Time to say goodbye to INSurE and hello to IN-REC-SUR-E?

Time to say goodbye to INSurE and hello to IN-REC-SUR-E?

Intubate-Surfactant- Extubate or INSURE has been around for awhile. The concept is to place an ETT while an infant is first on CPAP and then after pushing surfactant in quickly remove the ETT and put back on CPAP. This does not always go as planned though. If after surfactant the FiO2 remains above 30% many people would keep the ETT in place as they would surmise that the infant would fail if the tube was removed. They would probably be right.

Sustained inflations have fallen out of favour ever since the SAIL trial results were published and written about here . Having said that, the concept of using sustained inflation is to open the lung and expand closed alveoli to improve both oxygenation and gas exchange. Much like giving inhale nitric oxide to a collapsed lung is unlikely to make much difference, the question could be asked whether giving surfactant to a lung that is most collapsed will fail to deliver this compliance improving medication to the areas of the lung that most sorely need it. Our Italian colleagues therefore decided to undertake a study to look at providing surfactant to lungs after a recruitment manouver and see if this made a difference to the meaningful outcome of extubation failure after surfactant provision. The results are intriguing and as such here we go in looking at the study.

Optimizing Lung Expansion

The trial is the Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial and involved 35 NICUs in Italy. All infants enrolled were born from 24 + 0 weeks to 27 6/7 weeks gestational age at birth and all < 24 hours of age at enrollment. Each baby had to be on CPAP at the time of randomization and meet prespecified failure criteria of FiO2 of 0·30 or greater for target SpO2 of 87% to 94% for at least 30 min or in 10 Infants for rapid deterioration of clinical status or if pCO2 was > 65 mm Hg with a pH less than 7·20. Regardless of which arm they were randomized to all infants received 1-2 sustained inflation breaths using 25 cm H2O for 10-15 secs using a t-piece resuscitator after being started on CPAP as was the practice at the time. After randomization which could not be blinded, patients were then either given surfactant via INSURE without any further strategy for opening the lung or received the IN-REC-SUR-E approach. The latter involved putting the infant on high frequency oscillation starting with settings of mean airway pressure 8 cm H2O; frequency 15 Hz; ΔP15 cm H2O; and inspiration to expiration ratio of 1:2. Using this modality infants underwent stepwise recruitment methods prior to administering surfactant (poractant). The primary outome was the need for mechanical ventilation within the first 72 h of life. Infants met the primary outcome if they were not extubated within
30 min after surfactant administration or required reintubation before 72 h of life.

The Results

Based on a power calculation the authors needed 103 infants in each arm and they recruited 107 in the treatment and 111 in the control arm. In the per-protcol allocation 101 received the treatment and 111 the contol. While the strategies for extubation were not set out to be equal (units were allowed to extubate to anywhere from +6 to +8 for pressure levels), the groups were not different 7·0 cm H2O, SD 0·4 for the experimental group and control arms. Given the steps taken to open the lung in the lung recruitment arm, the FiO2 was lower at 28% prior to surfactant provision in the treatment group than in the usual INSURE approach at 42% prior to surfactant provision. All infants were extubated within 30 minutes of receiving surfactant. As the results demonstrate, whether there was an intention to treat analysis or per-protocol analysis the babies who received the intervention were more likely to remain extubated. The number needed to treat was 7 which is a pretty powerful measure. Interestingly, looking at secondary outcomes there are some interesting trends as well including less mortality which on a per-protocol analysis was significant but also a trend towards more PVL at 9% in the treatment arm and 4% in the control. The mean times to surfactant administration were 4 hours in the treatment group and 3 hours in the control but the high frequency manoeuvre had a mean duration of only 30 minutes. It is possible that the use of high frequency could have blown off CO2 to very low levels but I am uncertain if the short reduction in pCO2 could have contributed significantly to reduced cerebral perfusion if that trend is representative of something. Interestingly, pneumothroaces were not different between groups as no doubt as a reader you might wonder if use of high pressures to recruit the lungs when they are non compliant might have led to air leaks.

So it worked, now what?

First of all, the results to me make a lot of sense. Opening the lung before delivering surfactant and then seeing better chances of staying extubated doesn’t really surprise me. Some questions that come up now for me would be how this strategy would fare in those who are older at birth. I suspect given the greater chest wall support and lower likelihood of severe RDS this strategy might be even more effective at reducing FiO2 or perhaps CPAP need in terms of duration after extubation. I would think it unlikely to make a difference in reintubation though as most would remain extubated regardless. That is for another study though with a different outcome.

There will be centres that don’t like the use of HFOV for recruitment so what other strategies could be used in lieu of this? I hate to say it but there will also be calls to have a much larger study specifically designed to look at the secondary outcomes. Would a larger study find a significant increase in PVL or demonstrate that it was just a random finding? Might mortality be proven to be lower and even more so?

Regardless of the above what I think this paper does is give us reason to pause before giving INSURE and ask ourselves if we have done what we can to open the lung after intubating before rushing to squirt the surfactant in. Maybe increasing the provided PEEP and lowering the FiO2 somewhat before giving surfactant will help with distribution and increase your chances of first being able to extubate and secondly when you do keeping the tube out!

Time to say goodbye to INSurE and hello to IN-REC-SUR-E?

Aerosolized surfactant. Can we finally do away with intubation?

I have written about non-traditional methods of providing surfactant to newborns previously. The practice of intubating a preterm infant to administer surfactant and leaving the endotracheal tube in with a slow wean of ventilation is mostly a thing of the past (at least in my units). Strategies have evolved and have seen the development of the INSURE technique, LISA methods, use of an LMA to delivery surfactant and even simple deposition into the pharynx all with variable success.

The Holy Grail

To me at least, the Holy Grail of surfactant delivery has been aerosolization. A small non randomized study was done in by Finer et al in 2010 An open label, pilot study of Aerosurf® combined with nCPAP to prevent RDS in preterm neonates. This study noted a reduction in CPAP failure with nebulized surfactant but as a pilot was not large enough to move the needle. Since then the Cochrane group weighed in and declared that there was not enough evidence to support the practice. The CureNeb group anchored by Dr. Pillow though has now published a double blind RCT entitled Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomized controlled trial. It certainly sounds interesting and might help determine if the needle has indeed moved.

The Study

Poractant alfa at 200 mg/kg was used in this study and delivered via aerosolization using a vibrating membrane called the eFlow. The authors chose to look at infants from 29 0/7 to 33 6/7 weeks at birth and stratified them into two groups of 29 0/7 to 31 6/7 and 32 0/7 to 33 6/7 weeks. They estimated a need for 70 babies based on an anticipated failure rate of 30% in the control group vs 5% in the treatment group. Unfortunately, due to several reasons the study was only able to recruit 64 babies for randomization before being stopped due to the recruitment issues. The design of the study included adequate blinding with a sham procedure and there were predefined “failure criteria” necessitating intubation at the outset of the study. These criteria are acceptable to me as they are similar enough to my own practice and were:

1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at
2. More than four apnoeas/hour OR two apnoeas requiring bag
and mask ventilation.
3. Two capillary blood gas samples with a pH <7.2 and partial pressure of carbon dioxide >65 mm Hg (or partial pressure
of carbon dioxide in arterial blood (PaCO2) >60 mm Hg if
arterial blood gas sample).
4. Intubation deemed necessary by the attending physician.

What did they find?

The primary outcome CPAP failure within 72 hours of birth was indeed different in the two groups.

CPAP failure by 72 hours
CPAP + surfactant 11/32 (34%)
CPAP 22/32 (69%)

(RR (95% CI)=0.526 (0.292 to 0.950))

Clearly the event rates were quite off from what they expected in the power calculation but given that they found a difference as opposed to no difference at all the fact that they didn’t recruit the numbers they planned is of less importance.

However, what is interesting is when they looked at the planned analysis by stratification an interesting finding emerged.

Group 1 (29 0/7 to 31 6/7)

CPAP failure by 72 hours
CPAP + surfactant 12/21 (57%)
CPAP 12/19 (63%)

(RR (95% CI)=0.860 (0.389 to 1.90))

Group 2 (32 0/7 to 33 6/7

CPAP failure by 72 hours
CPAP + surfactant 1/11 (9%)
CPAP 10/13 (77%)

(RR (95% CI)=0.254 (0.089 to 0.727))

There were a number of secondary outcomes looked at as well which may be of interest to you but as the numbers here are quite small I will not comment other than to say there was no increased incidence of complications with surfactant administration in this fashion. Also for those who ultimately failed CPAP the time when they did so was quite delayed compared to CPAP alone. Age at intubation for nCPAP failure, hours 4.9 (2.7–10.6) 11.6 (9.0–31.1) 0.008*

What can we take from this?

I believe these results are encouraging even if the study is a small one. The message I take from this study is that aerosolization of surfactant delivers some amount of product to the lungs. Those with more significant RDS or smaller lungs (those in the 29 0/7 to 31 6/7 group) may not get enough surfactant to treat their RDS sufficiently to avoid intubation. Those with less significant RDS or a larger number of alveoli get “enough” of a dose delivered to the alveoli to make a difference and avoid intubation. It is worth stressing that there can be no specific comment about using this strategy in even more immature infants as they weren’t tested. If I had to guess though, I would expect no difference given the findings in the smaller group.
As a physician responsible for transport though I am interested in the potential benefits to those born in non-tertiary centres. Many centres lack individuals with the confidence and skill to regularly place endotracheal tubes. For these centres it may be that providing nebulized surfactant could delay the time to treatment failure, allowing more time for a trained transport team to arrive. Training of course would be needed in these centres on how to administer surfactant in this way but it is an interesting concept to consider. With a near tripling of the average time to treatment failure the extra hours on CPAP would be much appreciated when weather delays or difficulty securing air assets means long delays in transport team arrivals.

To be sure this isn’t the last study of this kind but it certainly is an interesting start and one that will no doubt produce questions that will help formulate the next study design.

Intratracheal instillation of steroids to prevent BPD

Intratracheal instillation of steroids to prevent BPD

Choosing to provide postnatal systemic steroids to preterm infants for treatment of evolving BPD has given many to pause before choosing to administer them. Ever since K Barrington published his systematic review The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. and found a 186% increase in risk of CP among those who received these treatments, efforts have been made to minimize risk when these are given.  Such efforts have included shortening the exposure from the length 42 day courses and also decreasing the cumulative dose of dexamethasone.  Fortunately these efforts have led to findings that these two approaches have not been associated with adverse neurodevelopmental outcomes.  Having said that, I doubt there is a Neonatologist that still doesn’t at least think about long term outcome when deciding to give dexamethasone.  The systemic application certainly will have effects on the lung but the circulating steroid in the brain is what occupies our thoughts.

What About Applying it Directly to the Lung

If you wanted to prevent BPD the way to do it would be to minimize the time infants are exposed to positive pressure ventilation.  Rather than giving steroids after a week or two maybe it would be best to give them early.  Recent evidence supports this for systemic steroids and has been written about recently. Hydrocortisone after birth may benefit the smallest preemies the most! This still involves providing steroid systemically.  Over the years, inhaled steroids have been tried as have intratracheal instillation of steroid with and without surfactant as a vehicle for distribution to the lung.  This month colleagues of mine anchored by Dr. G. t’Jong (a founding member of the “Tall Men of Pediatrics #TMOP) published a systematic review and meta-analysis of all such RCTs in their paper Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and metaanalysis.  The results of the study suggest that there may well be a role for this approach.

All of the included studies used a prophylactic approach of giving between the first 4 hours and the 14th day of postnatal age doses of pulmonary steroids with the goal of preventing death or BPD. The GA of enrolled infants ranged from 26 to 34 weeks, and the birth weight ranged from 801 to 1591 g. Out of 870 possible articles only 12 made the cut and compromised the data for the analysis.

Routes of steroid were by inhalation, liquid instillation though the endotracheal tube or by mixing in surfactant and administering through the ETT.

What Did They Find?

Using 36 weeks corrected age as a time point for BPD or death, the forrest plot demonstrated the following.  A reduction in risk of BPD or death of 15% with a range of 24% to only a 4% reduction.

Looking at the method of administration though is where I find things get particularly interesting.

What this demonstrates is that how you give the steroids matters.  If you use the inhalational or intratracheal instillation (without a vehicle to distribute the steroids) there is no benefit in reduction of BPD or death.  If however you use a vehicle (in both Yeh studies it was surfactant) you find a significant reduction in this outcome.  In fact if you just look at the studies by Yeh the reduction is 36% (CI 34 – 47%).  In terms of reduction of risk these are big numbers.  So big one needs to question if the numbers are real in the long run.

Why might this work though?

In the larger study by Yeh, budesonide was mixed with surfactant and delivered to intubated infants every 8 hours until FiO2 was less than 30%, they were extubated or a maximum of 6 doses were reached.  We know that surfactant spreads throughout the lung very nicely so it stands to reason that the budesonide could have been delivered evenly throughout the lung.  Compare this with inhalational steroid that most likely winds up on the plastic tubing or proximal airway.  The anti-inflammatory nature of steroids should decrease damage in the distal airways offsetting the effects of positive pressure ventilation.

Future Directions

I am excited by these findings (if you couldn’t tell).  What we don’t know though is whether the belief that the steroid stays in the lung is true. Are we just making ourselves feel better by believing that the steroid won’t be absorbed and move systemically.  This needs to be tested and I believe results of such testing will be along in the near future.

Secondly, we need a bigger study or at least another to add to the body of research being done.  Such a study will also need long term follow-up to determine if this strategy does at least have equal neurodevelopmental outcomes to the children who don’t receive steroid.  The meta-analysis above does show in a handful of studies that long term outcome was no different but given the history of steroids here I suspect we will need exceptionally strong evidence to see this practice go mainstream.

What I do believe is whether you choose to use steroids prophylactically using hydrocortisone or using intratracheal surfactant delivered budesonide, we will see one or both of these strategies eventually utilized in NICUs before long.


Intratracheal instillation of steroids to prevent BPD

Less Invasive Surfactant Administration with High Volume Surfactant

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?!

Intubating to give surfactant is so 2017!

Intubating to give surfactant is so 2017!

A real change is coming and with this post you will get a glimpse into where the next big thing in Neonatology is likely to be.  A catchy title for sure and also an exaggeration as I don’t see us abandoning the endotracheal tube just yet.  There has been a lot of talk about less invasive means of giving surfactant and the last few years have seen several papers relating to giving surfactant via a catheter placed in the trachea (MIST or LISA techniques as examples).  There may be a new kid on the block so to speak and that is aerosolized surfactant.  This has been talked about for some time as well but the challenge had been figuring out how to aerosolize the fluid in such a way that a significant amount of the surfactant would actually enter the trachea.  This was really a dream of many Neonatologists and based on a recently published paper the time may be now for this technique to take off.

A Randomized Trial of Aerosolized Surfacant

Minocchieri et al as part of the CureNeb study team published Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. This trial set out to obtain a sample size of 70 patients between 29 0/7 to 33 6/7 weeks to demonstrate a difference in need for intubation from 30% down to 5% in patients treated with CPAP (30% was based on the historical average).  The authors recognizing that the babies in this GA bracket might behave differently, further stratified the randomization into two groups being 29 0/7 – 31 6/7 weeks and 32 0/7 to 33 6/7 weeks.  Those babies who were on CPAP and met the following criteria for intubation were either intubated in the control group and given surfactant (curosurf) using the same protocol as those nebulized or had surfactant delivered via nebulisation (200 mg/kg: poractant alfa) using a customised vibrating membrane nebuliser (eFlow neonatal). Surfactant nebulisation(100 mg/kg) was repeated after 12 hours if oxygen was still required.  The primary dichotomous outcome was the need for intubation within 72 hours of life, and the primary continuous outcome was the mean duration of mechanical ventilation at 72 hours of age.

Criteria for intubation

1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at
2. More than four apnea/hour OR two apnea requiring BVM
3. Two cap gases with pH <7.2 and PaCO2 >65 mm Hg (or) >60 mm Hg if arterial blood gas sample).
4. Intubation deemed necessary by the attending physician.

Did It Work?

Eureka! It seemed to work as 11 of 32 infants were intubated in the surfactant nebulisation group within 72 hours of birth vs.22 out of 32 infants receiving CPAP alone (RR (95% CI)=0.526 (0.292 to 0.950)). The reduction though was accounted for by the bigger babies in the 32 0/7 to 33 6/7 weeks group as only 1 of 11 was intubated when given nebulized surfactant compared to 10 of 13 managed with CPAP.  The duration of ventilation in the first 72 hours was not different between the groups: the median (range) 0 (0–62) hour for the nebulization group and 9 (0–64) hours for the control group (p=0.220).  It is important in seeing these results that the clinicians deciding whether infants should be intubated for surfactant administration were blind to the arm the infants were in.  All administration of curosurf via nebulization or sham procedures were done behind a screen.

The total number of infants randomized were 66 so they did fall shy of the necessary recruitment but since they did find a difference the results seem valid.  Importantly, there were no differences in complications although I can’t be totally confident there really is no risk as this study was grossly underpowered to look at rarer outcomes.

Breaking down the results

This study has me excited as what it shows is that “it kind of works“.  Why would larger babies be the ones to benefit the most?  My guess is that some but not a lot of surfactant administered via nebulization reaches the alveoli.  Infants with lesser degrees of surfactant deficiency (32 0/7 to 33 6/7) weeks might get just enough to manage without an endotracheal tube.  Those infants (in particular less than 32 0/7 weeks) who have more significant surfactant deficiency don’t get enough and therefore are intubated.  Supporting this notion is the overall delay in time to intubation in those who were intubated despite nebulization (11.6 hours in the nebulization group vs 4.9 hours in the control arm).  They likely received some deposition in the distal alveoli but not enough to completely stave off an endotracheal tube.

One concerning point from the study though had to do with the group of infants who were intubated despite nebulization of surfactant.  When you look at total duration of ventilation (hours) it was 14.6 (9.0–24.8) in the control arm vs 25.4 (14.6–42.2) p= 0.029*.  In other words infants who were intubated in the end spent about twice as long intubated as those who were intubated straight away.  Not a huge concern if you are born at 32 weeks or more but those additional thousands of positive pressure breaths are more worrisome as a risk for CLD down the road.

As it stands, if you had an infant who was 33 weeks and grunting with an FiO2 of 35% might you try this if you could get your hands on the nebulizer?  It appears to work so the only question is whether you are confident enough that the risk of such things as pneumothorax or IVH isn’t higher if intubation is delayed.  It will be interesting to see if this gets adopted at this point.

The future no doubt will see a refinement of the nebulizer and an attempt to see how well this technique works in infants below 29 weeks.  It is in this group though that prolonging time intubated would be more worrisome.  I don’t want to dismiss this outright as I see this as a pilot study that will lead the way for future work that will refine this technique.  If we get this right this would be really transformative to Neonatology and just might be the next big leap.