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.
Prior Evidence
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.
Results
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.
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?
Surfactant administration is a frequent topic on this blog and as I look over the last five years there has been an evolution with its administration from InSure to LISA/MIST and even pharyngeal surfactant through an LMA. We have also discussed aerosolization of surfactant once and now a much larger trial is out that brings this technique which has to be the least invasive into the limelight. What gives me great pleasure is being able to highlight the article here Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial as the lead author is our CPS Fetus and Newborn Committee American of Pediatrics liaison Dr. James Cummings. Being able to review an article by a colleague and friend I think is always something that gives me some trepidation as what happens if the article is a poor one but in this case I feel pretty safe. The study was done by a large group of investigators known as the AERO-02 group and there are lots of gems to pick apart here.
On to the Study
This trial involving 22 NICUs enrolled Among 457 infants born with a GA from 23 to 41 (median 33) weeks and birth weight 595 to 4802 (median 1960) grams. In total, 230 infants were randomly assigned to aerosol; 225 received 334 treatments, starting at a median of 5 hours. The study allowed for repeat dosing of aerosolized surfactant up to 3 times with each treatment providing 6 mL/kg of 35 mg/mL calfactant suspension, 210 mg phospholipids/kg body weight, through a modified Solarys nebulizer shown below. The delivery device was like an inverted nipple placed in the mouth in order to deliver surfactant while the infant was on non-invasive support (CPAP, hi-flow or NIPPV).
From prior animal studies use of this method is thought to deliver approximately (14%), the surfactant dose used in or about 29 mg/kg reaching the distal alveolar bed. By allowing up to three treatments in 72 hours (there had to be a reduction in FiO2 with each treatment to allow a further one) the total delivered would be aboout 90 mg/kg although in some likely more and others less depending on depostion amounts. The study originally was planned as two cohorts but since they enrolled all in the first the second one was not used. The first cohort were:
1.nonintubated
2. had not previously received surfactant, 3. Between 1 hour to 12 hours of age,
4. Suspected or confirmed RDS requiring therapeutic administration of nasal respiratory support by nCPAP, HFNC, or NIPPV
5. Initially, there was an entry requirement FIO2 concentration of 0.25 to 0.40. Four months into the trial, it was discovered that several sites were using higher positive airway pressures to minimize FIO2. Because of this practice change, the minimum FIO2 requirement was removed in the fifth month of the trial
The trial was a pragmatic one where the authors did not specify what criteria were needed to decide when to intubate for surfactant. While this lack of standardization might turn some people off, many trials are headed this way as it represents “real life”. In other trials where you have rigid criteria if your own centre doesn’t typically use them the results of the trial in the end might just not apply. The question then is did this style of trial design in the end find a difference in outcome for the babies randomized to aerosolization or standard care with CPAP, HFNC or NIPPV to avoid intubation?
The Results
The trial met its number of patients required in the power calculation to find a difference in outcome. Demographics, receipt of antenatal steroids and levels of respiratory support at baseline were similar between groups. In the aerosol group. 225 infants received 334 treatments at a median age of 5 hours (interquartile range [IQR]: 3–7);149 (66%) received only one aerosol treatment, 43 (19%) received 2 treatments, and 33 (15%) received 3 treatments. It is also important to note that by defining the entry point of 1-12 hours of age, those with severe RDS would not have been enrolled here. Infants with apnea, or severe distress would not have been able to wait the hour time frame for entry and moreover since the aerosolization technique takes about an hour to administer those in need of urgent treatment would not be enrolled. As such we are really talking here about babies with mild to moderate RDS.
Intubation for surfactant occurred in 113 infants (50%) in the control group and 59 infants (26%) in the aerosol group, in an intent-to-treat analysis (P , .0001); RR: 0.51 (90% CI: 0.41–0.63). The number needed to treat to prevent 1 intubation is 5.
The impact of this approach was quite significant. Interestingly you would think that as GA decreased the effectiveness of the intervention would lessen but when the authors groups GA into two week brackets as shown below the only GA bracket that showed no difference in approach was the 23/24 week group. Having said that the numbers are very small on the lower end of GA for the study but again overall the results find a 50% reduction in need for intubation using this technique with the trend (by my eye) being that as GA increases the effectiveness seems to get even better.
The study was not blinded and as such the authors also took the time to look for evidence of bias in the study and found none. The last figure to show is the effect of this intervention on total duration of respiratory support between the two randomized groups. In other words while the use of the technique reduced your likelihood of intubation by 50% it didn’t get you off of non-invasive support any faster in the 72 hours after treatment.
Looking at complication rates between groups there was no difference as well.
Conclusions
I think what has been shown here is that aerosolized surfactant in a real world research model is safe and effective for mild to moderate RDS in reducing the need for intubation. For those infants with more significant RDS or severe apnea they will not be able to make it long enough to get these treatments. For others this does seem like something worth exploring as for those that you were going to commit to a non-invasive approach is there really any harm? There will be those that will fail but overall this data suggests that you could expect a 50% reduction in this occurrence for all your patients with mild to moderate RDS. The one fly in the ointment I see that could influence the effectiveness of this intervention is the level of support you are accustomed to using in your centre. It could be in those centres that are a bit “peepaphobic” and use a maximum of +5 or +6 on CPAP this intervention could be quite effective but in those that are willing to use +7or +8 the rate of intubation or surfactant might well be less. Regardless the intervention appears to be safe, well tolerated and can make a difference. If a delivery device could be prepared that increased deposition rates to even higher levels imagine how effective it just might be.
