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Editor—We enjoyed reading Morley’s systematic review of the timing of surfactant treatment.1 His overall conclusion that “the data from this systematic review show a 39% reduction in the neonatal mortality if the babies are treated with surfactant at birth compared with a few hours later” is valid only if a number of provisos are taken into account:
The surfactant should be natural or derived from mammalian lungs. The overview contained studies using bovine or porcine surfactants. It cannot be assumed that similar findings apply to the synthetic, protein free surfactants which, both animal studies2 and clinical trials,3 have shown, are not as good as natural surfactants. Exosurf has been studied and early and late treatment compared,4 but not as prophylaxis, and there are no comparative data for ALEC.
Prophylaxis is really treatment given before 15 minutes has elapsed. Prophylactic treatment defined by Morley as “surfactant given down an endotracheal tube at initial resuscitation” did not apply in at least four of the studies where treatment was within 5 to 15 minutes of birth.4
The babies must be between 24 and 31 weeks of gestation.
Follow up data from these studies are scanty. Follow up to school age showed improved pulmonary outcome in children who had been treated with a bovine surfactant.5 In another trial using human surfactant, not included in Morley’s review, babies treated prophylactically had lower Bayley scores at 12 months adjusted age.6
Morley suggests that “prophylactic treatment saves about seven extra lives for every 100 treated,” but this is based on “total mortality” which analyses just four trials. If all seven trials of prophylaxis and rescue treatment are included,4 7 and neonatal mortality is used as the endpoint, 33 babies (95% CI 20–100) would need to be treated to save an extra life. If these figures are used the cost analysis is considerably different. About 17 (not 7) extra doses of surfactant would be needed for every extra life saved, but the confidence interval on this figure is extremely wide (about 10–50 extra doses).
A major problem is that we have no trials comparing true prophylaxis, as defined by Morley, with early treatment, say within the first 30–60 minutes of life. We cannot therefore advise neonatologists which babies should be intubated at birth solely for the purpose of giving surfactant. Morley is probably correct in saying that for babies of less than 32 weeks’ gestation treatment with surfactant is warranted as soon as they are intubated for the treatment of RDS.
Dr Morley responds: I am pleased Professors Halliday and Soll enjoyed my article and have opened the debate. They are right that the only randomised trials of prophylaxisvs rescue surfactant treatment were with animal derived surfactants—I dislike the term “natural” surfactants because they are highly derived and far from natural.
Surprisingly, they persist in perpetuating the myth that synthetic surfactants are inferior to “natural” surfactants. Firstly, there has been no head to head trial of ALEC against a “natural” surfactant so we do not know about ALEC. Secondly, there has been no head to head trial of Curosurf against a synthetic surfactant so we do not know about Curosurf. These are the main surfactants in use in the UK. Thirdly, in the largest head to head trials of Exosurf against Survanta1-8 1-9 one showed a difference in air leak and both showed a slight difference in oxygenation and mean airway pressure, but only in the first three days. There was no difference in death, chronic lung disease, and other major outcomes.
Professors Halliday and Soll are overly pedantic in saying that four trials did not have true prophylaxis because the surfactant was given “within 15 minutes of birth.”
I agree that the meta-analysis clearly shows that prophylactic surfactant should be given to intubated infants from 25 to 31 weeks of gestation. The incidence of worrying respiratory distress syndrome after 31 weeks is so low that it would be wasteful to treat them prophylactically unless they were very ill.
The comments on follow up are well taken, but the review was not about follow up. The references Professors Halliday and Soll cite do not compare outcome in the prophylactic vs rescue trials.
The analysis does show that prophylactic treatment saves seven extra lives for every 100 infants treated at less than 32 weeks of gestation. But I do not understand why they want to use neonatal mortality as their outcome when total mortality is much more important. One of the reasons that there seems to be such a difference between the effect on total mortality and neonatal mortality in the meta-analysis is that data on total mortality were not available for the trial which enrolled babies from 29 to 32 weeks of gestation and had a 1% mortality rate. As prophylaxis will mainly be used on the smaller babies, I think the data without this trial are more realistic.
My opinion is that premature babies should be intubated only for the treatment of respiratory failure and not electively for surfactant treatment.