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AllThingsNeonatal posted a blog entry in All Things NeonatalA grenade was thrown this week with the publication of the Australian experience comparing three epochs of 1991-92, 1997 and 2005 in terms of long term respiratory outcomes. The paper was published in the prestigious New England Journal of Medicine; Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years. This journal alone gives “street cred” to any publication and it didn’t take long for other news agencies to notice such as Med Page Today. The claim of the paper is that the modern cohort has fared worse in the long run. This has got to be alarming for anyone reading this! As the authors point out, over the years that are being compared rates of antenatal steroid use increased, surfactant was introduced and its use became more widespread and a trend to using non-invasive ventilation began. All of these things have been associated with better short term outcomes. Another trend was declining use of post-natal steroids after 2001 when alarms were raised about the potential harm of administering such treatments. Where then does this leave us? I suppose the first thing to do is to look at the study and see if they were on the mark. To evaluate lung function the study looked at markers of obstructive lung disease at 8 years of age in survivors from these time periods. All babies recruited were born between 22-27 completed weeks so were clearly at risk of long term injury. Measurements included FEV1, FVC, FVC:FEV1 and FEF 25-75%. Of the babies measured the only two significant findings were in the FEV1 and ratio of FEV1:FVC. The former showed a drop off comparing 1997 to 2005 while the latter was worse in 2005 than both epochs. Variable 1991-92 1997 2005 %predicted value N=183 N=112 N=123 FEV1 87.9+/-13.4 92.0+/-15.7 85.4+/-14.4 FEV1:FVC 98.3+/-10 96.8+/-10.1 93.4+/-9.2 This should indeed cause alarm. Babies born in a later period when we thought that we were doing the right things fared worse. The authors wonder if perhaps a strategy of using more CPAP may be a possible issue. Could the avoidance of intubation and dependence on CPAP for longer periods actually contribute to injury in some way? An alternative explanation might be that the use of continuous oximetry is to blame. Might the use of nasal cannulae with temporary rises in O2 expose the infant to oxygen toxicity? There may be a problem here though Despite everyone’s best efforts survival and/or BPD as an outcome has not changed much over the years. That might be due to a shift from more children dying to more children living with BPD. Certainly in our own centre we have seen changes in BPD at 36 weeks over time and I suspect other centres have as well. With concerted efforts many centres report better survival of the smallest infants and with that they may survive with BPD. The other significant factor here is after the extreme fear of the early 2000s, use of postnatal steroids fell off substantially. This study was no different in that comparing the epochs, postnatal glucocorticoid use fell from 40 and 46% to 23%. One can’t ignore the possibility that the sickest of the infants in the 2005 cohort would have spent much more time on the ventilator that their earlier counterparts and this could have an impact on the long term lung function. Another question that I don’t think was answered in the paper is the distribution of babies at each gestational age. Although all babies were born between 22-27 weeks gestational age, do we know if there was a skewing of babies who survived to more of the earlier gestations as more survived? We know that in the survivors the GA was not different so that is reassuring but did the sickest possible die more frequently leaving healthier kids in the early cohorts? This bigger issue interestingly is not mentioned in the paper. Looking at the original cohorts there were 438 in the first two year cohort of which 203 died yielding a survival of 54% while in 1997 survival increased to 70% and in 2005 it was 65%. I can’t help but wonder if the drop in survival may have reflected a few more babies at less than 24 weeks being born and in addition the holding of post natal steroids leading to a few more deaths. Either way, there are enough questions about the cohorts not really being the same that I think we have to take the conclusions of this paper with a grain of salt. It is a sensational suggestion and one that I think may garner some press indeed. I for one believe strongly though as I see our rates of BPD falling with the strategies we are using that when my patients return at 8 years for a visit they will be better off due to the strategies we are using in the current era. Having said that we do have so much more to learn and I look forward to better outcomes with time!
This is something that I continue to hear from time to time even in 2016 and I imagine I will continue to hear rumblings about this in 2017. Certainly, there are physical limitations when a baby is born at less than 500g. Have you tried fitting a mask to deliver NIPPV or CPAP to a baby this small? I have and it didn’t work. The mask was simply too big to provide a seal and while I am all for INSURE and emerging minimally invasive surfactant techniques they still require transitioning to a form of non invasive positive pressure ventilation to allow extubation success. Certainly though above the 500g barrier it may be that the greatest impediment to extubation is our own bias. If this sounds a little familiar it is because I have written about this topic before Extubation failure is not a failure itself. The reason for bringing the topic up again though is that aside from needing to address our own fears there is a new systematic review that acts somewhat of a how to guide to optimizing your chance at a successful extubation. The review encompasses findings from 50 studies with successful extubation as defined as no need for reintubation within 7 days. Before getting into the details of the optimal approach it is worth reminding people that failure of extubation in even our smallest babies is not a failure itself. Such babies who “fail” up to 5 times do not suffer any long term consequences and may wind up with less risk of BPD than those who are kept intubated due to fear of failure. So After Reviewing The Evidence What Are the Recipes To Success? Continuous positive airway pressure Reduced extubation failure in comparison with head-box oxygen (risk ratio [RR], 0.59;95%CI, 0.48-0.72; number needed to treat [NNT], 6; 95%CI, 3-9). If you aren’t extubating to nCPAP then chances are I would bet your success rates are quite low. Head boxes certainly can tell you how much O2 a patient requires but do nothing to help inflate alveolar spaces. Nasal intermittent positive pressure ventilation (NIPPV) vs. CPAP Higher prevention of extubation failure (RR, 0.70; 95%CI, 0.60-0.81; NNT, 8; 95%CI, 5-13). This one is of particular interest to me. The evidence has suggested this for some time and with a number needed to treat of 8 it would seem illogical to use anything else at the outset, especially in the smallest of infants. The issue here though is that at least here in Canada the options for delivering such NIPPV are currently quite limited. At the moment we are limited to use of ventilator NIPPV and the stability of the CPAP offered from such devices and the imposed work of breathing are most likely inferior to that found in variable flow devices which at this point have been pulled from the market. See Comparison of nasal continuous positive airway pressure delivered by seven ventilators using simulated neonatal breathing. What I hope 2017 brings is a comparison of the effectiveness of extubation success using new variable flow devices capable of generating previously unreachable CPAP pressures above 9 or 10 cm H2O. Will these attain similar effectiveness to the NIPPV devices? Methylxanthines reduced extubation failure (RR, 0.48; 95%CI, 0.32-0.71; NNT, 4; 95%CI, 2-7) compared with placebo or no treatment. Ok, pretty much anyone working in Neonatology would assume this but what really is at the crux of the discussion in 2016 and beyond is “what dose?” It has been pretty clear during my career thus far that there are some preterm infants that just don’t respond to conventional doses of caffeine base from 2.5 – 5 mg/kg/d. In our own units we have increased doses to 6, 7 or 8 mg/kg/d to achieve some degree of respiratory stimulation and usually been limited by tachycardia in determining how high we can go. Given the sparse literature regarding safety on this topic we are relegated to ask ourselves what is worse, leaving a baby on a ventilator or using higher doses of caffeine? I have given some thoughts on this before as well Are we overdosing preemies on caffeine? Doxapram did not aid successful extubation (RR, 0.80; 95% CI, 0.22-2.97). For selfish reasons I have to admit I was happy to see this. We can’t access this medication very easily here in Canada so hearing that it doesn’t seem to work to enhance the likelihood of a successful extubation is somewhat of a relief. A Cautionary Note While I applaud the authors of the systematic review for performing such a thorough job I do feel the need to raise one concern with the analysis. It is not a major concern but one that I just feel the need to mention. Success if the studies was defined as not requiring reintubation within 7 days of extubation. My concern is that having such a lengthy time frame leaves the possibility that the decision to reintubate had nothing to do with the patient in fact not being ready. Seven days is a long time and much can happen in the life of a preterm infant in an NICU that triggers a reintubation. What if a patient needed to be transferred to a different NICU and for safe air transport it was deemed safest to replace the ETT? How many patients could have developed NEC or sepsis in the seven days? What if a PDA was being semi-electively ligated after a failed NSAID course? In the end the impact of such conditions could be minimal but I am less convinced that a patient failed extubation when up to 7 days have passed. I would be very interested to see a similar study looking at a period of 24 or 48 hours after extubation and seeing how many stay that way. Would the predictors of success stay the same? Probably but I suspect the number safely extubated would rise as well. featured image from the March of Dimes
Preterm infants born between 22 to 25 weeks gestational age has been a topic covered in this blog before. Winnipeg hospital now resuscitating all infants at 22 weeks! A media led case of broken telephone. Is anything other than “perfect practice” acceptable for resuscitating infants from 22 – 25 weeks? Winnipeg Hospital About to Start Resuscitating Infants at 23 weeks! I think it is safe to say that this topic stirs up emotions on both sides of the argument of how aggressive to be when it comes to resuscitating some of these infants, particularly those at 22 and 23 weeks. Where I work we have drawn a line at 23 weeks for active resuscitation but there are those that would point out the challenge of creating such a hard-line when the accuracy of dating a pregnancy can be off by anywhere from 5 – 14 days. Having said that, this is what we have decided after much deliberation and before entertaining anything further it is critical to determine how well these infants are doing not just in terms of survival but also in the long run. In the next 6 months our first cohort should be coming up for their 18 month follow ups so this will be an informative time for sure. Do Days Matter? This is the subject of a short report out of Australia by Schindler T et al. In this communication they looked at the survival alone for preterm infants in a larger study but broke them down into 3 and four-day periods from 23 to 25 weeks as shown below. The asterisk over the two bars means that the improvement in survival was statistically significant between being born in the last half of the preceding week and the first half of the next week. In this study in other words days make a difference. A word of caution is needed here though. When you look at the variation in survival in each category one sees that while the means are statistically different the error bars show some overlap with the previous half week. At a population level we are able to say that for the average late 23 week infant survival is expected to be about 30% in this study and about 55% at 24 +0-3 days. What do you say to the individual parent though? I am not suggesting that this information is useless as it serves to provide us with an average estimate of outcome. It also is important I believe in that it suggests that dating on average is fairly accurate. Yes the dates may be off for an individual by 5 – 14 days but overall when you group everyone together when a pregnancy is dated it is reasonably accurate for the population. Don’t become a slave to the number The goal of this post is to remind everyone that while these numbers are important for looking at average outcomes they do not provide strict guidance for outcome at the individual level. For an individual, the prenatal history including maternal nutrition, receipt of antenatal steroids, timing of pregnancy dating and weight of the fetus are just some of the factors that may lead us to be more or less optimistic about the chances for a fetus. Any decisions to either pursue or forego treatment should be based on conversations with families taking into account all factors that are pertinent to the decision for that family. Age is just a number as people say and I worry that a graph such as the one above that is certainly interesting may be used by some to sway families one way or another based on whether the clock has turned past 12 AM. At 23 weeks 3 days and 23 hours do we really think that the patient is that much better off than at 24 weeks 4 days and 1 hour?
The updated Cochrane review comes with a clear recommendation - that preterm infants (defined as <37 weeks / BW <2500 g) should be given probiotics to reduce the risk of NEC. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005496.pub4/abstract When reading the full review (look at the tables), my impression is that the effect among infants <1000 grams is less well documented. And I came across this editorial: http://www.jpeds.com/article/S0022-3476%2814%2900431-4/abstract What is your opinion about and/or the interpretation of the Cochrane review? If you use probiotics - do you use it for all preterms regardless of gestational age (i.e. also for the most immature & tiny babies)?