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 As a matter of fact I once tried thiopental as a single agent as a fellow (unpublished) which never saw the light of day due to difficulties with recruitment.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!
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.
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!
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.
Digesting this information it would seem that giving propofol prior to MIST may defeat the purpose of avoiding positive pressure ventilation as nearly all patients given propofol required nasal intermittent mandatory ventilation. As this is a small study we have to take the secondary outcomes with a grain of salt as the study would not have been powered to detect all these important outcomes such as IVH and pulmonary hemmorhage. Moreover the real question here would be whether BPD would be different between the groups but again not reported and even if it had been the numbers would be a little low to see a real difference.
The next steps I think will be to look at this question using medications such as atropine and fentanyl which I understand in other centres are in use. To do so though will require some pretty big numbers for enrolment. in the meantime what are we to do? Putting a catheter into the trachea I would think would be uncomfortable if not painful. Something should be given prior to the procedure but it is now on the research community to determine what that is and a what dose!
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.
The modern NICU is one that is full of patients on CPAP these days. As I have mentioned before, the opportunity to intubate is therefore becoming more and more rare is non-invasive pressure support becomes the mainstay of therapy. Even for those with established skills in placing an endotracheal tube, the number of times one gets to do this per year is certainly becoming fewer and fewer. Coming to the rescue is the promise of easier intubations by being able to visualize an airway on a screen using a video laryngoscope. The advantage to the user is that anyone who is watching can give you some great tips and armed with this knowledge you may be better able to determine how to adjust your approach.
For those of you who have followed the blog for some time, you will recall this is not the first time video laryngoscopy has come up. I have spoken about this before in Can Video Laryngoscopy Improve Trainee Success in Intubation. In that piece, the case was made that training residents how to intubate using a video laryngoscope (VL) improves their success rate. An additional question that one might ask though has to do with the quality of the intubation. What if you can place a tube using a video laryngoscope but the patient suffers in some way from having that piece of equipment in the mouth? Lucky for us some researchers from the Children’s Hospital of Philadelphia have completed a study that can help answer this additional question.
Video Laryngoscopy may work but does it cause more harm than good?
Using a video laryngoscope requires purchasing one first and they aren’t necessarily cheap. If they were to provide a better patient experience though the added cost might well be worth it. Pouppirt NR et al published Association Between Video Laryngoscopy and Adverse Tracheal Intubation-Associated Events in the Neonatal Care Unit. This study was a retrospective comparison of two groups; one having an intubation performed with a VL (n=161 or 20% of the group) and the other with a standard laryngoscope (644 or 80% of the group). The study relied on the use of the National Emergency Airway Registry for Neonates (NEAR4NEOs), which records all intubations from a number of centres using an online database and allows for analysis of many different aspects of intubations in neonates. In this case the data utilized though was from their centre only to minimize variation in premedication and practitioner experience.
Tracheal intubation adverse events (TIAEs) were subdivided into severe (cardiac arrest, esophageal intubation with delayed recognition, emesis with witnessed aspiration, hypotension requiring intervention (fluid and/or vasopressors), laryngospasm, malignant hyperthermia, pneumothorax/pneumomediastinum, or direct airway injury) vs non-severe (mainstem bronchial intubation, esophageal intubation with immediate recognition, emesis without aspiration, hypertension requiring therapy, epistaxis, lip trauma, gum or oral trauma, dysrhythmia, and pain and/or agitation requiring additional medication and causing a delay in intubation.
Looking at the patient characteristics and outcomes, some interesting findings emerge.
Patients who had the use of the VL were older and weighed more. They were more likely to have the VL used for airway obstruction than respiratory failure and importantly were also more likely to receive sedation/analgesia and paralysis. These researchers have also recently shown that the use of paralysis is associated with less TIAEs so one needs to bear this in mind when looking at the rates of TIAEs. There were a statistically significant difference in TIAEs of any type of 6% in the VL group to 19% in the traditional laryngoscopy arm but severe TIAEs showed not difference.
Given that several of the baseline characteristics might play a role in explaining why VL seemed superior in terms of minimizing risk of TIAEs by two thirds, the authors performed a multivariable analysis in which they took all factors that were different into account and then looked to see if there was still an effect of the VL despite these seemingly important differences. Interestingly, use of VL showed an Odds ratio of 0.43 (0.21,0.87 95% CI) in spite of these differences.
What does it mean?
Video laryngoscopy appears to make a difference to reducing the risk on TIAEs as an independent factor. The most common TIAE was esophageal intubation at 10% and reducing that is a good thing as it leads to fewer intubation attempts. This was also sen as the first attempt success was 63% in the VL group vs 44% in the other.
Now we need to acknowledge that this was not a randomized controlled trial so it could indeed be that there are other factors that the authors have not identified that led to improvements in TIAEs as well. What makes this study so robust though is the rigour with which the centre documents all of their intubations using such a detailed registry. By using one centre much of the variability in practice between units is eliminated so perhaps these results can be trusted. Would your centre achieve these same results? Maybe not but it would certainly be interesting to test drive one of these for a period of time see how it performs.