From the CAP trial we know that caffeine administration leads to less bronchopulmonary dysplasia. The question is how? The mechanism could help to design other studies, or help in a decision about clinical use where the question hasn’t been directly answered by CAP. One possibility is just that improving respiratory drive allows earlier more successful extubation, and less exposure to positive pressures; I think this is likely to be part of the mechanism. On the other hand there is now evidence of direct effects of caffeine on inflammation, which are mostly anti-inflammatory, and on apoptosis. This new study in neonatal rabbits (Nagatomo T, et al. Caffeine Prevents Hyperoxia-Induced Functional and Structural Lung Damage in Preterm Rabbits. Neonatology. 2016;109(4):274-81) exposed preterm cesarean delivered rabbits to 95% oxygen, and randomly divided into groups receiving either caffeine or control. Without going into all the methodologic details of this excellent study, the authors found that caffeine was highly protective against the reductions in lung function caused by hyperoxia. Caffeine use also reduced the size of the alveoli, but prevented the reduction in alveolar numbers caused by hyperoxia.
With other data this suggest that caffeine helps to protect immature lungs from the effects of too much oxygen. The impact of caffeine on bronchopulmonary dysplasia could be partly as a result of this effect.
Fascinating data, thank you. Could this also link in to the dramatic reduction in clinical PDA in the CAP trial?
I guess that is possible, although diagnosis of PDA was by usual clinical means in the CAP trial, there was no screening for PDA, and it may be that more echos are done, and people worry more about the PDA when the baby is intubated for longer, or when they have BPD.
I don’t know of any other proven direct effect of caffeine on ductal tissue, but there may be one.
Thank you for an interesting post (as always).
Given the evidence in favor of keeping the preterm infant on spontaneous non-invasive ventilation and the exponentially increasing number of methods directed at this aim, I think we at the moment don`t give respiratory drive its due share of attention.
One way of addressing respiratory drive this could be through old, but rather overlooked acquaintances – bilirubin and phototherapy.
Amin et al has in two original studies (2005 & 2015)[1;2] demonstrated that an increased level of bilirubin is associated with aggravated apnea amongst preterm infants. In 2014 Amin, Watchko and Bhutani  put forth that increased free bilirubin might be central in preterm apnea and its associated respiratory decompensation. Supporting this, our group recently in Neonatology published an association between markers of respiratory disease in the very preterm and carriage of the Gilbert genotype (UGT1A1*28 ) – the strongest known genetic predictor of increased unconjugated bilirubin amongst adults.
Findings from the only large RCT into phototherapy levels in the very preterm suggest that this might not be just theoretical considerations, but feasibly could have a clinic application. In 2006 Morris et al randomized 1974 ELBW infants to either “aggressive” phototherapy (low threshold for start of phototherapy) or “conservative” phototherapy (high threshold for start of phototherapy). Amongst the secondary outcomes the investigators reported a protective effect upon the risk of BPD from “aggressive” treatment ( OR 0.86; 0.78-0.96), the effect was retained also for your own favorite out-come combination of “BPD or death” (OR 0.90; 0.84-0.97).
1 Amin SB, Charafeddine L, Guillet R: Transient bilirubin encephalopathy and apnea of prematurity in 28 to 32 weeks gestational age infants. J Perinatol 2005;25:386-390.
2 Amin SB, Wang H: Unbound unconjugated hyperbilirubinemia is associated with central apnea in premature infants. J Pediatr 2015;166:571-575.
3 Amin SB, Bhutani VK, Watchko JF: Apnea in acute bilirubin encephalopathy. Semin Perinatol 2014;38:407-411.
4 Petersen JP, Ebbesen F, Hollegaard MV, Andersson S, Hougaard DM, Thorlacius-Ussing O, Henriksen TB: UGT1A1*28 Genotypes and Respiratory Disease in Very Preterm Infants: A Cohort Study. Neonatology 2016;109:124-129.
5 Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O’Shea TM, McDavid GE, Perritt RL, Van Meurs KP, Vohr BR, Grisby C, Yao Q, Pedroza C, Das A, Poole WK, Carlo WA, Duara S, Laptook AR, Salhab WA, Shankaran S, Poindexter BB, Fanaroff AA, Walsh MC, Rasmussen MR, Stoll BJ, Cotten CM, Donovan EF, Ehrenkranz RA, Guillet R, Higgins RD: Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med 2008;359:1885-1896.