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Caffeine seems to be good for preterm infants. We know that it reduces the frequency of apnea in the this population and moreover facilitates weaning off the ventilator in a shorter time frame than if one never received it at all. The earlier you give it also seems to make a difference as shown in the Cochrane review on prophylactic caffeine. When given in such a fashion the chances of successful extubation increase. Less time on the ventilator not surprisingly leads to less chronic lung disease which is also a good thing. I have written about caffeine more than once though so why is this post different? The question now seems to be how much caffeine is enough to get the best outcomes for our infants. Last month I wrote about the fact that as the half life of caffeine in the growing preterm infant shortens, our strategy in the NICU might be to change the dosing of caffeine as the patient ages. Some time ago though I wrote about the use of higher doses of caffeine and in the study analyzed warned that there had been a finding of increased cerebellar hemorrhage in the group randomized to receive the higher dosing. I don’t know about where you work but we are starting to see a trend towards using higher caffeine base dosing above 5 mg/kg/d. Essentially, we are at times “titrating to effect” with dosing being as high as 8-10 mg/kg/d of caffeine base. Does it work to improve meaningful outcomes? This month Vliegenthart R et al published a systematic review of all RCTs that compared a high vs low dosing strategy for caffeine in infants under 32 weeks at birth; High versus standard dose caffeine for apnoea: a systematic review. All told there were 6 studies that met the criteria for inclusion. Low dosing (all in caffeine base) was considered to be 5- 15 mg/kg with a maintenance dose of 2.5 mg/kg to 5 mg/kg. High dosing was a load of 5 mg/kg to 40 mg/kg with a maintenance of 2.5 mg/kg to 15 mg/kg. The variability in the dosing (some of which I would not consider high at all) makes the quality of the included studies questionable so a word of warning that the results may not truly be “high” vs “low” but rather “inconsistently high” vs. “inconsistently low”. The results though may show some interesting findings that I think provide some reassurance that higher dosing can allow us to sleep at night. On the positive front, while there was no benefit to BPD and mortality at 36 weeks PMA they did find if they looked only at those babies who were treated with caffeine greater than 14 days there was a statistically significant difference in both reduction of BPD and decreased risk of BPD and mortality. This makes quite a bit of sense if you think about it for a moment. If we know that caffeine improves the chances of successful extubation and we also know it reduces apnea, then who might be on caffeine for less than 2 weeks? The most stable of babies I would expect! These babies were all < 32 weeks at birth. What the review suggests is that those babies who needed caffeine for longer durations benefit the most from the higher dose. I think I can buy that. On the adverse event side, I suppose it shouldn’t surprise many that the risk of tachycardia was statistically increased with an RR of 3.4. Anyone who has explored higher dosing would certainly buy that as a side effect that we probably didn’t need an RCT to prove to us. Never mind that, have you ever taken your own pulse after a couple strong coffees in the morning? What did it not show? It’s what the study didn’t show that is almost equally interesting. The cerebellar hemorrhages seen in the study I previously wrote about were not seen at all in the other studies. There could be a lesson in there about taking too much stock in secondary outcomes in small studies… Also of note, looking at longer term outcome measures there appears to be no evidence of harm when the patients are all pooled together. The total number of patients in all of these studies was 620 which for a neonatal systematic review is not bad. A larger RCT may be needed to conclusively tell us what to do with a high and low dosing strategy that we can all agree on. What do we do though in the here and now? More specifically, if you are on call tomorrow and a baby is on 5 mg/kg/d of caffeine already, will you intubate them if they are having copious apneic events or give them a higher dose of caffeine when CPAP or NIPPV that they are already on isn’t cutting it? That is where the truth about how you feel about the evidence really comes out. These decisions are never easy but unfortunately you sometimes have to make a decision and the perfect study hasn’t been done yet. I am not sure where you sit on this but I think this study while certainly flawed gives me some comfort that nothing is truly standing out especially given the fact that some of the “high dose” studies were truly high. Will see what happens with my next patient!
As time goes by, I find myself gravitating to reviews of Canadian research more and more. We have a lot of great research happening in this country of ours and especially when I see an author or two I know personally I find it compelling to review such papers. Today is one of those days as the lead author for a paper is my colleague Dr. Louis here in Winnipeg. Let me put his mind at ease in case he reads this by saying that what follows is not a skewering of the paper he just published using Canadian Neonatal Network data (CNN). Over the last twenty years that I have had the privilege of working in the field of Neonatology we continue to discuss the same things when it comes to the PDA. Does it really cause problems or is it an association for many outcomes? Does treatment make a difference? If you treat then what should you use (ibuprofen, indomethacin, paracetamol)? When should you treat and if you treat early should it be in the first few days or right after birth using a prophylactic approach (provided within 12 hours of delivery)? It is the prophylactic approach which is the subject of this post! Why treat prophylactically? The TIPP trial reported the results in 2001 of the study whose goal was to determine if prophylactic indomethacin use could improve neurosensory impairment at 18 months by reducing rates of severe IVH. The results of the study are well known and showed that while the rates of severe IVH and PDA ligations were reduced through this approach, there was no actual effect on long term outcome. The use of this approach fell off after that for many years but recently resurfaced as some units in Canada opted to start the practice again as the two benefits seen above appeared to be worth using the approach. The thought from a family centred approach, was that eliminating the stress for families of informing them their tiny preterm infant had a serious intracranial bleed and potentially avoiding a surgical ligation with probably vocal cord impairment afterwards were good enough outcomes to warrant this practice. Having used this approach myself I have to admit one consequence is that indomethacin was so effective at closing the PDA most of the time that over time one begins to assume the PDA is in fact closed and is less likely to go hunting for one when the baby is misbehaving later on in their course. What if it didn’t close though? Are there any predictors that can increase our index of suspicion? Answering the question The CNN provides a large database to look retrospectively to answer such a question. In this article, the authors looked at a period from 2010 to 2015 including all infants < 28 weeks gestational age at birth yielding a very large sample of 7397 infants. Of these 843 or 12% received prophylactic indomethacin and from there a little over half (465) still had a PDA. From there, 367 received treatment with eventually 283 needing only medical, 11 having a PDA ligation and 73 having both medical and surgical closure. From this analysis so far I can tell you that providing prophylactic indomethacin certainly does not guarantee closure! When a myriad of risk factors were put into logistic regression a number of interesting risk factors arose accounting for more of less risk of a PDA that needed surgical ligation despite prophylactic treatment. Much like all infants in the NICU, the risk for a persistent PDA was highest with declining GA. The combination of outborn status and short interval of ruptured membranes predicted higher risk. No doubt this is reflective of less frequent antenatal steroid use and even if provided time for it to work. Looking at medical or surgical treatment, surfactant therapy increased risk which may be explained by an improvement in oxygenation contributing to increased left to right shunting as PVR drops. Maternal hypertension and longer duration of rupture of membranes again play a role in reducing risk likely through the mechanism of the former increasing endogenous steroid production and the latter again allowing for steroids to be provided. What can we learn from this paper? I suppose the biggest benefit here is the realization that even with prophylactic indomethacin we are not assured of closure. In particular if there is a lack of antenatal steroid use or a stressed fetus one should be vigilant for the PDA. Interestingly, all of the risks seem to point towards antenatal steroid use. The bottom line then is that this reinforces what is already known and should be the focus of improvement strategies for centres. Increase the rate of antenatal steroid use and you will reduce the risk of a PDA even in the baby receives prophylactic indomethacin. I am happy to report that our centre has taken one step towards this goal by reinforcing to our Obstetrical colleagues that when they receive a call from a referring centre and have a woman who might be in labour it is better to err on the side of caution and just give the steroid course. If they are wrong on arrival then one can always repeat a course later on as we do although repeated courses of steroids are in and of themselves a contentious issue. What can your centre do to improve your results when it comes to antenatal steroid coverage?
In April of this year the ALPS trial results were published in the New England Journal of Medicine (Antenatal Betamethasone for Women at Risk for Late Preterm Delivery) and I took the time to review the paper at the time Antenatal Steroids After 34 weeks. Believe the hype? In the analysis I focused on an issue which was relevant at the time, being a shortage of betamethasone. In a situation when the drug of choice is in short supply I argued that while the benefits of giving steroid to women at risk of delivery between 34 0/7 to 36 6/7 weeks was there, if I had to choose (as I did at the time) I would save the doses for those at highest risk of adverse outcome. Since the blog post though a couple of things have come out in the literature that I believe are worth sharing as it could truly influence practice. Practice Advisory: Antenatal Corticosteroid Administration in the Late Preterm Period The American College of Obstetricians and Gynecologists, moved by the results of the ALPS trial issued the following recommendations (shortened in places). Betamethasone may be considered in women with a singleton pregnancybetween 34 0/7 and 36 6/7 weeks gestation at imminent risk of preterm birth within 7 days. Monitoring of late preterms for hypoglycemia (already being done) Do not give in the setting of chorioamnionitis. Tocolysis or delayed delivery for maternal indications should not be done in order to to allow for administration of late preterm antenatal corticosteroids. Do not provide if the pregnancy was already exposed to antenatal corticosteroids. The exclusions above such as twins and triplets, diabetic pregnancies and previous receipt of steroids were included since the study had not included these patients. As the ACOG states in the summary, they will be reviewing such indications in the future and providing recommendations. I would imagine that if I were in a US based practice then this post might seem like old news since many centres would have started doing this. Given that the readers of this blog are based in many different countries around the globe and at least in Canada this has not become commonplace I thought it would be worth the update! Antenatal corticosteroids for maturity of term or near term fetuses: systematic review and meta-analysis of randomized controlled trials I posted the abstract for this review on my Facebook page the other day and it certainly garnered a lot of interest. Some of my readers indicated the practice is already underway. I was curious what a systematic review would reveal about the topic since the ACOG was so moved by the ALPS study in particular. Perusing through the Society of Obstetricians and Gynecologists of Canada (SOGC) I can’t find any commentary on this topic and certainly there are no new clinical practice guidelines since the ALPS study landed on my desktop. Here are the pooled results from 6 trials: Lower risk of RDS (relative risk 0.74, 95% confidence interval 0.61 to 0.91) Mild RDS (0.67, 0.46 to 0.96) Moderate RDS (0.39, 0.18 to 0.89) Severe RDS (0.55, 0.33 to 0.91) Transient tachypnea of the newborn (0.56, 0.37 to 0.86) Shorter stay on a neonatal intensive care unit (−7.64 days, −7.65 to −7.64) So across the board patients who receive antenatal steroids after 34 weeks still continue to see a benefit but looked at a different way the real benefit of the intervention is easier to see and that is through looking at the number needed to treat (NNT). For those of you who are not familiar with this analysis, this looks at how many patients one would need to treat in order to avoid the outcome in 1 patient. For the outcomes above as an example the NNT for RDS overall is about 59 while for TTN 31 patients. Severe RDS which is less common after 34 weeks you might expect to require more patients to treat to help 1 avoid the outcome and you would be correct. That number is 118 patients. It is interesting to look at the impact of steroids in pregnancies below 34 weeks (taken from the Cochrane review on the subject) as the NNT there is 23! If you were to break these benefits down from 23-27 weeks though where the risk of RDS is quite high the NNT would be even lower. Steroids help, no question to reduce neonatal complications but as you can see even when there is a reduction in risk for various outcomes, the number of women you need to treat to get one good outcome is quite different. Some Discussion With Obstetrics Is Needed Here As you read through this post you may find yourself saying “Who cares? if there is a benefit at all most moms would say give me the steroids!” The issue here has to do with long term outcome. To put it simply, we don’t know for this type of patient. We know clearly that for patients at high risk of adverse outcomes eg. 24 week infant, the reduction in risks of infection, NEC, PDA, BPD etc from receiving antenatal steroids translates into many long term benefits. What about the patient who say is 35 weeks and would have none of those risks? Yes we are avoiding some short term outcomes that let’s be honest can be scary for a new parent but what are we trading this benefit for. The concern comes from what we know about steroids impact on the developing brain. Steroids lead to a developmental arrest but in very preterm infants there is no doubt that the protective effect on all of these other outcomes more than offsets whatever impact there is there. Incidentally I wrote about this once before and the section of interest appears at the end of the relevant post Not just for preemies anymore? Antenatal steroids for elective c-sections at term. In the absence of these other conditions could there be a long term impact in babies 34 – 36 6/7? My suspicion is that the answer is no but discussion is needed here especially in the absence of an endorsement by our Canadian SOGC. Having said all that I expect the future will indeed see an expansion of the program but then I do hope that someone takes the time to follow such children up so we have the answer once and for all.