This post is special to me. A redemption of sorts. When I was a fellow in Edmonton in the early 2000s my fellowship project was to see whether heliox (helium/oxygen) given to piglets with meconium aspiration syndrome (MAS) would improve ventilation and measures of pulmonary hypertension vs controls. Why heliox? There had been work done with this gas for other conditions and the lower viscosity of the gas (who hasn’t sucked on a helium balloon to see the effect of helium) means that the flow of the gas in a tube is more linear that regular air. Turbulent flow as with air/oxygen mixtures creates more resistance to flow than linear flow with heliox. Imagine if you will this linear flow slipping more easily past particles of meconium partially blocking airways and you get the idea of why heliox might work. One thing to bear in mind though is that as your FiO2 goes up the percentage of helium drops so the properties described work best at low FiO2 so flow is more linear.
I collected meconium from diapers in the NICU and created a NS slurry of meconium and then instilled it into the trachea’s of these piglets through a tracheostomy (they were too small to intubate for me at least). A flow probe was put around the pulmonary artery to look for evidence of pulmonary hypertension. We saw some interesting trends but the paper never saw the light of day for a variety of reasons that I won’t go in to here. Originally I had wanted to do the study as a small RCT in humans but I was advised that although heliox is an inert gas I should do the animal study first. That was the end of the heliox story as far as I was concerned as I hadn’t thought much about it since that time. I will admit though that anytime I had a baby with bad meconium aspiration syndrome though the thought did pop into my head.
The Study Has Arrived
Imagine my surprise when this week an RCT from China entitled A randomized single‐center controlled trial of synchronized intermittent mandatory ventilation with heliox in newborn infants with meconium aspiration syndrome came across my inbox. The authors used a power calculation based on some previous work in RDS using heliox to determine they needed 28 neonates in each arm to show a difference. In the end they managed 71 total with 35 in the heliox and 36 in the control arm. Inclusion criteria were a diagnosis of MAS on x-ray, GA ≥37 weeks and ≤42 weeks, need for intubation due to a pH <7.2/PCO2 >60 mmHg. The study could not be blinded as one would not be able to hide the large tanks for heliox so for any study like this it would be unavoidable. One thing that differs in terms of management from my own practice is that the authors in this study used SIMV pressure limited ventilation as the ventilatory strategy as opposed to AC/VG that my unit would typically use. Initial ventilator PIP of 15–28 cmH2O, PEEP of 4–10 cmH2O, and RR of 15–45 breaths/min; FiO2 of 0.21 to 1 to reach the target oxygen saturation (SpO2) of 90%–95%. The intervention group received heliox for 6 hours and then switched over to air/oxygen while the control group was ventilated with air/oxygen from the start. The extubation criteria included PIP ≤15 cmH2O, gradually enhanced effective spontaneous breathing, a ventilator breathing frequency ≤10/min, and normal blood gas analysis results. The main outcomes were PaO2/FiO2 (P/F), the extubation time and the hospital length of stay in the NICU. Aside from measuring the ventilatory responses and time of extubation the authors also examined the effect of heliox as an anti-inflammatory agent based on previous results demonstrating markers of inflammation can be attenuated by use of the gas.
The Results
To start with, the babies in both arms were equivalent at the start of the study in terms of inflammatory markers and some clinical variables.
As you will see from the following figures a number of important findings are noted. The main marker of oxygenation used for this study was the PaO2/FiO2 ratio and this was statistically different (301 ± 22 vs. 260.64 ± 24.83, p < .001). Secondly, extubation time (78 ± 30 vs. 114 ± 28.07, p < .001 and length of hospital stay in days were also shorter 15.3 ± 4.2 vs. 19.11 ± 4.01, p < .001.
The authors state that the following markers of pO2, pH and pCO2 shown in the graphs were all significantly improved in the heliox group but looking at the first two I find that hard to believe as the curves look almost superimposed. pCO2 however could be different in particular given the linear flow described above so ventilation might be improved.
Finally, across the board, markers of inflammation were noted to improve with administration of heliox as well as markers of myocardial injury. The gas may have done what it was supposed to do.
I wish the conclusions were that easy
I want to like this paper so badly. Sadly, I have some pretty significant reservations. It is helpful to see that the two groups began at a similar PaO2/FiO2 ratio. What is missing though is the ventilatory requirements to get to that point. There is no information provided as to the mean airway pressures or PIP/PEEP for each group over time to get a sense of whether the two groups in terms of severity of illness were the same. Yes we know that the inflammatory markers at the start were similar but could the difference in changes of inflammation relate to a progressive rise in the control group that were just sicker rather than a protective effect of heliox to reduce inflammation? Also when one looks at the change in pCO2 how do you interpret that without knowing the minute ventilation to achieve those data points? It is really unfortunate that the authors did not use oxygenation index (MAP X FiO2/PaO2) as this would have taken the ventilation component at least into account. Would be helpful as well to know the weaning strategy in each group as without blinding might the authors have reacted more aggresively with weaning of the ventilator to get to extubatable settings knowing that the babies were receiving the intervention. As there was no weaning strategy planned out from the start we can only guess. Lastly, one could have possibly gotten around the inability to hide the heliox tanks by having a Neonatologist not on service take each blood gas data and sight unseen suggest changes to ventilation without being able to see which arm a baby was in.
I will end on a positive note though. It has been almost twenty years since I did the piglet study using heliox. I had always hoped that this research would see the light of day in a human model although my piglet data didn’t show much benefit however the intervention was shorter than this study. I think this study is worthy of being repeated using a different mode of ventilation that does not rely on manual changes to PIP but rather by using a VG mode the baby would be gradually weaned as compliance improves. Any further study needs to address differences that were missing from this paper as well. I don’t think this is the last we will see of heliox and I look forward to seeing another paper although if it takes another twenty years I may be out of this line of work.
With American Thanksgiving coming up this weekend a post about “cold turkey” seemed apropos. You can’t work in Neonatology and not be familiar with CPAP. We have learned much about this modality in the last couple decades as clinicians have moved more and more towards non-invasive support as the preferred strategy for supporting newborns regardless of gestational age. Ask a Neonatologist how they use CPAP and you will find varied opinions about how high to go and how quickly to wean. I have written about one weaning strategy before on this blog using monitor oxygen saturation histogram data to make such decisions Improve your success rate in weaning from CPAP. One question though that has often been asked is what level of CPAP is best to remove a baby from? In particular for our smallest infants who may have BPD or reduced pulmonary reserve due to lower numbers of alveoli as they continue to develop should you discontinue at +5, +4 or +3? This question is what some creative authors from Texas sought to answer in the paper being discussed today.
To Wean or Not To Wean?
Kakkilaya V et al published Discontinuing Nasal Continuous Positive Airway Pressure in Infants ≤32 Weeks Gestational Age: A Randomized Control Trial in the Journal of Pediatrics this October. The authors studied infants from 23+0 to 32+6 weeks gestational age at birth and looked at whether a strategy of discontinuing from +5 or weaning from +5 to +3 then stopping resulted in fewer failures from stoppage. Infants were recruited in two ways. Some infants were intubated with planned extubation to pressures from +5 to +8 while others were on CPAP always. The study included 226 infants or which 116 were assigned to control so had removal of CPAP at +5 if after 24 hours they met the stability criteria below. The other 110 infants reduced CPAP from +5 once every 24 hours if the same criteria were met. Reasons for restarting CPAP were also as shown below at the bottom of Table 1. If an infant failed then they went back to the level of CPAP they had been on previously when stability criteria were met. Once they had stability criteria at that level again for 24 hours the wean could resume.
Did they manage to find a difference?
Table 5 reveals the significant finding here which is that for the primary outcome there was no difference and it didn’t matter whether the infants were ventilated or not. One finding that was different was the number of neonates who failed to stop CPAP two or more times. This favoured the weaning approach. Aside from that the groups were comparable and there really wasn’t much benefit seen from one approach versus the other.
Thoughts About the Study
The study was a fairly straightforward one and although there wasn’t a significant result found there are some questions that I think we can think about.
The stability criteria did not have results from histogram analysis included as a measure of stability. I can’t help but wonder if addition of this approach would have identified some infants who were actually not ready to wean. Having said that, one challenge is to come to an agreement on what a stable histogram is. Based on a survey from my own colleagues recently I would say like many things in Neonatology, we are all over the map. If this study were to be repeated using histograms for decisions on weaning some sort of agreement would be needed on what qualifies as a stable histogram.
Our group has already tended to use +4 as the final weaning step for our ELBW and VLBW infants based on anecdotal experience that many of these kids if stopped at +5 will fail even when they seem to be stable. Repeating this study looking at weaning from +4 to +3 before stopping vs stopping at +4 could be interesting as well.
Finally, I do wonder if the wean was too fast to show a difference. It is not uncommon practice in the smallest infants to keep them on +4 for a couple days even if it seems that the histograms would indicate the baby is ready to stop CPAP. Perhaps a weaning strategy of allowing a minimum of q48h instead of q24h would have found different results?
I do think the authors explored a great question and I would be reluctant here to “throw the baby out with the bathwater”. There is something here but based on the methodology (which I don’t think is flawed per se) I think they just couldn’t prove what I suspect is true.
Knowing when to extubate an ELBW is never an easy task. Much has been written about extubation checklists including such measures as mean airway pressure minimums and oxygen thresholds as well as trials of pressure support at low rates. The fact remains that no matter how hard we try there are those that fail even when all conditions seem to be met for success. The main culprit has been thought to be weakening of the diaphragm as the infant stays on the ventilator for longer periods of time. Specifically, myofibrillar contractile dysfunction and myofilament protein loss are what is occurring leading to a weakened diaphragm which may be incapable of supporting the infant when extubated even to CPAP. More recently in Neonatology the use of point of care ultrasound (POCUS) has gained in popularity and specifically use of lung ultrasound has helped to better classify various disease conditions not only in determining which disease is active but also following its course. Using POCUS to measure thickness and excursion of the diaphragm has been employed in the adult world so using it in neonates to determine extubation readiness seems like a logical next step.
An Observational Cohort Study
Bahgat E et al published Sonographic evaluation of diaphragmatic thickness and excursion as a predictor for successful extubation in mechanically ventilated preterm infants in the European Journal of Pediatrics. This small study sought to look at preterm infants born under 32 weeks and assessed a number of measurements of their diaphragm bilaterally including thickness of both during the respiratory cycle and the excursion (measured as most caudad and cephalad position during respiration). All patients underwent a similar process prior to extubation using PSV with a support of +4 over peep with measurements taken 1 hour prior to planned extubation. All infants met unit criteria for a trial of extubation based on blood gases, FiO2 and MAP being less than 8 cm H2O. All infants received a PSV trial for 2 hours before being extubated to CPAP +5. The sonographic assessment technique is laid out in the paper and the study end point was no reintubation in the 72 hours after extubation. The decision to reintubate was standardized as follows: more than six episodes of apnea requiring stimulation within 6 h, or more than one significant episode of apnea requiring bag and mask ventilation, respiratory acidosis (PaCO2 > 65 mmHg and pH < 7.25) or FiO2 > 60% to maintain saturation in the target range (90–95%).
Differences between the groups at baseline included a longer median day of extubation by 3 days, total duration of mechanical ventilation, higher mean airway pressure and FiO2 all in in the failure group.
Results of the study find a key difference in measurements
Looking at table 2 below the main finding of the study was that the biggest difference between those infants who succeeded and those that failed was the excursion of the diaphragm rather than the thickness. The greater the excursion the better the chance at successful extubation. In experienced hands the measurement does not take that long to do either.
As the authors point out in the paper:
“A right hemidiaphragmatic excursion of 2.75 mm was associated with 94% sensitivity and 89% specificity in predicting successful extubation. A left hemidiaphragmatic excursion of 2.45mmwas associated with 94% sensitivity and 89% specificity in predicting successful extubation”
Is this the holy grail?
There is no question that this technique adds another piece to the puzzle in helping us determine when it is safe to extubate. If I can pick one fault with the study it is the use of a pressure of +5 to support the extubated infants. If you look at the mean level of MAP the infants were on prior to extubation in the two groups it was 6.3 in the successful group and 6.6 in those who failed. By choosing to extubate the group that was already on a mean of about 24% to an even lower pressure level I can’t help but wonder what the results would have looked like if extubation occurred at a non-invasive level above that when they were intubated. Our unit would typically choose a level of +7 to extubate such infants to and avoid pulmonary volume loss so what would the results show if higher pressures were used (someone feel free to take this on).
One thing though that is borne out of all this however is that if diaphragmatic weakening happens in the neonate with prolonged ventilation as well it would be supported by the long length of ventilation in the failure group that also has less diaphragmatic thickness and excursion. What this study in my mind really says is that extubation should occur as early as possible. Every time you hear someone say “why don’t we wait one more day” you can now imagine that diaphragm getting just a little weaker.
As I said on a “tweet” recently “No one should brag about having a 100% extubation success rate”. If that is your number you are waiting too long to extubate. Based on the information here it should be a reminder that the plan for extubation needs to start as soon as the tube is inserted in the first place.
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!
Retrospective Experience
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.
Prophlyactic
• 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.
Rescue
• 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!
