I have reviewed many articles on this site in the last few years. My favourite pieces are ones in which I know the authors and I have to say my ultimate favourite is when I know the authors as colleagues. Such is the case this time around and it pertains to a topic that is not without controversy. Nasal High Frequency Oscillatory Ventilation or NHFOV for short is a form of non-invasive ventilation that claims to be able to prevent reintubation whether used prophylactically (extubation directly to NHFOV) or as a rescue (failing CPAP so use NHFOV instead of intubation). I have written about the topic before in the piece Can Nasal High Frequency Ventilation Prevent Reintubations? but this time around the publication we are looking at is from my own centre!
One of our former fellows who then worked with us for a period of time Dr. Yaser Ali decided to review our experience with NHFOV in the paper Noninvasive High-Frequency Oscillatory Ventilation: A Retrospective Chart Review. Not only is one of our fellows behind this paper but an additional former fellow and current employee Dr. Ebtihal Ali and two of my wonderful colleagues Dr. Molly Seshia and Dr. Ruben Alvaro who both taught be a few things about this chosen career of mine.
The study involved our experience with using this technique (Draeger VN500 providing HFOV through first a RAM cannulae and then later with the FlexiTrunk Midline Interface (FlexiTrunk Midline Interface, Fisher & Paykel Healthcare) either using a prophylactic or rescue approach. The settings were standardized in both approaches as follows.
• Frequency of 6 to 8 Hz. • Mean airway pressure (MAP)2 cmH2Oabove the MAP of invasive ventilation (whether conventional or high-frequency ventilation). • Amplitude to achieve adequate chest oscillation while at rest.
• Frequency of 6 to 8 Hz. • MAP 1 to 2 cm H2O higher than positive end expiratory pressure (PEEP) on CPAP or biphasic CPAP. • Amplitude to achieve adequate chest oscillation while at rest.
All in all there were 32 occasions for 27 patients in which prophylaxis was used in 10 and rescue in 22. In the rescue group 77% of the time transfer onto NHFOV was done due to apneic events. The study was retrospective and lacked a control group as such so when it comes to the prophylactic approach it is impossible to know how many of these babies would have done fine with CPAP or Biphasic CPAP. Having said that, in that arm the intervention was successful in keeping babies extubated for at least 72 hours in 6/10. Since I really don’t know if those same babies would have done just as well with CPAP I will stop the discussion about them now.
The Rescue Group
These infants were on a fair bit of support though prior to going on to HFNOV with a mean SD CPAP of 7.9 cm H2O; while for the biphasic CPAP, the levels were 10.2 cm H2O and 7.7 cm H2O. In the rescue group 73% of the infants did not get intubated.
Let’s Process This For A Minute
I think most of you would agree that an infant on CPAP of +8 or NIPPV who is having repetitive apnea or significant desaturations would inevitably be intubated. In three quarters of these patients they were not but I can assure you they would have been if we had not implemented this treatment. When you look at the whole cohort including prophylactic and rescue you can see that the only real difference in the babies were that the ones who were on lower MAP before going onto NHFOV were more likely to fail.
Interestingly, looking at the effect on apnea frequency there was a very significant reduction in events with NHFOV while FiO2 trended lower (possibly due to the higher MAP that is typically used by 1-2 cm H2O) and pCO2 remained the same.
If pCO2 is no different how does this treatment work if the results are to be believed? Although high frequency ventilation is known for working well to clear CO2 I don’t think when given via this nasal interface it does much in that regard. It may be that the oscillations mostly die out in the nasopharynx. I have often wondered though if the agitation and higher mean airway pressures are responsible compared to straight CPAP or biphasic CPAP alone. There is something going on though as it is hard to argue with the results in our centre that in those who would have been otherwise intubated they avoided this outcome. You could argue I suppose since the study was not blinded that we were willing to ride it out if we believe that NHFOV is superior and will save the day but the information in Table 3 suggests that the babies on this modality truly had a reduction in apnea and I suspect had the sample size been larger we would have seen a reduction that was significant in FiO2.
My thoughts on this therefore is that while I can’t profess that a prophylactic approach after extubation would be any better than going straight to CPAP, I do wonder if NHFOV is something that we should have in our toolkits to deal with the baby who seems to need reintubation due to rising FiO2 and/or apnea frequency. What may need to be looked at prospectively though is a comparison between higher pressures using CPAP and NHFOV. If you were to use CPAP pressures of +10, +11 or +12 and reach equivalent pressures to NHFOV would these advantages disappear?
If you work in Neonatology you no doubt have listened to people talk in rounds or at other educational sessions about the importance of opening the lung. Many units in the past were what you might call “peepaphobic” but over time and with improvements in technology many centers are adopting an attitude that you use enough PEEP to open the lung. There are some caveats to this of course such as there being upper limits to what units are comfortable and not just relying on PEEP but adding in surfactant when necessary to improve pulmonary compliance.
When we think about giving nitric oxide the importance of opening the lung can’t be stressed enough. I have heard it said many times when a baby has been found to be a “non responder” to inhaled nitric oxide that they may have been so because the lung wasn’t open. What we mean by this is that the distal alveoli are open. One can administer all the iNO in the world but if the majority of alveoli are collapsed the drug can’t get to the pulmonary vasculature and cause the pulmonary vasodilation that is so sorely needed in the presence of hypoxemic respiratory failure. Surfactant and inhaled nitric oxide in the presence of hypoxemic respiratory failure could be a great combo as one would help open the alveoli and then the iNO could address any pulmonary vasoconstriction which might be exacerbating the hypoxemic state.
Study Tests This Theory
Researchers in Chile led by Gonzalez A published Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial in the Journal of Perinatology. The concept of this study was to compare in a double blind RCT for 100 patients (based on a power calculation looking for a 25% reduction in treatment failure) whether provision of surfactant as up to 2 doses and iNO would be better than just iNO alone. Included infants needed an oxygenation index (OI = MAPXFiO2/pO2) of 20 or more to qualify and treatment failure was an OI of 40 or more. The patients recruited were similar in common characteristics including types of conditions that would benefit from iNO. RDS, meconium aspiration syndrome and pneumonia certainly have been shown to benefit from surfactant before while in the PPHN category that is questionable. In order to ensure that it was not just the primary disease but pulmonary hypertension that was present as well, all patients required confirmation of pulmonary hypertension prior to enrollment via ECHO with either a TR jet indicating a pulmonary pressure at least 2/3 of systemic or right to left shunting at the ductal or atrial level.
The results of the study demonstrated a clear difference in the primary outcome.
Patients receiving the combination of surfactant prior to starting iNO showed a faster reduction in OI than those receiving iNO alone. In fact the reduction in primary outcome of treatment failure was over 50% different while the power calculation had been based on only a 25% difference. That’s ok as this means there were more than enough patients to demonstrate a difference. As a secondary outcome the rate of ECMO or death was also different between the groups favouring use of surfactant.
It works so now what?
Who doesn’t like seeing a study that confirms what you have long believed. I feel that this study validates the teaching I received throughout the years about ensuring the lung is open before giving iNO. There are some caveats to this however. About 90% of the patients studied had conditions present (RDS, MAS, pneumonia) for which surfactant would have been indicated anyway. If this study had been done let’s say in patients with asphyxia induced pulmonary hypertension and clear lungs the surfactant may have made no difference as the lungs were already open. I mention this as I don’t think readers of this analysis need to jump to the conclusion that every time there is a patient with PPHN that you MUST give surfactant. What I think this illustrates though is the importance of first asking the question if iNO is being considered “Have I opened the lungs?”. The next time you encounter such a patient consider whether you are using enough PEEP and whether surfactant is indicated. The bottom line is if the lung isn’t open then all the iNO in the world isn’t going to make much difference!
I doubt there is a unit in the world where at least once a day a discussion ensues about whether an infant is ready to wean or come off their CPAP. For many years we have made the decision based on a variety of markers. Some people would comment on the work of breathing, others on the FiO2 or what the oxygen saturations are at the moment as we round on the patient. Our unit has been pulling oxygen histograms off the patient monitor for years now to provide a more objective measurement to determine if an infant is ready or not. What is a histogram? It is a bar graph representation of the percentage of time in a 24 hour period that an infant has spent in several different oxygen saturation ranges.
They looked at 36 babies (24 control and 12 cases) in which controls were babies who successfully weaned off CPAP when on less than or equal to 30% oxygen in the first week of life and compared them to infants who failed and had to go back on. Success was defined as remaining off CPAP for 7 consecutive days while failure was having to go back on with in 7 days of discontinuation. All infants were <1250g at birth or less then or equal to 30 weeks gestational age at delivery. Infants were enrolled prospectively in an observational case-control study. During the study goal oxygen saturations were 90-95% and oxygen histograms were monitored q6h by respiratory therapists. Importantly, during the study there was no standard approach to weaning patients off of CPAP but as per many NICUs, discontinuation occurred when FiO2 was low and there were only 1-2 events per day requiring stimulation. The authors controlled for a number of potential factors which could influence success such as GA, BW, Sex, receipt of antenatal steroids, ventilation, caffeine dose, FiO2 prior to weaning and surfactant but found no differences between groups.
What did they find though?
As you might expect there was a difference found and it was in the histograms. The infants who ultimately succeeded in coming off CPAP were better oxygenated in the 24 hours prior to coming off CPAP. Of note, the cases had a median FiO2 of 22% and the controls 21% which was not statistically different.
Looking at the above figure you can see that there were statistically significant differences in the two groups with the babies who successfully weaned off CPAP having significantly higher levels of oxygen saturation in the 95% and above ranges. The authors concluded “The optimal value of oxygen saturation achievement >95% to predict CPAP-weaning success by Youden index was 31.6% with a sensitivity of 75% and specificity of 75%.”
In other words if you have about 30% of the time spent above 95% in the 24 hours prior to coming off CPAP you have a pretty good chance of success!
Applying the information
Who doesn’t like a study that validates your own practice?! The study is really a beginning though as the study tells us that for babies that are mildly ill (as evidenced by being on room air or 22%) that you can utilize the histogram data to make decisions about when it is best to stop CPAP. What this study though examined is a particular population of small infants who were all taken off CPAP in the first week of life. Would the same principals apply to an older infant or one who is larger at birth? I would like to think so but there are many infants who are on oxygen with BPD who are also weaning off CPAP after many weeks of age. We use histograms in this population as well to guide our weaning but an important measurement that must be taken into account is the FiO2. I can really manipulate a histogram to show anything I want for a baby on oxygen. If it is better from one day to the next is it because the lungs have improved or has the average FiO2 simply been higher in the preceding 24 hours? Conversely if it is worse does the infant have atelectasis or pneumonia or has nursing been more restrictive in FiO2?
Further studies in this area need to create an objective tool that takes into account level of support and mean FiO2 when interpreting the histogram. Failure to do so would lead at times to incorrect decisions if you solely look at a bar graph. As with everything in NICU, the devil is in the details!
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.
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.
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?!
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.