Lodha A, et al. Association of Early Caffeine Administration and Neonatal Outcomes in Very Preterm Neonates. JAMA Pediatr. 2014. First, a study of which I was a co-author; we examined from the CNN whether infants that received caffeine starting in the first 2 days of life had different outcomes from those whose caffeine started later. The outcomes of interest were survival and bronchopulmonary dysplasia, as well as PDA and retinopathy, all things which have been reported as potentially being affected by caffeine; and the babies of interest were less than 31 weeks gestation. Of course the secondary analyses of the CAP trial showed that infants who received caffeine at 3 days of life or earlier had better short term respiratory outcomes, but that adjusted analysis showed no effect on BPD. In this new study the unadjusted analysis showed no effect on either mortality or BPD, the adjusted analysis (adjusted for gestational age, SGA, being intubated on day 2, where you were born, surfactant and SNAP score) did show an association with less BPD, but no effect on mortality. PDA was less frequent in both adjusted and unadjusted analyses. There were 5000 babies in the analysis, and nearly 4000 of them got caffeine in the first 2 days of life, which I think is evidence of a change in practice after the CAP trial, as 40% of the babies were still intubated on day 2 by which time they were getting caffeine. I was a bit surprised that only 40% of the babies in the ‘later’ caffeine group were on assisted ventilation on day 2, as that means that hundreds of babies less than 31 weeks gestation who were breathing spontaneously were not getting caffeine by day 2. I thought it had become routine to administer caffeine to babies in this gestational age group who were not intubated, or just before extubation in the first day or 2 of life. There was also less NEC stage 2 or more, less severe RoP, and less ‘severe neurological injury’ among infants with early compared to late caffeine, none of which were very convincing after adjusting the analyses, but all of which suggest there isn’t a safety issue. These data are clearly only observational, but tend to confirm the implications of the CAP trial, and that caffeine use is safe, even with very early use.

Alur P, et al. Serum caffeine concentrations and short-term outcomes in premature infants of 29 weeks of gestation. J Perinatol. 2014. These data were from a center that does weekly caffeine serum concentrations while infants are receiving the drug. Which is certainly not something I have ever done, and I think is not necessary, however it does give an opportunity to perform a retrospective study like this, which showed that the infants who had higher average caffeine concentrations had less BPD, they also got home earlier from the hospital and had no clear adverse effects. On the multivariate logistic regression analysis, higher caffeine concentration was associated with less BPD, but increased gestational age was not, which makes me wonder if there was some confounding, and if the lower levels were found in the least mature babies, but I don’t know why that would be. It might partly explain the statistical findings though.

Marcus CL, et al. Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age. Am J Respir Crit Care Med. 2014;190(7):791-9. This very long term follow up of some babies from the CAP trial showed that children from both groups had more sleep apnea than expected for their age, but there were no differences between groups. Which is both reassuring (with regard to the effects of caffeine) and a little surprising (why do they have more obstructive apnea than the general population?)

Katheria AC, et al. A Pilot Randomized Controlled Trial of Early versus Routine Caffeine in Extremely Premature Infants. American journal of perinatology. 2015(EFirst). I would have called this a pilot trial comparing giving caffeine very very early versus very early! 21 infants who were not intubated in the DR were randomized within the first 2 hours of age to get caffeine immediately or wait until 12 hours. Of course the study is too small to say a lot, except that the cardiovascular and respiratory differences are all in the direction of better function in the very very early group. With regard specifically to the cardiovascular differences, echocardiograms performed during the interval where the treatments were different between groups showed higher SVC flow and Right Ventricular Output in the caffeine group, with difference in LVO. Blood pressure was also different until the ‘control’ group got caffeine, after which there was difference. Bill Meadow (Soloveychik V, et al. Acute hemodynamic effects of caffeine administration in premature infants. J Perinatol. 2009;29(3):205-8.) previously showed an effect of caffeine (not necessarily very early, or very very early) on both blood pressure and LVO in 31 preterm infants. In his study, only infants with a closed PDA were included, which probably accounts for the difference in echocardiographic effects.

These cardiovascular effects of caffeine deserve further study, and the use of very very early caffeine might well turn out to be valuable, especially as these infants will almost all be receiving caffeine at some point in their lives, giving it immediately after stabilization could possibly reduce cardiovascular dysfunction, as well as improving respiratory outcomes.

McPherson C, et al. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. 2015. This study, in contrast, shows adverse effects (potentially) of caffeine therapy. 74 preterm infants, less than 31 weeks gestation were randomized to get caffeine citrate before 24 hours of age in either standard dose, (20 mg/kg) or a high loading dose (of 80 mg/kg). After the loading period, which took a total of 48 hours, patients in both groups received the same dose (10 mg/kg/day). The patients in the high dose group did worse. They had more cerebellar hemorrhages, there were more tone problems at term equivalent age, and more abnormal neurologic signs at that age. At 2 years there was no difference between the groups.

This study certainly should inhibit other studies of very high loading doses of caffeine. Keeping to 20 mg/kg looks like the right place to be at present. Starting very early could well be a good idea, but needs more study, to ensure efficacy and safety.