When I began my career in Neonatology we initially ventilated primarily with pressure limited time cycled modes of ventilation and only supported some of the breaths as in SIMV modes. With time and emerging research a movement to using set volumes came about and in many centres supporting every breath using an assist control mode or similar version. Although I don’t have access to it in my centre, ventilators such as the Avea also allow for automated FiO2 control in addition to having a choice of two different volume targeting modes. The difference between the modes is the subject of a study entitled Comparison of volume guarantee and volume-controlled ventilation both using closed loop inspired oxygen in preterm infants: a randomised crossover study (CLIO-VG study). I suppose it shouldn’t be a big surprise that as technology advances and we fine tune practice, different modes for volume targeting would arise.
What’s the difference?
Volume Controlled Ventilation (VCV) – flow based on a set volume and measurement of the PIP every 2 ms. Next breath is given the greater of PEEP+2 cm H2O or PIP-2 cmH2O. The ventilator at the end of each breath is able to determine if the baby is still demanding flow and continues providing flow but stops when inspiratory flow is <25% of peak set flow. There is constant inspiratory flow and peak volumes.
Volume Guarantee (VG)- inspiratory pressure is adjusted breath to breath. These breaths have a decelerating flow instead of a fixed flow as in VCV.
Using automated FiO2 control for both groups the study design was a crossover one. The concept was that better ventilation would help to keep O2 saturations more reliably in a target range of 90-95% and that one of these modes might be superior than the other in doing so. Infants in the study were born at 23+0 – 36+6 weeks and had to be intubated and on >21% FiO2 to be part of the study. Each group spent 12 hours in each arm with the starting mode randomly chosen before switching over to the other mode.
Based on a power calculation in which the authors selected looking for a 5% difference they determined they needed 19 patients in the study overall. The median GA of the infants was 25 weeks (IQR 24-28) with a BW of 685g.
On a personal note, I use only VG in my centre so I am pleased to see there is really no difference in the primary outcome but the trend in the secondary outcomes at least puts a slight smile on my face as well!
Who doesn’t love a good match up?! Supporting neonates in need of resuscitation after delivery has been the subject of many studies over the years. The movement has certainly been to non-invasive support with CPAP or NIPPV but some babies need some degree of support with PPV after delivery when they simply won’t breathe. Prior to intubation the rise of the t-piece resuscitator has meant that practitioners can set a PIP and PEEP and with only a finger press to deliver a tidal volume at set pressure and with the finger released provide CPAP through the same device. The only problem potentially with use of these devices is the imposed work of breathing (iWOB) which has been measured in other studies. Any device I have used has provided ventilation through a mask so imagine my surprise to come across a new device called rPAP using prongs from the original infant flow design. From the manufacturers website the company claims that their design used with either a mask or nasal prongs reduces iWOB by 92% compared to other comparable machines! Imagine my greater surprise to see a head to head RCT comparing this new device to standard t-piece resuscitators with a mask.
The intervention was completed with one of three outcomes were met.
Stable and breathing on method of support after a minimum of 10 minutes of support.
At 30 minutes when respiratory support could continue as decided by the clinician without crossover allowed.
Looking at the appendices for the trial it appears that one could use either device to administer PPV or CPAP but the point of the trial was that the devices would be used to support the infants until one of the three above criteria were met. If the claims about reduced iWOB were true compared to other devices in use then one might expect to see a difference in the primary outcome of incidence of intubation or death within 30 minutes of birth.
In total there were 250 infants recruited with 127 assigned to the rPAP and the other 123 to t-piece resuscitation. The mean GA in the trial was 24.8 weeks and the baseline characteristics between groups were similar although the group randomized to the rPAP has more c-sections and more general anesthetic exposure compared to the t-piece group. Lastly, humidification of gases during resuscitation was similar between the two groups.
How Did They Compare?
It just might be that the claims of decreased iWOB might have merit. In Figure 2 below the Kaplan-Meier curves show a difference favouring the rPAP device when looking at the primary outcome. This difference was significant with 41 of 124 infants (33.1%) in the rPAP group and in 55 of 122 infants (45.1%) in the T-piece group having the primary outcome of intubation or death within the first 30 minutes of life. Moreover when looking at the adjusted odds ratio it was still significant at 0.53; 95% CI, 0.30-0.94. The incidence of intubation and death in the first 72 hours although trending towards favouring the new system did not reach statistical significance.
Finally, none of the secondary outcomes reached statistical significance which included such things as death in the delivery room, use of surfactant, or PPV in the DR.
Does it make sense?
If you had asked me to tell you prior to the study whether resuscitation with nasal prongs vs a mask would be different I would have said a mask would be better due to less leak. Turns out based on this data that I would be wrong in that guess. A look at the website though for the rPAP device indicates that it can be used with a mask or nasal prongs. It would have been nice in the study presented here to have used a mask as a third arm with the rPAP device as it leaves me wondering a bit whether it was the interface that mattered more than the type of driver used? Maybe I am wrong and by using prongs it allows the infant to have less iWOB than with a mask over the mouth and nose? Could it be that it has more to do with that that the type of driver whether it is a traditional t-piece resuscitator or the new rPAP device? Regardless, I have a suspicion that these results will resonate with people. A posting of the abstract alone has garnered a lot of attention on twitter this week so clearly this is of interest.
I don’t think there is much fault to find in this study other than my question of why they didn’t choose to have a head to head comparison with masks as well but perhaps that is for another study. I imagine we will see this approach adopted in many centres around the world as they replace their traditional t-piece resuscitators in need of replacement. I also suspect there will be many that will want a larger study before adopting this strategy to look more closely with come faith in the results at secondary outcomes in particular having to do with safety.
One thing is for certain. There will be more studies to come!
Here in Winnipeg we don’t use t-piece resuscitators for any resuscitation. I did use them in my past position in Edmonton and I came to appreciate them for their ease of use. For the majority of infants, setting a PIP and a PEEP and then using your finger to occlude and release offers a relatively simple and less difficult approach to ventilation than using a self inflating or jackson-rees bag. I say the majority of infants, as most infants are not born from 22-32 weeks but the lion’s share are born at gestations older than that. The larger more mature infants have lungs that are much more forgiving to excessive ventilation. For the smallest of infants though questions have remained for some time around the volumes delivered to the fragile lung when a fixed pressure is used in the presence of moment to moment changes in compliance.
Measuring Tidal Volume in Intubated At Risk Infants
Vaidya R et al published Tidal volume measurements in the delivery room in preterm infants requiring positive pressure ventilation via endotracheal tube feasibility study in Journal of Perinatology. The prospective observational study looked at 10 infants born at < 32 weeks with a mean GA of 23.9(±1.5) weeks and mean BW 618.5(±155)g. A mean of 17.8 minutes of recordings were examined using the setup below and in total looked at 8175 individual breaths. All patients in the study were intubated with non-cuffed ETT but by only including intubated infants in the delivery room the issue of mask leak was avoided. As in many units the target Vt was 4-6 mL/kg. It wasn’t specified what criteria they use for setting initial pressures but the included patients had a mean PIP of 24.4±5 and PEEP of 5.9 ±2.4. Importantly, those providing ventilation with the t-piece resuscitator were blinded to the data on tidal volume measurements.
How Good Were They At Meeting Their Goal?
It turns out that they weren’t that great (I am not faulting them by the way) as it is a challenge to try and adjust pressures based on chest rise. We are not good at it at all. As shown in the figure below there was a wide range of volumes administered. In fact here is the breakdown. The goal Vt between 4-6 was only 25% of the time. In other words you are dealing with either a risk of atelectotrauma or volutrauma 75% of the time. It is worth noting that the neonatal flow sensor has a dead space of 1 mL. If that is the case and the infants on average were about 600g that is almost 2 mL/kg in non-ventilated space that this volume is going into. It doesn’t change the numbers that much if you factor that in but it does mean that some infants who were getting a measured 3 mL/kg were actually seeing under 2 mL/kg of lung ventilation. On the other hand those getting 7 mL/kg were actually seeing under 6 mL/kg so were in target. Bottom line though is that when using fixed pressure settings in the presence of changing compliance even if one is adjusting pressure in real time it is difficult to maintain stable volumes in target range. The authors also demonstrate in another graph that even in individual patients there is fluctuation as well.
Call to Action
I think this study is actually quite useful in confirming what I imagine many have always suspected. We just aren’t that great at assessing tidal volume when we watch the chest rise. As many have noted, the first 6 breaths at least in an animal model can damage the lungs. Imagine what excessive or low volumes can do to the lung over 18 minutes?!
What this study does is demonstrate especially in the smallest and most vulnerable infants that if ventilation is needed one should put the infant onto a volume guaranteed mode of ventilation ASAP. Ventilators should be in the resuscitation area as we have in our hospital and not have to be brought in should the baby be intubated. Hand bagging even with a t-piece resuscitator should be kept to a minimum. At risk is the development of BPD and knowing that even in experienced hands we just aren’t that good at delivering tidal volumes in a target range we need to strive to minimize the time that we expose our infants to such modalities. Ventilation isn’t always avoidable but when needed my advice is to control volume and allow pressures to fluctuate as resistance and compliance change. Especially after administration of surfactant the pulmonary mechanics are changing constantly and no matter how good you are you just won’t be able to keep pace. Let the ventilator do it!
This post is a written as a tribute to John Minski RRT who taught me much about ventilation over the years and has been a champion for innovation in our unit. As he prepares to move on to the next phase of his life I thought it would be a nice send off to talk about something that he has been passionate about for some time. That passion is inhaled nitric oxide for more than just pulmonary hypertension.
This is actually nothing really new. For a review on the background behind the theory you can read The potential of nitric oxide releasing therapies as antimicrobial agents. While we think of iNO as being a drug for pulmonary hypertension it has other capabilities. It can diffuse across cell membranes and damage pathogens by causing nitrosative and oxidative damage. The amount of iNO needed though to accomplish this bactericidal action is much higher than the typical levels of 20 – 40 ppm that we use. Last year in August Bogdanovski et al published Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease. They describe a protocol of providing 30 minute doses of 160 ppm for 21 days in a 24 year old patient with cystic fibrosis who was infected with mycobacterium abscessus. While they were not able to eradicate the organism, they were able to demonstrate functional improvement in the patient. Also notable was the absence of adverse effects in terms of methemoglobin levels. Other prior research in-vitro has shown iNO at high levels to be truly bacteriocidal as per the review above.
In this paper they describe the use of iNO at 160 ppm in 5 spontaneously breathing patients with confirmed COVID19 infection. This was provided as a rescue therapy in the absence of any high quality therapies for this disease. The protocol was to give them the same dose of 160 ppm for 30 minutes at a time until resolution of their symptoms with those that received multiple treatments getting anywhere from 5-9 courses. In each case after each 30 minute period the treating physicians measured levels of methemoglobin and nitrogen dioxide and found in each patient acceptable levels after these brief exposures.
Of the 5 patients treated 2 died from COVID19 and three survived. The two patients who died interestingly were the ones who each only received one treatment each. The other three received 5, 8 and 9 treatments respectively. The authors recorded mean arterial pressure, heart rate, respiratory rate, SpO2/FiO2 and finally measurements of inflammatory markers in the two patients who died (E) and the 3 who survived in (F) in the figure below.
What is interesting from the figure above is the reduction in respiratory rate during treatment (certainly could be placebo from believing they will get better) but the oxygenation during the treatment improved as well. Could this be from a reduction in associated pulmonary hypertension? Certainly could be. Looking at the patients who died in (E) vs the ones in (F) who survived (patient 3 not shown) demonstrate that use of iNO stopped the rise in CRP and in the case of those who died reduced it significantly. There could be an argument made then that the changes in respiratory pattern observed during treatment are associated with a concomitant attenuation of inflammation. This treatment just might work but of course needs far more studies to be certain of that. On that note a review of iNO for this type of indication reveals there are currently 16 studies enrolling in this area of research so I imagine there will be more info to come with this story.
What about the neonate with pneumonia?
I sent this paper around to my colleagues and it generated some great discussion. I am no Ethicist but the question raised was could this be considered a “last ditch” treatment for the neonate succumbing to a pneumonia? I have no doubt if you are reading this that you will have seen in neonatal units around the world that there are infants who develop pneumonia unresponsive to traditional treatments such as iNO at regular doses, antibiotics, higher PEEP, surfactant etc. If we have this knowledge with respect to the potential use of iNO at high dose and a positive impact on pulmonary infective disease is this something that should be offered to parents?
We have no date to my knowledge in babies on the use of this type of dosing but it comes down to a question of what is the alternative? If a patient is dying on the ventilator are we at the point of knowledge here that it is worth offering the family this treatment? One could do so with full disclosure about the lack of neonatal data both for effectiveness and safety. Or do you fall on the side of it could be harmful and expedite death so should not be used. If you use it though and wait till the patient is in extremus on 100% oxygen might it be too late? Do parents have the right to know when they ask the question “is there anything else you can do?” For me I think the answer is that there should be a discussion with this evolving research out there. I am comfortable with it as long as the parents understand the potential for it to make things worse and shorten their time with their child. Alternatively if they choose not to that is their prerogative but should they have the choice when the competing outcome is death?
I can’t tell you whether you should or shouldn’t offer this in your institution but my suspicion is that you will be discussing this among colleagues before long. Who knows you might just one day say you saw it here first!
Thanks John M for the inspiration and keep sending those articles!
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.