InSurE (Intubate, Surfactant, Extubate) has been the standard approach for some time when it comes to treating RDS. Less Invasive Surfactant Administration (LISA) or Minimally Invasive Surfactant Administration (MIST) have been growing in popularity as an alternative technique. More than just popular, the techniques have been shown to reduce some important short term and possibly long term outcomes when used instead of the InSurE approach. Aldana-Aquirre et al published the most recent systematic review on the topic in Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. They demonstrated that when looking at 6 RCTs with 895 infants, the overall results indicate that use of LISA instead of InSurE leads to a lower rate of death or bronchopulmonary dysplasia (BPD) at 36 weeks (risk ratio (RR)=0.75 (95% CI 0.59 to 0.94), p=0.01) and the need for mechanical ventilation within 72 hours of birth (RR=0.71 (0.53 to 0.96), p=0.02) or anytime during the patient stay in the NICU (RR=0.66 (0.47 to 0.93), p=0.02). This study has been out for two years this month and yet here we are at least in my centre still performing InSurE.
Why is that?
One reason likely has something to do with the expression “you can’t teach an old dog new tricks”. We know how to do InSurE and we are pretty good at it. Performing the LISA technique is not just about putting a catheter in the airway and instilling surfactant. There are several steps that need to be done in order to ensure that the surfactant goes where it is supposed to so there is training required but such training is available in videos posted on the internet or I am sure available from centres willing to share their methods. Still it takes someone declaring we need to change before anything will happen. The second reason for this insistence on the status quo has been the availability of only a large volume surfactant in Canada at 5 ml/kg while in European centres the volume administered was half that. Now a low volume surfactant is available in Canada but some centres have been slow to make a switch due to comfort with the current product. The drawback to the current product is the concern that you can’t use it for LISA techniques since the centres practicing this technique use the low volume form.
Can High Volume Be Used For Lisa?
Researchers in London, Ontario performed a retrospective cohort study of 43 infants in their institution who underwent the MIST approach for surfactant administration in their study High-volume surfactant administration using a minimally invasive technique: Experience from a Canadian Neonatal Intensive Care Unit. In 2016, London instituted a change in practice to provide MIST for infants born at ≥28 weeks and/or with a birth weight ≥ 1,000 g with respiratory distress syndrome. Surfactant was provided over 1-3 minutes via a MAC catheter guided through the vocal cords with Magill forceps. What I like about this study is the reproducibility of it as the authors describe very nicely how the steps were done. What I also appreciate is the provision of sucrose and atropine prior to the procedure. Not a rapid sequence induction but it does do something to address the risk of bradycardia and discomfort with cannulation of the trachea. The results I think speak for themselves that this is indeed possible as 41/43 neonates underwent the procedure with successful instillation of surfactant confirmed by absence of recovered surfactant in aspirated stomach contents.
All of these infants qualified for BLES based on an oxygen requirement on non-invasive support of 40% or more. These patients are similar to our own in Winnipeg in terms of qualifying criteria for surfactant but perhaps a little higher tolerance of FiO2 before intubating. Additional evidence that surfactant was indeed received was the reduction to room air in 85% of patients within 24 hours and also the need for a second dose of surfactant in only 10%.
Aside from oxygen desaturation in about 50% during BLES administration the adverse effects were fairly limited and similar to what one would see with InSurE.
What now?
BLES can be administed via MIST despite concerns about the higher volume of surfactant. What many centres need to address I suspect is that while we think we are practicing InSurE, in many cases we are not. The goal of that procedure is to provide the surfactant over a few seconds and then get the ETT out right away. How often does that happen though in reality? Have you ever found yourself leaving the ETT in till the baby gets to NICU and extubating there? Seems safer right? What if in the elevator or hallway on the way to NICU the baby deteriorates and needs intubation? How long does the ETT stay in? Twenty minutes, 30, 45, 60 or longer? Thinking about that in a different way, what does that translate into in terms of number of PPV breaths? Well at a rate of 60 breaths a minute that means 1800, 2700, 3600 and more breaths before the ETT is removed. I have often wondered if this in itself explains why InSurE seems to be repeatedly identified as being inferior to MIST. If you intubated, gave the surfactant and pulled the ETT out right away in all cases might the two techniques actually be equivalent.
The question now really is how do we get past our tendencies and embrace a change in practice that by design will not allow us to delivery any positive pressure breaths?!
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 Administrationand 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!
In July 2016 I published a blog post No more intubating for meconium? Not quite. In this post I highlighted the recent recommendations to modify the approach to the non vigorous infant born through meconium. The traditional approach of electively intubating such infants for tracheal suctioning before beginning PPV was replaced by provision of PPV first. The rationale here was that delaying the establishment of ventilation while trying to intubate for most situations was more risky than just trying to establish a functional residual capacity (FRC). The naysayers pointed out that while this recommendation is possibly warranted for less experienced intubators, perhaps in the hands of those with more skill, tracheal suctioning would be the better option if it could on average be done quickly.
It has been over two years since that recommendation and change in practice. Isn’t it about time someone looked at whether or not this was a good thing to do?
A Comparison of Two Time Periods
Chiruvolu A et al published Delivery Room Management of Meconium-Stained Newborns and Respiratory Support in this month’s Pediatrics. In this paper the authors compared 4 hospitals with a retrospective period of one year before the NRP changes (October 1, 2015, to September 30, 2016) to a one year prospective period (October 1, 2016, to September 30, 2017) after implementation of the new guidelines. In the retrospective cohort there were 11163 mothers delivered at ≥35 weeks’ gestation. Meconium stained amniotic fluid (MSAF) was present in 1303 (12%) deliveries with 130 (10%) of newborns who were nonvigorous. During the prospective time period, a total of 10 717 mothers delivered at ≥35 weeks’ gestation. MSAF was noted in 1282 (12%) deliveries, yielding 101 (8%) newborns who were nonvigorous. Therefore the study compared these 130 newborns in the retrospective cohort to the 101 in the prospective time period. The authors note that aside from the approach to MSAF there were no changes in care during this time in the delivery room.
A few differences exist though in the cohorts that are worth mentioning that were statistically significant. Firstly, the incidence of preterm and post-term infants were both higher in the prospective cohort (both 6% vs 1%). Secondly, the incidence of fetal distress was higher in the prospective cohort 57% vs 43%. All of these factors would tend to favour the retrospective cohort doing better than the prospective and so the authors in their results controlled for these differences. Not surprisingly the rate of intubation in the retrospective group was 70% vs 2% in the prospective arm.
What were the results?
The results shown in table 3 in terms of the Odds ratios have been adjusted for the aforementioned differences of preterm post-term and fetal distress. There are several things here worth noting. The risk of admission was significantly higher for respiratory distress.
Oxygen needs and mechanical ventilation along with surfactant therapy were also notably higher. One things that showed no difference at all was the mean apgar score at 1 and 5 minutes. This is an interesting finding given the hypothesis that drove the change in practice. If establishing an FRC is the goal of the intervention to provide earlier PPV then shouldn’t the retrospective group have worse apgars due to less effective resuscitation? Maybe or maybe not. This really depends on the staff in the resuscitation room at the 4 hospitals. It might be that the staff were quite skilled so the intubations may have gone smoothly with minimal reductions in FRC compared to the prospective group. What would this study look like if done in a centre with less experienced people capable of intubation.
Also interesting in this study is that when isolating comparisons to those admitted to the NICU and those specifically diagnosed with MAS there were no differences between groups for such outcomes as length of stay, oxygen therapy, mechanical ventilation (MV) or days of MV. Given that the group sizes though were quite small (7 and 11 for MAS) we do have to take this data with a grain of salt as it really is too small to make any certain conclusions. A larger study would need to be done looking at these types of outcomes to really get a better handle on whether the approach to MSAF matters to these individual outcomes.
Final Thoughts
What this study does for me is raise an eyebrow. The change in practice does not seem to yield “better babies”. Secondly what we do see even when controlling for differences that would affect hospital admissions for respiratory distress is an increase in admission rate. In times when beds are becoming increasingly precious as census for many units swell one has to ask whether this approach is truly the better way to go. Perhaps it was wrong for the NRP to declare that for all practitioners it is best to provide PPV rather than intubate. This may have been too simplistic. If you have experienced intubators perhaps it would be best to continue to intubate first in this setting rather than provide PPV. What this study does is certainly raise questions and begs for a larger study to be done to determine whether these results can be replicated. If they are then I suspect the NRP may be headed down a different path for recommendations yet again.
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 
The risk of admission was significantly higher for respiratory distress.
Oxygen needs and mechanical ventilation along with surfactant therapy were also notably higher. One things that showed no difference at all was the mean apgar score at 1 and 5 minutes. This is an interesting finding given the hypothesis that drove the change in practice. If establishing an FRC is the goal of the intervention to provide earlier PPV then shouldn’t the retrospective group have worse apgars due to less effective resuscitation? Maybe or maybe not. This really depends on the staff in the resuscitation room at the 4 hospitals. It might be that the staff were quite skilled so the intubations may have gone smoothly with minimal reductions in FRC compared to the prospective group. What would this study look like if done in a centre with less experienced people capable of intubation.