I knew it was a matter of time before a study looking at this strategy came out. Whether you intubate using INSURE or a LISA/MIST technique (passing a semi-rigid catheter through the vocal cords to give surfactant while a baby is on CPAP) there would have to be those that argue the placement of the laryngoscope blade in the mouth and passage of the catheter through the trachea must be uncomfortable. Given such concerns, why wouldn’t you want to provide some sedation to the patient? The main concern would be suppression of respiratory drive and need for intubation or PPV. LISA/MIST usage has been found in systematic reviews to lead to less risk of BPD but what if sedation leads to more PPV especially with uncontrolled tidal volumes on these fragile lungs? Will the benefits remain?
Propofol Before MIST
Dekker et al published Sedation during minimal invasive surfactant therapy: a randomised controlled trial in which they looked at infants receiving surfactant administration by MIST in infants born at 26 – 36 weeks with stratification of results into two groups (26–31+6 and 32–36+6 weeks). The intervention was to give a relatively small dose of propofol 1 mg/kg compared to the typical dose of 2.5 mg/kg prior to using MIST. Physicians were unblinded to the intervention but nurses were asked (they were blinded) to determine the COMFORTneo score as a measure of discomfort or pain. The primary outcome was the percentage of infants with a score <14 during the procedure. A power calculation to determine numbers needed for the study indicated 39 per arm and was based on a previous study (not using propofol though). While it does not appear that a sham was used for a placebo arm, sucrose was utilized for additional comfort in both arms.
The Results Please
Sedation seemed to work even at this lower dose of propofol as the group who received it had a higher percentage with a score <14 (32/42 (76%) vs 8/36 (22%), p<0.001). Moreover, the overall mean scores were also lower (12±3 vs 17±4; p<0.001). When looking at rates of complications though some interesting but perhaps not surprising findings emerge.
A greater risk of desaturation events existed in the group receiving even a low dose of propofol. Not surprisingly with a greater risk of oxygen desaturation there was a need for more nasal intermittent mechanical ventilation (93% vs 47%). Finally, while the numbers are small the incidence of grade 3 or 4 IVH was 0 in the group that received no sedation and 5% in the group that did. While non significant it is worth pointing out that as with all of the listed complications, this study was underpowered for any meaningful secondary outcome conclusions. Given what we know about the interaction of positive pressure ventilation and risks of IVH it is just something to raise an eyebrow at for now.
What is the biggest problem with the study?
As I see it the absence of the placebo group such that the Neonatologists knew who received propofol and who did not makes it difficult to know if there really was a true need for PPV. In the sedation group the percentage of babies that received nasal IMV almost matches perfectly those that experienced desaturation events (93 and 91%) but in the non-sedated group it was 47% and 69%. Were Neonatologists more apt to let the desaturations sit without PPV if they knew the infant did not get propofol and conversely assume they needed PPV if they received a sedative? It seems to me that the study would have been improved with the use of the sham procedure. The scoring by the nurses who were blinded shows that even with a lower dose of propofol than normal though it still provides some sedation.
I would stay tuned in this area as I am sure this will not be the last we hear of this but for now I would suggest that sedation for MIST/LISA should not be routinely done, at least based on this study.
A few years ago targeted echocardiography (or functional echo) became all the rage. As trainees in this field have become spread across this country and others it is natural that attention would turn to other deficiencies in Neonatology. The new thing on the block appears to be Neonatal Neurocritical Care with the concept being that building teams devoted to the pursuit of better neuro outcomes for babies is needed. I am not here to say otherwise but to acknowledge that this is a good thing for our field. Building a local expertise for such at risk infants is a wise plan as with anything if we focus and a small area and put lots of hours in you can only get better.
New CPS Statement
This past month the CPS released a new position statement entitled Neuroprotection from acute brain injury in preterm infants . As Chair of the committee and writer of this blog I thought it might be nice to point out the timely release of this statement. One of the authors Dr. Khorshid Mohammad was recently in Winnipeg for our POCUS workshop and spoke about neurocritical care for neonates as part of the meeting. I would encourage you to read through the new statement but wanted to point out a couple interesting recommendations that serve as a departure from practice (or at least my own).
Antenatal steroids should be given to those 34 0 – 34 6/7 weeks.
This is something that comes out of the literature that has looked more broadly at the group from 34 0/7 – 36 6/7 weeks. The recommendation really is an acknowledgement that if there is benefit it is likely coming from those infants just past the 34 week mark. Older infants may benefit but the numbers needed to treat are so high that it calls into question the real need for such treatment.
A new approach to treating hypotension
An approach that moves away from treating numbers is recommended. How many times have you been asked how low a blood pressure should be allowed to drift before starting inotropes? Evidence is mounting that early use of inotropes themselves is linked to IVH. A more nihilistic approach is favoured here by looking at measures of end organ impact before instituting such therapy. What is the urine output, perfusion and lactate should motivate treatment more than just the number itself. If you are fortunate enough to have targeted echocardiography at the ready it is recommended to utilize that modality to help guide your treatment as well.
I won’t go through the whole document as I would love for you to read it yourself and see how it may apply to your own centre. I think the statement is significant though in that it really does marshal in a new era in the field of neuroprotection. I am pleased that the CPS is taking a position on this and if you need any other guidance be sure to visit our webpage at the Fetus and Newborn Committee which can be found at:
To be sure there are fans of both HFNC and CPAP out there. I have often heard from other Neonatologists that they use HFNC and find positive results while other centres refuse to use it in favour of the tried and true CPAP. Turning to the literature you will find some conflicting results with some studies suggesting equity and others more recently favouring CPAP. There has been speculation as to why one would be superior to the other and now we appear to have some answers as to where the differences lie.
A Physiologic Study
Liew et al published Physiological effects of high-flow nasal cannula therapy in preterm infants this month in an elegant study of 40 infants. The study was fairly simple in design either randomizing infants <37 weeks to starting with nCPAP +6 and then transitioning to 8 l/min HFNC followed by stepwise reductions of 1 l/min until 2 l/min was reached or the reverse, starting with 2 l/min and working their way up and then transitioning to nCPAP+6. All infants were on one or the other modality at the start and were all at least 3 days old, they were randomized to one or the other arm regardless of where they started off. Physiologic measurements were taken at each step including the following:
Mv -Minute ventilation
pEEP – nasopharyngeal end-expiratory pressure
pEECO2 -nasopharyngeal end-expiratory CO2
RR – respiratory rate;
SpO2 – oxygen saturation
TCCO2 – transcutaneous CO2
Vt – tidal volume
A Fabian device was used to deliver either HFNC or CPAP at the different flows for all patients.
The authors certainly found some interesting results that I think shed some light on why comparisons of HFNC and CPAP have been so inconsistent.
Table 2 contains the results of the study and I will point out the main findings below.
1. Flow matters – Compared to nCPAP+6 which is fairly consistent flows below 6 l/min deliver pEEP that is below 6 cm H2O.
2. Keep the mouth shut – With CPAP whether the mouth is open or closed the Fabian device delivers +6 cm H2O. As you can see from the table, when the mouth is open transmitted pressures drop off substantially. The infant put on a flow of even 6-8 l/min of HFNC sees pressures less than +6 consistently.
3. As flows increase end expiratory CO2 decreases. HFNC seems to help wash out CO2
4. Low flow rates on HFNC do not seem to help with ventilation as much as higher flow rates. In order to maintain Mv these infants at 2 l/min flow become tachypneic. The low pressures produced likely cause some atelectasis and hence tachypnea.
Size matters! Beware of excessive pressures.
An additional finding of this study was that on “multiple linear regression, flow rate, mouth position, current weight and gestation but not prong-to-nares ratio significantly predicted pEEP and account for a significant amount of its variance (F(4431)=143.768, p<0.0001), R2=0.572, R2=adjusted 0.568).” Essentially, infants under 1000g in particular could see pEEP levels as high as 13 cm H2O with flows of 8 l/min. The variability in transmitted pressures with HFNC is shown nicely in this figure from the study.
As flows increase above 6 l/min the actual pressures delivered become less reliable.
Looking at this data, it becomes evident why HFNC may be failing in its attempt to dethrone nCPAP. In order to achieve higher pressures and provide comparable distending pressure to nCPAP you need higher flows. With higher flows though come the problem of greater variability in delivered pressure. While the average pressure delivered may be equivalent or even higher than a CPAP of +6, in some infants (especially those below 1000g) one may be delivering significantly higher pressures than intended which may help with oxygenation and preventing intubation but others may be seeing far less than needed.
What it comes down to is that nCPAP is better at delivering a consistent amount of pressure. Studies using lower flows of HFNC likely failed to show superiority to CPAP as they just didn’t deliver enough pressure. An example of this was the study by Roberts CT et al Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants, in which flows of 6-8 l/min were used. Other studies using higher pressures could have been problematic due to open mouths, or larger babies not receiving as much benefit.
I am not saying that we should throw out HFNC entirely however. Depending on the unit you practice in you might not be able to use CPAP but HFNC may be allowed. If you had to choose between no support or HFNC I would likely go with the HFNC. For me at least, if I want to delivery reliable pressures in my tertiary care NICU I will be calling for the CPAP.
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.
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
(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
(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
(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.
This post has the potential to be polarizing as sustained inflations while common as an approach after delivery in Europe has not been widely adopted in Canada and the United States. Some time ago I wrote about sustained inflations and a reader commented that I should wait for the results of the The Sustained Aeration for Infant Lungs (SAIL) trial before forming a final opinion on whether this is a good strategy or not. The previous blog post on this topic was Is It Time To Use Sustained Lung Inflation in NRP? and was followed by Is expired CO2 the key to making sustained inflation a standard in resuscitation? The first post concluded that there was a concerning trend towards more IVH in those who received sustained inflations (SI) while the second showed both a reduction in BPD and duration of mechanical ventilation with this approach. I suggested that maybe we were really onto something here and then I was asked to wait before coming to a conclusion until the SAIL trial was done. Well that day has come.
The SAIL trial
This trial led by Dr. H. Kirpalani and involving 18 NICUs in 9 countries was a big endeavour. The paper was just published and is entitled Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants The SAIL Randomized Clinical Trial. The trial compared SI of 15 seconds at a peak pressure of 20 cmH2O, followed if needed by a second SI of 15 seconds
at a peak of 25 cmH2O to traditional PPV for infants who after initial 30 seconds of CPAP required further intervention to establish breathing. These were provided via facemask or nasopharyngeal tune attached to a t-piece resuscitator. In both groups after the initial intervention standard resuscitation steps were carried out. The primary outcome was death or BPD at 36 weeks PMA. A data safety monitoring board (DSMB) was formed as well and it is this group that became very important to the conclusions of the study and led to its early termination. All infants were 23 weeks 0 days’ to 26 weeks 6 days’ GA. Before the study was terminated the final totals were 215 patients in the SI arm and 211 in the traditional PPV group.
The trial was stopped after the DSMB identified an excessive number of early deaths within 48 hours in the SI group. The findings were “11 of 16 early deaths in the sustained inflation group vs 1 of 3 in the standard
resuscitation group were considered possibly related to allocation group”. A number of these deaths occurred in the highest risk group of those born at 23-24 weeks but it was enough to stop recruitment.
With respect to the primary outcome the results showed no difference between the two approaches. In saying this however, if the study did not recruit enough patients as planned to demonstrate a difference one has to question whether the study had enough power to find a benefit.
To answer this question the authors performed a Bayesian Analysis to determine the probability that adding more patients would have led to a different conclusion. That is to determine if they would have found a difference favouring SI. In the end they found that their conclusions would not have changed. Sustained inflations in infants from 23 weeks 0 days’ to 26 weeks 6 days’ GA do not confer a benefit and may be associated with a higher likelihood of death within 48 hours of birth.
What do we do with these results?
I think this is it. I can’t see a research ethics board allowing another study at this point. This by neonatal standards was a big study given the relative scarcity of infants at these gestational ages. The fact that no difference was found in rates of death or survival with BPD for those at highest risk of these outcomes suggests to me that looking at older GA at birth will not produce different results. Sustained inflation to establish FRC and initiate respiration was a good concept backed by animal research. Moreover, clinical work out of Edmonton in recent years suggested potential benefits but with the publication of this study I suspect we will need as a neonatal community to look at other strategies to decrease rates of BPD. Concerns over increased risk of death in my opinion mean this ship has SAILed,