with this strategy infants without lung disease also receive surfactant.

Surfactant rescue treatment is given to infants with established Respiratory Distress Syndrome (RDS). Because only infants with established disease are treated, this approach minimises both the risk and the cost.

While for some babies a single dose is adequate, for many the effect of a single dose is transient. Many trials used automatic retreatment schedules. A single dose may be sufficient if after dosing, the oxygen requirement falls below 30%. From clinical trials there is no benefit giving more than 2 doses but in the clinical setting, a third dose may be considered in some circumstances. The optimum timing of the second dose is not established but is currently given between 6 and 12 hours after the first dose. There is no benefit in administering surfactant after 18 - 24 hours of age.

There is no published experience on the use of surfactant outside of the neonatal intensive care unit. However a report suggests that its administration by transport teams before removal from the referring hospital is possible and improves outcome.¹

Evidence for the usefulness of surfactant

A systematic review of 35 randomised controlled trials on surfactant administration to over 6 000 infants showed that there was a reduction in mortality of 30 - 40% and that there was a reduction in pulmonary air leak.^2,3 These trials used both prophylactic and treatment strategies for surfactant administration and the beneficial effects were found for both. A meta-analysis of 3 trials directly comparing the prophylactic and treatment strategies showed that there was a reduction in pneumothorax with the prophylactic strategy.² Other differences were noted but these were not consistent.

The OSIRIS trial compared early versus delayed selective administration of surfactant. Infants who received surfactant before 2 hours of age had reduced mortality and decreased long-term oxygen dependence (increased survival without oxygen to both 28 days and to expected date of delivery).⁴ The trial also showed that there was no benefit in using more than 2 doses. Following this strategy would increase the use of surfactant by about 25% but this added expense may be offset by the reductions in the cost of care of these infants.

In a systematic review of trials comparing natural and synthetic surfactant, the only clearly significant difference found was a reduction in pneumothorax with natural surfactant.⁵ There was also a trend to reduced mortality with natural surfactant. At the present moment it is uncertain whether there is a clear advantage for one surfactant preparation over the other in terms of mortality, chronic lung disease or retinopathy of prematurity

Antenatal steroids

An additive effect has been shown when both surfactant and antenatal steroids are administered.^6-9

Long Term Outcome

Studies on outcome to 2 years of age have not shown any long term adverse effect of surfactant and the neurodevelopmental outcome is at least not worse than without surfactant.^10-13

Cost Effectiveness

Studies on the cost-effectiveness of surfactant therapy show that in spite of the high cost of the drug, its use reduces costs per survivor. This is seen both with prophylactic and treatment strategies.^14,15 For larger infants the use of surfactant results in actual cost savings.

Recommendations

1. Surfactant should be given as early as possible to all preterm infants on mechanical ventilation for RDS.
2. However larger infants greater than 32 weeks may only require exogenous surfactant if the F₁0₂ is > 0.5 - 0.6
3. The use of surfactant does not obviate the need for antenatal steroids or strategies to reduce the incidence of preterm birth.
4. Until further evidence becomes available, it should be used only under neonatal intensive care conditions* and administered by experienced, trained personnel.
5. Where an infant is born away from neonatal intensive care facilities exogenous surfactant may be administered by personnel trained in endotracheal intubation before transfer for intensive care.

* Neonatal intensive care conditions include monitoring facilities for oxygen and cardiorespiratory status and close supervision of ventilation and fluid therapy.

Reference

1. Bhuta T, Walker K, Jones N, Halliday R, Berry A. Surfactant Administration by the Newborn Emergency Transport Service. In Press.
2. Soll RF and McQueen MC. Respiratory distress syndrome. In: Effective Care of the Newborn Infant. Sinclair JC, Bracken MB (eds). Oxford University Press. 1992 pp 325-355.
3. Jobe AH. Pulmonary surfactant therapy New Eng J Med 1993; 328 (12): 861-68.
4. OSIRIS Collaborative Group. Early versus delayed administration of a synthetic surfactant: the judgement of OSIRIS. Lancet 1992; 340: 1363-1369.
5. Soll RE Natural surfactant extract vs synthetic surfactant in the treatment of established respiratory distress syndrome. In: Sinclair JC, Bracken MB, Soll RF, Horbar JD (eds) Neonatal Module of The Cochrane Database of Systematic Reviews, [updated 01 September 1997]. The Cochrane Library. The Cochrane Collaboration; Issue 4, Oxford: Update Software; 1997. Updated quarterly.
6. Farrell EE, Silver RK, Kimberlin LV, Wolf ES, Dusik JM. Impact of antenatal dexamethasone administration on respiratory distress syndrome in surfactant-treated infants. Am J Obstet Gynecol 1989;161:628-33.
7. Jobe AH, Mitchell BR, Gunkel HJ. Beneficial effects of the combined use of preterm corticosteroids and postnatal surfactant on preterm infants. Am J Obstet Gynecol 1993; 168: 508-13.
8. Gunkel JH, Mitchell BR. Observational evidence for the efficacy of antenatal steroids from randomised studies of surfactant replacement. Am J Obstet Gynecol 1995; 173: 281-5.
9. White A, Marcucci M, Andres E, Edwards K, Long W. Antenatal steroids and neonatal outcomes in controlled clinical trials of surfactant replacement. Am J Obstet Gynecol 1995; 173: 286-90.
10. Sauve R, Long W, Vincer M, Bard H, Derleth D, Stevenson D, Pauly T, Robertson C, and the American and Canadian Exosurf Neonatal Study Groups. Outcome at 1-year adjusted age of 957 infants weighing more than 1,250 grams with respiratory distres s syndrome randomised to received synthetic surfactant or air placebo. J Pediatr 1995; 126: S75-80.
11. Saigal S, Robertson C, Koravangattu S, Bingham W, Casiro 0, MacMurray B, Whittfield M, Long W and the Canadian Exosurf Neonatal Study Group. One-year outcome of 232 premature infants with birthweights of 750 to 1,240 grams and respiratory distress syndrome randomised to rescue treatment with two doses of synthetic surfactant or air placebo. J Pediatr 1995; 126: S61-7
12. Survanta Multidose Study Group. Two-year follow-up of infants treated for neonatal respiratory distress syndrome with bovine surfactant. J Pediatr 1994; 124: 962-7.
13. Kraybill EN, Brose CL, Corbet AJ, Garcia-Prats J, AS Bill D, Edwards K, Long W. Double-blind evaluation of developmental and health status to age 2 years of infants weighing 700 to 1,350 grams treated prophylactically at birth with a single dose of synthetic surfactant or air placebo. J Pediatr 1995; 126: S33-42.
14. Mugford M, Piercy J, Chalmers I. Cost implications of different approaches to the prevention of respiratory distress syndrome. Arch Dis child 1991; 66: 757-64.
15. Mauskopf JA, Backhouse ME, Jones D, Wold DE, Mammel MC, Mullet M, Guthries R Long WA. Synthetic surfactant for rescue treatment of respiratory distress syndrome in premature infants weighing from 700-1,350 grams: Impact of hospital resource use and charges. J Pediatr 11995; 126: 94-101.

Participants

This guideline was formulated by and represents the views of the following people *:

Chairperson
Jacqueline Ho
Sr Lecturer/Neonatal Paediatrician
Asean Sheffield Medical College
lpoh

March 1998

* Addresses are correct at the time of formulation of the Guideline.

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