It has been over two years since I have written on this subject and it continues to be something that I get excited about whenever a publication comes my way on the topic. The last time I looked at this topic it was after the publication of a randomized trial comparing in which one arm was provided automated FiO2 adjustments while on ventilatory support and the other by manual change. Automated adjustments of FiO2. Ready for prime time? In this post I concluded that the technology was promising but like many new strategies needed to be proven in the real world. The study that the post was based on examined a 24 hour period and while the results were indeed impressive it left one wondering whether longer periods of use would demonstrate the same results. Moreover, one also has to be wary of the Hawthorne Effect whereby the results during a study may be improved simply by being part of a study.
The Real World Demonstration
So the same group decided to look at this again but in this case did a before and after comparison. The study looked at a group of preterm infants under 30 weeks gestational age born from May – August 2015 and compared them to August to January 2016. The change in practice with the implementation of the CLiO2 system with the Avea ventilator occurred in August which allowed two groups to be looked at over a relatively short period of time with staff that would have seen little change before and after. The study in question is by Van Zanten HA The effect of implementing an automated oxygen control on oxygen saturation in preterm infants. For the study the target range of FiO2 for both time periods was 90 – 95% and the primary outcome was the percentage of time spent in this range. Secondary outcomes included time with FiO2 at > 95% (Hyperoxemia) and < 90, <85 and < 80% (hypoxemia). Data were collected when infants received respiratory support by the AVEA and onlyincluded for analysis when supplemental oxygen was given, until the infants reached a GA of 32 weeks
As you might expect since a computer was controlling the FiO2 using a feedback loop from the saturation monitor it would be a little more accurate and immediate in manipulating FiO2 than a bedside nurse who has many other tasks to manage during the care of an infant. As such the median saturation was right in the middle of the range at 93% when automated and 94% when manual control was used. Not much difference there but as was seen in the shorter 24 hour study, the distribution around the median was tighter with automation. Specifically with respect to ranges, hyperoxemia and hypoxemia the following was noted (first number is manual and second comparison automated in each case).
Time spent in target range: 48.4 (41.5–56.4)% vs 61.9 (48.5–72.3)%; p<0.01
Hyperoxemia >95%: 41.9 (30.6–49.4)% vs 19.3 (11.5–24.5)%; p<0.001
< 90%: 8.6 (7.2–11.7)% vs 15.1 (14.0–21.1)%;p<0.0001
< 85%: 2.7 (1.4–4.0)% vs 3.2 (1.8–5.1)%; ns
Hypoxemia < 80%: 1.1 (0.4–1.7)% vs 0.9 (0.5–2.1)%; ns
What does it all mean?
I find it quite interesting that while hyperoxemia is reduced, the incidence of saturations under 90% is increased with automation. I suspect the answer to this lies in the algorithmic control of the FiO2. With manual control the person at the bedside may turn up a patient (and leave them there a little while) who in particular has quite labile saturations which might explain the tendency towards higher oxygen saturations. This would have the effect of shifting the curve upwards and likely explains in part why the oxygen saturation median is slightly higher with manual control. With the algorithm in the CLiO2 there is likely a tendency to respond more gradually to changes in oxygen saturation so as not to overshoot and hyperoxygenate the patient. For a patient with labile oxygen saturations this would have a similar effect on the bottom end of the range such that patients might be expected to drift a little lower then the target of 90% as the automation corrects for the downward trend. This is supported by the fact that when you look at what is causing the increase in percentage of time below 90% it really is the category of 85-89%.
Is this safe? There will no doubt be people reading this that see the last line and immediately have flashbacks to the SUPPORT trial which created a great deal of stress in the scientific community when the patients in the 85-89% arm of the trial experienced higher than expected mortality. It remains unclear what the cause of this increased mortality was and in truth in our own unit we accept 88 – 92% as an acceptable range. I have no doubt there are units that in an attempt to lessen the rate of ROP may allow saturations to drop as low as 85% so I continue to think this strategy of using automation is a viable one.
For now the issue is one of a ventilator that is capable of doing this. If not for the ventilated patient at least for patients on CPAP. In our centre we don’t use the Avea model so that system is out. With the system we use for ventilation there is also no option. We are anxiously awaiting the availability of an automated system for our CPAP device. I hope to be able to share our own experience positively when that comes to the market. From my standpoint there is enough to do at the bedside. Having a reliable system to control the FiO2 and minimize oxidative stress is something that may make a real difference for the babies we care for and is something I am eager to see.
We can always learn and we can always do better. At least that is something that I believe in. In our approach to resuscitating newborns one simple rule is clear. Fluid must be replaced by air after birth and the way to oxygenate and remove CO2 is to establish a functional residual capacity. The functional residual capacity is the volume of air left in the lung after a tidal volume of air is expelled in a spontaneously breathing infant and is shown in the figure. Traditionally, to establish this volume in a newborn who is apneic, you begin PPV or in the spontaneously breathing baby with respiratory distress provide CPAP to help inflate the lungs and establish FRC.
Is there another way?
Something that has been discussed now for some time and was commented on in the most recent version of NRP was the concept of using sustained inflation (SI) to achieve FRC. I have written about this topic previously and came to a conclusion that it wasn’t quite ready for prime time yet in the piece Is It Time To Use Sustained Lung Inflation In NRP?
The conclusion as well in the NRP textbook was the following:
“There are insufficient data regarding short and long-term safety and the most appropriate duration and pressure of inflation to support routine application of sustained inflation of greater than 5 seconds’ duration to the transitioning newborn (Class IIb, LOE B-R). Further studies using carefully designed protocols are needed”
So what now could be causing me to revisit this concept? I will be frank and admit that whenever I see research out of my old unit in Edmonton I feel compelled to read it and this time was no different. The Edmonton group continues to do wonderful work in the area of resuscitation and expand the body of literature in such areas as sustained inflation.
Can you predict how much of a sustained inflation is needed?
This is the crux of a recent study using end tidal CO2 measurement to determine whether the lung has indeed established an FRC or not. Dr. Schmolzer’s group in their paper (Using exhaled CO2 to guide initial respiratory support at birth: a randomised controlled trial) used end tidal CO2 levels above 20 mmHg to indicate that FRC had been established. If you have less CO2 being released the concept would be that the lung is actually not open. There are some important numbers in this study that need to be acknowledged. The first is the population that they looked at which were infants under 32 6/7 weeks and the second is the incidence of BPD (need for O2 or respiratory support at 36 weeks) which in their unit was 49%. This is a BIG number as in comparison for infants under 1500g our own local incidence is about 11%. If you were to add larger infants closer to 33 weeks our number would be lower due to dilution. With such a large number though in Edmonton it allowed them to shoot for a 40% reduction in BPD (50% down to 30%). To accomplish this they needed 93 infants in each group to show a difference this big.
So what did they do?
For this study they divided the groups in two when the infant wouldn’t breathe in the delivery room. The SI group received a PIP of 24 using a T-piece resuscitator for an initial 20 seconds. If the pCO2 as measured by the ETCO2 remained less than 20 they received an additional 10 seconds of SI. In the PPV group after 30 seconds of PPV the infants received an increase of PIP if pCO2 remained below 20 or a decrease in PIP if above 20. In both arms after this phase of the study NRP was then followed as per usual guidelines.
The results though just didn’t come through for the primary outcome although ventilation did show a difference.
Duration of mechanical ventilation (hrs)
The reduction in hours of ventilation was impressive although no difference in BPD was seen. The problem though with all of this is what happened after recruitment into the study. Although they started with many more patients than they needed, by the end they had only 76 in the SI group and 86 in the PPV group. Why is this a problem? If you have less patients than you needed based on the power calculation then you actually didn’t have enough patients enrolled to show a difference. The additional compounding fact here is that of the Hawthorne Effect. Simply put, patients who are in a study tend to do better by being in a study. The observed rate of BPD was 33% during the study. If the observed rate is lower than expected when the power calculation was done it means that the number needed to show a difference was even larger than the amount they originally thought was needed. In the end they just didn’t have the numbers to show a difference so there isn’t much to conclude.
What I do like though
I have a feeling or a hunch that with a larger sample size there could be something here. Using end tidal pCO2 to determine if the lung is open is in and of itself I believe a strategy to consider whether giving PPV or one day SI. We already use colorimetric devices to determine ETT placement but using a quantitative measure to ascertain the extent of open lung seems promising to me. I for one look forward to the continued work of the Neonatal Resuscitation–Stabilization–Triage team (RST team) and congratulate them on the great work that they continue doing.
A grenade was thrown this week with the publication of the Australian experience comparing three epochs of 1991-92, 1997 and 2005 in terms of long term respiratory outcomes. The paper was published in the prestigious New England Journal of Medicine; Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years. This journal alone gives “street cred” to any publication and it didn’t take long for other news agencies to notice such as Med Page Today. The claim of the paper is that the modern cohort has fared worse in the long run. This has got to be alarming for anyone reading this! As the authors point out, over the years that are being compared rates of antenatal steroid use increased, surfactant was introduced and its use became more widespread and a trend to using non-invasive ventilation began. All of these things have been associated with better short term outcomes. Another trend was declining use of post-natal steroids after 2001 when alarms were raised about the potential harm of administering such treatments.
Where then does this leave us?
I suppose the first thing to do is to look at the study and see if they were on the mark. To evaluate lung function the study looked at markers of obstructive lung disease at 8 years of age in survivors from these time periods. All babies recruited were born between 22-27 completed weeks so were clearly at risk of long term injury. Measurements included FEV1, FVC, FVC:FEV1 and FEF 25-75%. Of the babies measured the only two significant findings were in the FEV1 and ratio of FEV1:FVC. The former showed a drop off comparing 1997 to 2005 while the latter was worse in 2005 than both epochs.
This should indeed cause alarm. Babies born in a later period when we thought that we were doing the right things fared worse. The authors wonder if perhaps a strategy of using more CPAP may be a possible issue. Could the avoidance of intubation and dependence on CPAP for longer periods actually contribute to injury in some way? An alternative explanation might be that the use of continuous oximetry is to blame. Might the use of nasal cannulae with temporary rises in O2 expose the infant to oxygen toxicity?
There may be a problem here though
Despite everyone’s best efforts survival and/or BPD as an outcome has not changed much over the years. That might be due to a shift from more children dying to more children living with BPD. Certainly in our own centre we have seen changes in BPD at 36 weeks over time and I suspect other centres have as well. With concerted efforts many centres report better survival of the smallest infants and with that they may survive with BPD. The other significant factor here is after the extreme fear of the early 2000s, use of postnatal steroids fell off substantially. This study was no different in that comparing the epochs, postnatal glucocorticoid use fell from 40 and 46% to 23%. One can’t ignore the possibility that the sickest of the infants in the 2005 cohort would have spent much more time on the ventilator that their earlier counterparts and this could have an impact on the long term lung function.
Another question that I don’t think was answered in the paper is the distribution of babies at each gestational age. Although all babies were born between 22-27 weeks gestational age, do we know if there was a skewing of babies who survived to more of the earlier gestations as more survived? We know that in the survivors the GA was not different so that is reassuring but did the sickest possible die more frequently leaving healthier kids in the early cohorts?
This bigger issue interestingly is not mentioned in the paper. Looking at the original cohorts there were 438 in the first two year cohort of which 203 died yielding a survival of 54% while in 1997 survival increased to 70% and in 2005 it was 65%. I can’t help but wonder if the drop in survival may have reflected a few more babies at less than 24 weeks being born and in addition the holding of post natal steroids leading to a few more deaths. Either way, there are enough questions about the cohorts not really being the same that I think we have to take the conclusions of this paper with a grain of salt.
It is a sensational suggestion and one that I think may garner some press indeed. I for one believe strongly though as I see our rates of BPD falling with the strategies we are using that when my patients return at 8 years for a visit they will be better off due to the strategies we are using in the current era. Having said that we do have so much more to learn and I look forward to better outcomes with time!
I know how to bag a baby. At least I think I do. Providing PPV with a bag-valve mask is something that you are taught in NRP and is likely one of the first skills you learned in the NICU. We are told to squeeze the bag at a rate of 40-60 breaths a minute. According to the Laerdal website, the volume of the preterm silicone bag that we typically use is 240 mL. Imagine then that you are wanting to ventilate a baby who is 1 kg. How much should you compress the bag if you wish to delivery 5 mL/kg. Five ml out of a 240 mL bag is not a lot of squeeze is it? Think about that the next time you find yourself squeezing one. You might then say but what about a t-piece resuscitator? A good choice option as well but how much volume are you delivering if you set the initial pressures at 20/5 for example? That would depend on the compliance of the lung of course. The greater the compliance the more volume would go in. Would it be 5 mL, 10 ml or even 2.5 mL based on the initial setting? Hard to say as it really depends on your seal and the compliance of the lung at the pressure you have chosen. If only we had a device that could deliver a preset volume just like on a ventilator with a volume guarantee setting!
Why is this holy grail so important?
It has been over 30 years since the importance of volutrauma was demonstrated in a rabbit model. Hernandez LA et al published Chest wall restriction limits high airway pressure-induced lung injury in young rabbits. The study used three models to demonstrate the impact of volume as opposed to pressure on injuring the lung of preterm rabbits. Group 1 were rabbit ventilated at pressures of 15/30/45 cm H2O for one hour, group 2 rabbits with a cast around their thorax to limit volume expansion and group 3 sets of excised lungs with no restriction to distension based on the applied pressures. As you might expect, limitation of over distension by the plaster cast led the greatest reduction in injury (measured as microvascular permeability) with the excised lungs being the worst. In doing this study the authors demonstrated the importance of over distension and made the case for controlling volume more than pressure when delivering breaths to avoid excessive tidal volume and resultant lung injury.
The “Next Step” Volume Ventilator BVM
Perhaps I am becoming a fan of the Edmonton group. In 2015 they published A Novel Prototype Neonatal Resuscitator That Controls Tidal Volume and Ventilation Rate: A Comparative Study of Mask Ventilation in a Newborn Manikin. The device is tablet based and as described, rather than setting a PIP to deliver a Vt, a rate is set along with a volume to be delivered with a peep in this case set at +5. This study compared 5 different methods of delivering PPV to a 1 kg preterm manikin. The first was a standard self inflating bag, the next three different t-piece resuscitators and then the Next Step. For the first four the goal was to deliver a pressure of 20/5 at a rate of 40-60 breaths per minute. A test lung was connected to the manikin such that each device was used for a one minute period at three different levels of compliance (0.5 ml/cmH2O, 1.0 ml/cmH2O and then 2.0 ml/cm H2O representing increasing compliance. The goal of the study was to compare the methods in terms of delivering a volume of 5 mL to this 1 kg model lung. The order in which the devices were used was randomized for the 25 participants in the study who were all certified in NRP and included some Neonatologists.
Some Concerning Findings
As I said at the beginning, we all like to think we know how to ventilate a newborn with BVM. The results though suggest that as compliance increases our ability to control how much volume we deliver to a lung based on a best guess for pressures needed is lacking. One caveat here is that the pressures set on the t-piece resucitators were unchanged during the 1 minute trials but then again how often during one minute would we change settings from a starting point of 20/5?
Without putting in all the confidence intervals I can tell you that the Next Step was the tightest. What you notice immediately (or at least I did) was that no matter what the compliance, the self inflating bag delivers quite an excessive volume even in experienced hands regardless of compliance. At low compliance the t-piece resuscitators do an admirable job as 5-6 ml/kg of delivered Vt is reasonable but as compliance improves the volumes increase substantially. It is worth pointing out that at low compliance the Next Step was unable to deliver the prescribed Vt but knowing that if you had a baby who wasn’t responding to ventilation I would imagine you would then try a setting of 6 ml/kg to compensate much like you would increase the pressure on a typical device. How might these devices do in a 29 week infant for example with better compliance than say a 24 week infant? You can’t help but wonder how many babies are given minutes of excessive Vt after birth during PPV with the traditional pressure limited BVM setup and then down the road how many have BPD in part because of that exposure.
I wanted to share this piece as I think volume resuscitation will be the future. This is just a prototype or at least back then it was. Interestingly in terms of satisfaction of use, the Next Step was rated by the participants in the study as being the easiest and most comfortable to use of all the devices studied. Adding this finding to the accuracy of the delivered volume and I think we could have a winner.
This is becoming “all the rage” as they say. I first heard about the strategy of feeding while on CPAP from colleagues in Calgary. They had created the SINC * (Safe Individualized Feeding Competence) program to provide an approach to safely introducing feeding to those who were still requiring CPAP. As news of this approach spread a great deal of excitement ensued as one can only imagine that in these days when attainment of oral feeding is a common reason for delaying discharge, could getting an early start shorten hospital stay? I could describe what they found with the implementation of this strategy but I couldn’t do it the same justice as the presenter of the data did at a recent conference in Winnipeg. For the slide set you can find them here. As you can imagine, in this experience out of Calgary though they did indeed find that wonderful accomplishment of shorter hospital stays in the SINC group. We have been so impressed with the results and the sensibility of it all that we in fact have embraced the concept and introduced it here in both of our units. The protocol for providing this approach is the following.
I have to admit, while I have only experienced this approach for a short time the results do seem to be impressive. Although anecdotal a parent even commented the other day that she felt that SINC was instrumental in getting her baby’s feeding going! With all this excitement around this technique I was thrown a little off kilter when a paper came out suggesting we should put a full stop to feeding on CPAP!
What caused my spirits to dampen? This study enrolled preterm infants who were still on CPAP at ≥ 34 weeks PMA and were taking over 50% of required feeding volumes by NG feeding. The goal was to look at 15 patients who were being fed on CPAP +5 and with a mean FiO2 of 25% (21-37%) using video fluoroscopic swallowing studies to determine whether such patients aspirate when being fed. The researchers became concerned when each of the first seven patients demonstrated abnormalities of swallowing function indicating varying degrees of aspiration. As such they took each patient off CPAP in the radiology suite and replaced it with 1 l/min NP to achieve acceptable oxygen saturations and repeated the study again. The results of the two swallow studies showed remarkable differences in risk to the patient and as such the recruitment of further patients was stopped due to concerns of safety and a firm recommendation of avoiding feeding while on CPAP was made.
Table 2. Percentage of all swallows identified with swallowing dysfunction
Variable Mean ± s.d.
Mean ± s.d.
Mean ± s.d.
Mild pen. %
Deep pen. %
Nasopharyngeal reflux %
Taking these results at face value it would seem that we should put an abrupt halt to feeding while on CPAP but as the saying goes the devil is in the details…
CPAP Using Ram Cannulae
Let me start off by saying that I don’t have any particular fight to pick with the RAM cannulae. They serve a purpose and that is they allow CPAP to be delivered with a very simple set of prongs and avoid the hats, straps and such of more traditional CPAP devices. We have used them as temporary CPAP delivery when moving a patient from one area to another. As the authors state the prongs are sized in order to ensure the presence of a leak. This has to do with the need to provide a way for the patient to exhale when nasal breathing. Prongs that are too loose have a large leak and may not deliver adequate pressure while those that are too tight may inadvertently deliver high pressure and therefore impose significant work of breathing on the patient. Even with appropriate sizing these prongs do not allow one to exhale against a low pressure or flow as is seen with the “fluidic flip” employed with the infant flow interface. With the fluidic flip, exhalation occurs against very little resistance thereby reducing work of breathing which is not present with the use of the RAM cannula.
Trying to feed an infant who is working against a constant flow as delivered by the RAM cannulae is bound to cause problems. I don’t think it should be a surprise to find that trying to feed while struggling to breathe increases the risk of aspiration. Similarly, under treating a patient by placing them on nasal prongs would lead to increased work of breathing as while you may provide the needed O2 it is at lower lung volumes. Increasing work of breathing places infants at increased risk of aspiration. That is what I would take from this study. Interestingly, looking at the slide set from Calgary they did in fact use CPAP with the fluidic flip. Smart people they are. It would be too easy to embrace the results of this study and turn your nose to the SINC approach to feeding on CPAP. Perhaps somewhere out there someone will read this and think twice about abandoning the SINC approach and a baby will be better for it.
* SINC algorithm and picture of the fluidic flip courtesy of Stacey Dalgleish and the continued work of Alberta Health Services
This may sound familiar as I wrote about this topic in the last year but the previous post was restricted to infants who were under 1000g. High Flow Nasal Cannula be careful out there had a main message that suggested the combined outcome of BPD or death was more prevalent when HFNC is used alone or with CPAP than when CPAP is used alone. The question remains though whether this applies to larger infants. Without looking at the evidence for that combined outcome most people would say there is unlikely to be a difference. Larger more mature babies have a much lower risk of BPD or death so proponents of HFNC would say it is simpler to use and helps prevent nasal breakdown as well. The question remains as to whether all outcomes are the same in larger infants and that is the point of this post.
A Non-Inferiority Trial
First off it is important to understand what this type of trial is. The first requirement is that the two treatments have both been compared to a placebo and found to be both effective. Once you establish that you have a choice between two treatment options then you eliminate the placebo and compare them head to head. What you are looking for in this type of trial is to determine not whether one is better than the other but that there is no difference in a clinical outcome of interest. If you find no difference then the next step is to look at other outcomes that might be of interest and see if there are any benefits to picking one versus the other. In the case of CPAP vs HNFC, if a non-inferiority trial showed no difference in an important outcome such as length of stay but nasal breakdown was less with HFNC it might lead a unit to use HFNC for their infants. Okay, now that we have that cleared up we can move on to an actual study examining this very subject.
This was an interesting study with a great name (The HIPSTER trial) that enrolled infants > 28 weeks and 0 days with none of the infants receiving surfactant but either being randomized to HFNC or CPAP after delivery. These infants were your typical modern day cohort of babies who may avoid intubation and surfactant by establishing FRC early with positive pressure applied to the nose through one of these devices. The end point for the study was treatment failure within 72 hours. If an infant failed in the HFNC they could have a trial of CPAP whereas in the CPAP group they were intubated. For each infant in the HFNC group flow was set from 6-8 l/min and for CPAP 6-8 cmH2O.
Treatment was considered to have failed if an infant receiving maximal support (high-flow therapy at a gas flow of 8 liters per minute or CPAP at a pressure of 8 cm of water) met one or more of the following criteria:
FiO2 of 0.4 or higher
Arterial or free flowing cap gas with a pH of 7.2 or less plus a pCO2 > 60 mm Hg obtained at least 1 hour after starting treatment
Two or more episodes of apnea requiring positive-pressure ventilation within a 24-hour period or six or more episodes requiring any intervention within a 6-hour period.
Infants with an urgent need for intubation and mechanical ventilation.
So what happened?
The trial randomized 583 infants (278 HFNC, 286 CPAP) but was halted by the data and safety monitoring committee after an analysis of the first 515 revealed that the outcome was worse in the HFNC group (25.5% failure rate vs 13.3 for CPAP). Interestingly treatment failures were more common in babies below and above 32 weeks so it was not just the smallest infants who failed.
Another interesting finding was that the most common reason for treatment failure was criteria 1 (FiO2 > 40%) while intubation was higher for all infants but did not reach statistical significance. Curiously what did reach a significant difference was criteria #4 (18.4% urgent intubations in the CPAP group vs 5.6% in the HFNC group). You might be tempted to therefore ponder which is worse, a little O2 or being intubated but you need to recall the trial design which was set up to provide this kind of result. If you failed HFNC you were placed on CPAP whereas if you failed CPAP you were intubated. In the HFNC group, 78 infants were deemed to have failed but 28 of them were in fact “rescued by CPAP”. It therefore isn’t a fair comparison when it comes to urgent intubation since if you failed CPAP there wasn’t another option.
Not a total loss
Nasal trauma was indeed much lower in the HFNC group, occurring only 8.3% vs 18.5% of the time with CPAP. Pneumothorax was also found to be significantly different with none of the patients in the HFNC group having that complication vs 2.1% in the CPAP group. What this study tells us is that as a primary modality to treat newborns with RDS who have not received surfactant it is preferable to use CPAP in the first 72 hours. Some of you may say it might not say that at all but consider the impact of having more babies exposed to high FiO2. We know from other studies that high FiO2 can be quite damaging to preterm infants and this study was certainly not powered to look at all those important outcomes such as ROP, PVL and BPD. The authors report them and found no difference but without adequate power to show a difference I wouldn’t take much comfort in those findings.
I think were things may settle out though is what to do in more mature infants. There is no question that for those on chronic respiratory support there is some risk of nasal breakdown. Although I don’t have much experience with HFNC I would think that for the older patient who either already has BPD at 36 weeks or is close to that point but reliant on +4 or +5 CPAP that HFNC might help “give them a break”. As such I don’t see this as a total loss but rather an option to try when CPAP for whatever reason is not tolerated.
As a primary therapy for non-invasive management RDS I will keep my CPAP for all babies thank you.