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?
Surfactant administration is a frequent topic on this blog and as I look over the last five years there has been an evolution with its administration from InSure to LISA/MIST and even pharyngeal surfactant through an LMA. We have also discussed aerosolization of surfactant once and now a much larger trial is out that brings this technique which has to be the least invasive into the limelight. What gives me great pleasure is being able to highlight the article here Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial as the lead author is our CPS Fetus and Newborn Committee American of Pediatrics liaison Dr. James Cummings. Being able to review an article by a colleague and friend I think is always something that gives me some trepidation as what happens if the article is a poor one but in this case I feel pretty safe. The study was done by a large group of investigators known as the AERO-02 group and there are lots of gems to pick apart here.
On to the Study
This trial involving 22 NICUs enrolled Among 457 infants born with a GA from 23 to 41 (median 33) weeks and birth weight 595 to 4802 (median 1960) grams. In total, 230 infants were randomly assigned to aerosol; 225 received 334 treatments, starting at a median of 5 hours. The study allowed for repeat dosing of aerosolized surfactant up to 3 times with each treatment providing 6 mL/kg of 35 mg/mL calfactant suspension, 210 mg phospholipids/kg body weight, through a modified Solarys nebulizer shown below. The delivery device was like an inverted nipple placed in the mouth in order to deliver surfactant while the infant was on non-invasive support (CPAP, hi-flow or NIPPV).
From prior animal studies use of this method is thought to deliver approximately (14%), the surfactant dose used in or about 29 mg/kg reaching the distal alveolar bed. By allowing up to three treatments in 72 hours (there had to be a reduction in FiO2 with each treatment to allow a further one) the total delivered would be aboout 90 mg/kg although in some likely more and others less depending on depostion amounts. The study originally was planned as two cohorts but since they enrolled all in the first the second one was not used. The first cohort were:
2. had not previously received surfactant, 3. Between 1 hour to 12 hours of age,
4. Suspected or confirmed RDS requiring therapeutic administration of nasal respiratory support by nCPAP, HFNC, or NIPPV
5. Initially, there was an entry requirement FIO2 concentration of 0.25 to 0.40. Four months into the trial, it was discovered that several sites were using higher positive airway pressures to minimize FIO2. Because of this practice change, the minimum FIO2 requirement was removed in the fifth month of the trial
The trial was a pragmatic one where the authors did not specify what criteria were needed to decide when to intubate for surfactant. While this lack of standardization might turn some people off, many trials are headed this way as it represents “real life”. In other trials where you have rigid criteria if your own centre doesn’t typically use them the results of the trial in the end might just not apply. The question then is did this style of trial design in the end find a difference in outcome for the babies randomized to aerosolization or standard care with CPAP, HFNC or NIPPV to avoid intubation?
The trial met its number of patients required in the power calculation to find a difference in outcome. Demographics, receipt of antenatal steroids and levels of respiratory support at baseline were similar between groups. In the aerosol group. 225 infants received 334 treatments at a median age of 5 hours (interquartile range [IQR]: 3–7);149 (66%) received only one aerosol treatment, 43 (19%) received 2 treatments, and 33 (15%) received 3 treatments. It is also important to note that by defining the entry point of 1-12 hours of age, those with severe RDS would not have been enrolled here. Infants with apnea, or severe distress would not have been able to wait the hour time frame for entry and moreover since the aerosolization technique takes about an hour to administer those in need of urgent treatment would not be enrolled. As such we are really talking here about babies with mild to moderate RDS.
Intubation for surfactant occurred in 113 infants (50%) in the control group and 59 infants (26%) in the aerosol group, in an intent-to-treat analysis (P , .0001); RR: 0.51 (90% CI: 0.41–0.63). The number needed to treat to prevent 1 intubation is 5.
The impact of this approach was quite significant. Interestingly you would think that as GA decreased the effectiveness of the intervention would lessen but when the authors groups GA into two week brackets as shown below the only GA bracket that showed no difference in approach was the 23/24 week group. Having said that the numbers are very small on the lower end of GA for the study but again overall the results find a 50% reduction in need for intubation using this technique with the trend (by my eye) being that as GA increases the effectiveness seems to get even better.
The study was not blinded and as such the authors also took the time to look for evidence of bias in the study and found none. The last figure to show is the effect of this intervention on total duration of respiratory support between the two randomized groups. In other words while the use of the technique reduced your likelihood of intubation by 50% it didn’t get you off of non-invasive support any faster in the 72 hours after treatment.
Looking at complication rates between groups there was no difference as well.
I think what has been shown here is that aerosolized surfactant in a real world research model is safe and effective for mild to moderate RDS in reducing the need for intubation. For those infants with more significant RDS or severe apnea they will not be able to make it long enough to get these treatments. For others this does seem like something worth exploring as for those that you were going to commit to a non-invasive approach is there really any harm? There will be those that will fail but overall this data suggests that you could expect a 50% reduction in this occurrence for all your patients with mild to moderate RDS. The one fly in the ointment I see that could influence the effectiveness of this intervention is the level of support you are accustomed to using in your centre. It could be in those centres that are a bit “peepaphobic” and use a maximum of +5 or +6 on CPAP this intervention could be quite effective but in those that are willing to use +7or +8 the rate of intubation or surfactant might well be less. Regardless the intervention appears to be safe, well tolerated and can make a difference. If a delivery device could be prepared that increased deposition rates to even higher levels imagine how effective it just might be.
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!
The Canadian Pediatric Society has a statement on the use of premedication before non-emergent intubation which was written in 2011 and reaffirmed in 2018. After reviewing available medications for use the recommended strategy was atropine, fentanyl and succinylcholine. This combination does involve three different medications, the first being to prevent bradycardia, the second to sedate and the third to paralyze. With the use of three medications however there is always room for error so it is very alluring to try and use one medication to provide optimal conditions for intubation. As a matter of fact I once tried thiopental as a single agent as a fellow (unpublished) which never saw the light of day due to difficulties with recruitment. Nonetheless I was after a simpler solution to providing good conditions for intubation so it is not surprising that others are also looking at single agents as well.
Propofol Would Seem Like a Good Contender
Propofol has been used in the adult and Pediatric world for some time. It causes a decreased level of conciousness and amnesia surrounding the events for which it was given. It is short acting often wearing off within minutes which would seem perfect for procedural sedation. On the downside one of its side effects is hypotension so in a fragile neonate this might be something to be watch for.
Dose finding study
de Kort et al published Propofol for endotracheal intubation in neonates: a dose-finding trial this month. It is an interesting study design for those unfamiliar with dose finding studies. The goal was to begin with a low but starting dose for propofol at 1 mg/kg/dose and escalate by 0.5 mg/kg/dose until adequate sedation was reached WITHOUT signficant adverse side effects. Moreover the authors built on previous work in this area to attempt to break the patients into 8 groups as shown in this figure.
All patients were less than 28 days so allocation was based on gestational age and whether a patient was greater or less than 10 days of age at dosing. Level of intubation readiness was evaluated using a standardized tool called the Intubation Readiness Score.
Side effects were hypotension, myoclonus, chest wall rigidity, persistent respiratory and/or circulatory failure and bronchospasm. Blood pressure was assessed via an indwelling catheter if available or by cuff if not available. Importantly any mean blood pressure after provision of propofol less than the gestational age met the criteria for declaring hypotension.
The study was terminated early due to low inclusion in some groups after 91 total patients had been enrolled. In the end there were only enough patients in Groups 3 (26 – 29 weeks and <10 days) and 5 (30 – 36 weeks and < 10 days) enrolled to analyze fully. The results of the dose finding analysis are shown below.
Walking through group 3, there were 5 patients enrolled at the 1 mg/kg level and based on poor levels of sedation in all the dosing for next 5 were increased to 1.5 mg/kg. As intubating conditions improved, the authors found that at a dose of 2 mg/kg while conditions were optimal, hypotension became a significant problem with 59% being hypotensive. The management of hypotension included 54% needing volume resuscitation and inotropes in 10%. Curiously the hypotension often did not appear until 2 hours or more after drug delivery. When the authors did a step down to 1.75 mg/kg as a intubation dose they found it was inadequate for providing good conditions for intubation albeit with less hypotension.
Not the right drug
The goal of this study was to find the optimal dose that provided good intubation conditions without significant side effects. The strength of this study was that it included babies across a wide range of gestational ages from 26+0 to 36+6 weeks gestational age. While the authors were unable to recruit enough patients to fill each group the stoppage of the study made sense as it was clear that the goal of the study would not be met. Propofol would be a great single agent if it weren’t for the issues found in this study. This is not to say that the drug is a poor choice for Pediatrics but in the Neonatal world I just don’t think it has a place. I would welcome further testing on other single agent drugs but that of course is an analysis for another post!
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.