After the initial phase of surfactant deficiency of the very preterm infant, inhibition and destruction of surfactant are common, the inflammation of the oxygen exposed preterm lung is probably important in the pathophysiology of bronchopulmonary dysplasia, and the adverse effects on surfactant function have led to trials of later surfactant supplementation, in the hope that lung injury might be reduced.
Previous trials have not shown much benefit (Laughon M, et al. A Pilot Randomized, Controlled Trial of Later Treatment With a Peptide-Containing, Synthetic Surfactant for the Prevention of Bronchopulmonary Dysplasia. Pediatrics. 2009;123(1):89-96., Ballard RA, et al. Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide. The Journal of pediatrics. 2015.) there are some short term improvements in gas exchange, but no longer term benefit is evident. The details of these studies differ, Laughon and colleagues gave ‘late’ surfactant (1 of 2 doses of lucinactant, Surfaxin) or placebo to 139 infants with birth weight 600 to 900 grams, on ventilators between 3 and 10 days of age, (when they started the study it was just day 3). Ballard’s group studied 511 ELBW infants still intubated at 7 to 14 days of age, all of whom were getting inhaled nitric, and half were randomized to get up to 5 doses of Infasurf.
The new trial was a French multicenter study: Hascoet JM, et al. Late Surfactant Administration in Very Preterm Neonates With Prolonged Respiratory Distress and Pulmonary Outcome at 1 Year of Age: A Randomized Clinical Trial. JAMA Pediatr. 2016;170(4):365-72. 118 infants of less than 33 weeks gestation were randomized at 14 days if they were still ventilated and needing more than 30% oxygen. Treated babies received one dose of poractant (Curosurf) or placebo, and the primary outcome variable was time to first successful extubation, which was clearly defined, as were the criteria for when you should try to extubate a baby. The primary outcome was not affected by surfactant. 35.7 days compared to 38.3 in the controls, with wide standard deviations of about 20 days.
Oxygen needs did decrease after surfactant for about 24 hours, but no other short term clinical benefits were shown. Oxygen needs at 36 were not different; there were some minor effects at 1 year of age, fewer surfactant babies than controls had been re-admitted for respiratory problems, but that is about it.
One could ask why doesn’t this work? The rationale is reasonable, and several studies have shown short term responses; but when you put this together with the data from the Ballard study, which had some similarities, and a much bigger sample size, there doesn’t seem to be much of a signal. Maybe a single dose is not enough? But the Ballard study allowed up to 5 doses. Maybe it isn’t the right surfactant? But Curosurf has all the goodies that you would want. Maybe it was the wrong group of babies? But the patient selection was practical and reflects babies who have long-term problems.
I think the answer is that the surfactant dysfunction is probably more of an epiphenomenon, an indicator of the on-going inflammation and dysfunction of the lungs of the extremely preterm baby, rather than being causal.
Or perhaps a mixture of surfactant and steroids would be a better prospect? If direct pulmonary administration of steroids is effective when given early, maybe giving the combination later would be more effective than either steroids or surfactant alone. Which will lead me on to the next post, another trial of pulmonary steroid treatment, this time from Japan.