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Use of caffeine in the NICU as a treatment for apnea of prematurity is a topic that has certainly seen it’s fair share of coverage on this blog. Just when you think there is an aspect of treatment with caffeine that hasn’t been covered before, along comes a new paper to change my mind. The Caffeine for Apnea of Prematurity study or CAP, demonstrated that caffeine given between 3-10 days of age reduced the incidence of BPD in those treated compared to those receiving placebo. As an added benefit, in follow-up studies of these patients there appeared to be a benefit to neurodevelopmental outcomes as well at 18-21 months but this was lost by school age with groups being equivalent. In recent years evidence has mounted that starting caffeine earlier in the time course (<3 days and in many cases in the first hour after birth) has led to less need for intubation and BPD. What has really not been known though is whether the use of caffeine in this way might have any long term benefits aside from these short term outcomes. Dr. Abhay Lodha from Calgary and a group of researchers led by Prakesh Shah from the Canadian Neonatal Network using our robust Canadian network data have tried to answer this with their paper Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants The group studied were <29 weeks’ gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network centres. As defined in the paper “Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months’ corrected age.” There were 2018 neonates included in the analysis with 1545 in the early group and 563 in the late. It is worth noting that there were 473 infants lost to follow-up meaning that there was about an 80% follow-up rate. Looking at the characteristics of those infants lost to follow-up there were no striking differences that one would expect between them and the group followed. What did they find? The odds of BPD (aOR 0.61; 95% CI 0.45–0.81), PDA (aOR 0.46; 95% CI 0.34–0.62), and Severe Neurologic Injury – parenchymal injury or GR III/IV IVH or PVL (aOR 0.66; 95% CI 0.45–0.97) were reduced in the early- caffeine group. The primary outcome was also found to be significantly different as per the table below demonstrating the odds after logistic regression analysis. So early caffeine seems to be good. Is that all then? I am very happy to see these results but a few questions remain. Before we get too enthusiastic, I find myself thinking back to the early 2000s after the initial CAP results showed an apparent difference in outcome. The question is whether the reduction in odds seen here for the primary outcome will persist as these children age. Will we see a tendency for the differences to vanish as these children enter school age? I suspect we might but that doesn’t mean all is lost here. What the authors have demonstrated clearly is that early caffeine is not harmful as there is no suggestion of those infants exposed to caffeine so shortly after birth fare worse than those treated later. Also as the authors state, what isn’t clear is how caffeine works to decrease the risk of developmental impairment. In the discussion they offer some insightful thoughts as to what may be at play and I agree that certainly an anti-inflammatory effect may be responsible for some of the effect. I do wonder though if one could tie the reductions to the lower likelihood of BPD. Development of BPD has been shown many times over to be associated with worse developmental outcomes. Aside from the anti-inflammatory effect mentioned, could the avoidance of early intubation and therefore reduced risk of BPD from positive pressure ventilation be the reason? In the end if the results persistent into school age, the reason won’t really matter and I hope it does. Will see what happens when we revisit this cohort in a few years but in the meantime I think this paper certainly confirms in my mind the need to give caffeine and make sure it’s provided early!
Skin to skin care or kangaroo care is all the rage and I am the first one to offer my support for it. Questions persist though as to whether from a physiological standpoint, babies are more stable in an isolette in a quiet environment or out in the open on their mother or father’s chests. Bornhorst et al expressed caution in their study Skin-to-skin (kangaroo) care, respiratory control, and thermoregulation. In a surprising finding, babies with an average gestational age of 29 weeks were monitored for a number of physiological parameters and found to have more frequent apnea and higher heart rates than when in an isolette. The study was small though and while there were statistical differences in these parameters they may not have had much clinical significance (1.5 to 2.8 per hour for apnea, bradycardia or desaturation events). Furthermore, does an increase in such events translate into any changes in cerebral oxygenation that might in turn have implications for later development? Tough to say based on a study of this magnitude but it certainly does raise some eyebrows. What if we could look at cerebral oxygenation? As you might have guessed, that is exactly what has been done by Lorenz L et al in their recent paper Cerebral oxygenation during skin-to-skin care in preterm infants not receiving respiratory support.The goal of this study was to look at 40 preterm infants without any respiratory distress and determine whether cerebral oxygenation (rStO2)was better in their isolette or in skin to skin care (SSC). They allowed each infant to serve as their own control by have three 90 minute periods each including the first thirty minutes as a washout period. Each infant started their monitoring in the isolette then went to SSC then back to the isolette. The primary outcome the power calculation was based on was the difference in rStO2 between SSC and in the isolette. Secondary measures looked at such outcomes as HR, O2 sat, active and quiet sleep percentages, bradycardic events as lastly periods of cerebral hypoxia or hyperoxia. Normal cerebral oxygenation was defined as being between 55 to 85%. Surprising results? Perhaps its the start of a trend but again the results were a bit surprising showing a better rStO2 when in the isolette (−1.3 (−2.2 to −0.4)%, p<0.01). Other results are summarized in the table below: Mean difference in outcomes Variable SSC Isolette Difference in mean p rStO2 73.6 74.8 -1.3 <0.01 SpO2 (median) 97 97 -1.1 0.02 HR 161 156 5 <0.01 % time in quiet sleep 58.6 34.6 24 <0.01 No differences were seen in bradycardic events, apnea, cerebral hypoexmia or hyperoxemia. The authors found that SSC periods in fact failed the “non-inferiority” testing indicating that from a rStO2 standpoint, babies were more stable when not doing SSC! Taking a closer look though one could argue that even if this is true does it really matter? What is the impact on a growing preterm infant if their cerebral oxygenation is 1.3 percentage points on average lower during SSC or if their HR is 5 beats per minute faster? I can’t help but think that this is an example of statistical significance without clinical significance. Nonetheless, if there isn’t a superiority of these parameters it does leave one asking “should we keep at it?” Benefits of skin to skin care Important outcomes such as reductions in mortality and improved breastfeeding rates cannot be ignored or the positive effects on family bonding that ensue. Some will argue though that the impacts on mortality certainly may be relevant in developing countries where resources are scarce but would we see the same benefits in developed nations. The authors did find a difference though in this study that I think benefits developing preterm infants across the board no matter which country you are in. That benefit is that of Quiet Sleep (QS). As preterm infants develop they tend to spend more time in QS compared to active sleep (AS). From Doussard- Roossevelt J, “Quiet sleep consists of periods of quiescence with regular respiration and heart rate, and synchronous EEG patterns. Active sleep consists of periods of movement with irregular respiration and heart rate, and desynchronous EEG patterns.” In the above table one sees that the percentage of time in QS was significantly increased compared to AS when in SSC. This is important as neurodevelopment is thought to advance during periods of QS as preterm infants age. There may be little difference favouring less oxygen extraction during isolette times but maybe that isn’t such a good thing? Could it be that the small statistical difference in oxygen extraction is because the brain is more active in laying down tracks and making connections? Totally speculative on my part but all that extra quiet sleep has got to be good for something. To answer the question of this post in the title I think the answer is a resounding yes for the more stable infant. What we don’t know at the moment except from anecdotal reports of babies doing better in SSC when really sick is whether on average critically ill babies will be better off in SSC. I suspect the answer is that some will and some won’t. While we like to keep things simple and have a one size fits all answer for most of our questions in the NICU, this one may not be so simple. For now I think we keep promoting SSC for even our sick patients but need to be honest with ourselves and when a patient just isn’t ready for the handling admit it and try again when more stable. For the more stable patient though I think giving more time for neurons to find other neurons and make new connections is a good thing to pursue!