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.
This topic has been making its rounds for awhile now. Periodically whether on Twitter or via email I get asked this exact question. Anecdotally, the numbers of babies in the NICUs across many units in Canada seem to be lower as estimated by various Neonatologists. The question is whether this is real or not and without national data it is tough to say for sure. This week though a research letter came out of the UK entitled Change in the Incidence of Stillbirth and Preterm Delivery During the COVID-19 Pandemic. The authors compared two time periods at a single centre ; St George’s University Hospital, London in 2 epochs: from October 1, 2019, to January 31, 2020 (preceding the first reported UK cases of COVID-19), and from February 1, 2020, to June 14, 2020. Specifically they wanted to look at the rate of stillbirths and preterm births during these two time periods.
What did they find?
There were 1681 births in the prepandemic period and 1718 births during the pandemic. There were no differences in maternal characteristics before and after so presumably if there is a difference in rates of stillbirth and preterm birth it might be the influence of the pandemic. As it is an observational study though it certainly is possible that unmeasured factors are different in the groups but let’s give them the benefit of the doubt.
The rate of stillbirth was up and by a significant margin but the rate of preterm birth was not. There certainly was a trend though towards an increase in preterm delivery prior to 34 weeks. While I don’t know what the cause of all this is for sure it sure is fun to speculate.
Possible reasons for higher rates of stillbirth
It has been documented that rates of perforated appendicitis in our own centre increased during the pandemic. As the population became frightened of leaving the home, more and more people waited longer to go to the hospital to seek care. I can’t help but wonder if the same thing may have happened here. Might the pattern of seeking care by women for decreased fetal movement shifted ever so slightly? What about the frequency of prenatal visits? In Manitoba a COVID modified approach was done with fewer visits than normal. It certainly is possible that women by having fewer visits could have in some cases missed clinical findings that might have alerted a midwife or obstetrician to a reason to deliver early.
Possible reasons for a decline in preterm birth
The authors here did not find a difference but in fairness out of the number of pregnancies the number of preterm births would have been about 10% so difficult to really find a difference. Given that under 34 weeks showed a trend to a lower number let’s assume that there might be a difference (or not).
At least in terms of the perception of lower rates, this might be a case of confirmation bias. One of my colleagues who initally sent me an email from another institution two weeks later sent another that said “I thought we were seeing lower rates and now we are packed to the rafters”. It could well be that we are all noticing when the census is low and not paying attention to the times when it rises. Every time the numbers drop it seems to confirm our suspicions.
It wasn’t from people choosing to delay family planning as it was too early to see a change in birth rate. I do worry though that we may see declining admissions in the latter part of the year and then a “boom” when a vaccine is produced as families once again choose to conceive. This happened similarly during the Zika epidemic in Brazil.
It could also be that the finding is real. During the pandemic essentially all pregnant women went on extended rest. Instead of dealing with stressful daily tasks like battling traffic, being late for work and working altogether they were told to stay at home. Financial stress could have then been a factor but at least in Canada the government provided $2000 a month to offset the job losses. It is quite possible at least in my mind that an extended period of rest could have truly led to less preterm birth.
The Future
The next step I imagine will be for larger organizations such as the Public Health Agency of Canada to publish their data on this and see what happened across Canada during this period. When we are able to look at tens of thousands of pregnancies we will have enough numbers to drill down whether there has been a change for our smallest infants or not.
Let me start off by giving thanks to John Minski for this article and in fact for many others that have been reviewed on this blog. John is a registered respiratory therapist in Winnipeg with a passion for respiratory care like no other. John frequently sends articles my way to think about for our unit and this one was quite sensational to me. As readers of this blog I thought you might find it pretty interesting as well.
Why Would A Mask Cause Apnea
To begin with this seems counterintuitive as don’t we use masks when babies are apneic to help them breathe? While this is true and they are great for support, what if a baby is breathing already but has laboured respirations and you choose to apply a mask and provide PEEP to support their breathing efforts. Surprisingly there is evidence that this may induce apnea. The evidence comes from studies in term infants and one such study to demonstrate this finding was Effects of a face mask and pneumotachograph on breathing in sleeping infants by Dolfin T et al. While tidal volumes improved with facemask application, respiratory frequency after mask application dropped by 6 breaths a minute. This may have been offset by a rise in tidal volume as minute ventilation was unchanged. Regardless there was a slowing of the respiratory rate which was found in other studies as well.
The cause of this slowing has been attributed to the Trigemiocardiac Reflex (TCR). The trigeminal nerve branches all pass through the area around the mouth and nose as shown in this figure.
Applying the mask can cover these nerves and as they become compressed, This can trigger the TCR leading to apnea & reductions in HR and blood pressure (in the case of V1).
What About In Preterm Infants?
Preterm infants are a good group to study this phenomenon in as they as a group are more apt to need respiratory support after birth and have increased tendency towards apena and bradycardia compared to their term counterparts. That is what was done in a retrospective fashion by researchers from the Czech Republic who restarted research that largely occured in the early 1980s on the TCR so congratulations to them for digging this up and deciding to look at this in preterm infants.
The Study
Kypers KL et al published The effect of a face mask for respiratory support on breathing in preterm infants at birth in Resuscitation in late 2019. The study retrospecitively looked at the immediate delivery room outcomes for 429 infants (median (IQR) gestational age of 28+6 (27+1-30+4) weeks and divided them into those born who breathed but needed respiratory support with a mask and those who were apneic at birth.
As shown in the above table of the 368 babies who showed signs of breathing but had a facemask applied to provide either PEEP or anticipate the need for PPV about half stopped breathing after facemask application. In the figure below it is worth noting that the median time for this to happen was only 5 seconds and the duration of apnea was almost half a minute with 80% of these babies needing PPV to come out of it. Of those who continued breathing there were marked differences in timing of respiratory support and whether sustained inflations were employed. You were also more likely to intubate the infant if they had stopped breathing.
Lastly, there was an inverse correlation seen between gestational age and likelihood of apnea after facemask application of 1.424 (1.281 – 1.583 95% CI)
What are the implications here?
The TCR appears to happen in preterm infants when you apply a mask to support respiration more commonly than at term and the risk increases as GA decreases. This is not a good combination as it means that those that are at increasing risk of lung injury from positive pressure ventilation may be at higher risk of going apneic soley from placement of a mask over the mouth and nose. Yet this has been a staple of neonatal resuscitation for as long as I and I suspect almost anyone can remember.
What I think this really begs for is a follow-up study on the use of nasal prongs placed in the nares to provide CPAP right after delivery. This approach is what we in our centre strive to do anyway but there are many centres I suspect that still employ the mask and bag to provide CPAP either through a PEEP valve or manually compressing the exit flow end of the anaesthesia bag. If compression of the tissues around the mouth and nose could be averted, could the TCR be avoided as well with the use of prongs in this fashion. If a patient goes apneic after a mask is placed over the mouth and nose and then goes on to require PPV with provision of large tidal volumes to a 26 week infants lungs the damage is likely done and the die cast that this infant will develop enough lung injury to potentially be labelled as having BPD down the road.
I would like to thank the authors again for picking up on research that is over 35 years old and sparking new life into this area of Neonatology!
In recent years we have moved away from measuring and reporting gastric residuals. Checking volumes and making decisions about whether to continue feeding or not just hasn’t been shown to make any difference to care. If anything it prolongs time to full feeds without any demonstrable benefits in reduction of NEC. This was shown in the last few years by Riskin et al in their paper The Impact of Routine Evaluation of Gastric Residual Volumes on the Time to Achieve Full Enteral Feeding in Preterm Infants. Nonetheless, I doubt there is a unit in the world that has not had the following situation happen. It is 2 AM and the fellow on call is notified that they need to come and see a patient. On arrival the bedside nurse shows them a syringe that contains dark green murky fluid. The fellow is told that NG tube placement was just being checked and this is what was aspirated. The infant is fine in terms of exam but the question is asked “What should I do with this fluid”. The decision is made that the fluid looks “gross” and they discard it and then decide to resume feedings with a fresh batch of milk. Both parties feel good about discarding what looked totally unappealing for anyone to ingest and the night goes on. If this sounds familiar it should as I suspect this happens frequently.
Logical Fallacy
A colleague of mine introduced me to this concept and I think it may apply here. Purdue University’s writing lab defines a Logical Fallacy in this way “Fallacies are common errors in reasoning that will undermine the logic of your argument. Fallacies can be either illegitimate arguments or irrelevant points, and are often identified because they lack evidence that supports their claim.”
I think we may have one here that has pervaded Neonatology across the globe. Imbedded in the fallacy is the notion that because the dark green aspirates look gross and we often see such coloured aspirates in patients with necrotizing enterocolitis or other bowel disease, all green aspirates must be bad for you. The second fallacy is that the darker the aspirate the more seriously you should consider discarding it. This may surprise you but on their own there isn’t much of anything that has been shown to be wrong with them. Looking for evidence to demonstrate increased rates of NEC or other abdominal issues in an otherwise well patient finds pretty much nothing to support discarding.
The main reason for the share of this paper is what is in Table 3.
Although not significantly different the mean estimates for concentration of bile acids in the pale and dark green aspirates came close to being different. Other nutritional content such as fat, protein and carbohydrate were no different. As the bile became darker though the bile acids tended to increase. It is this point that is worthy of discussion.
A Breakdown of the Aspirate
I’m with you. When you look at that murky dark green fluid in the syringe it just seems wrong to put that back into a belly. Would you want to eat that? Absolutely not but when you break it down into what is in there, suddenly it doesn’t seem so bad. We assume that we would not want to refeed such putrid looking material and that is where the logical fallacy exists. What evidence do we have that refeeding that fluid is bad? As I said above not much at all. Looking at the fact that there is actual nutritional calories in that fluid and bile acids as well you come to realize that throwing it away may truly not be in the best interest of the baby. Calories may wind up in the garbage and along with them, bile acids.
Bile acids are quite important in digestion as they help us digest fat and moreover as they enter the ileum they are reabsorbed in large quantities which go to further help digestion. In addition bile acid concentrations are what helps draw fluid into bile and promotes bile flow. By throwing these bile acids out we could see lower bile volumes and possible malabsorption from insufficient emulsification of fat.
The other unmeasured factors in this fluid are the local hormones produced in the bowel such as motilin which helps with small bowel contractility. Loss of this hormone might lead to impairment of peristalsis which can lead to other problems such as bacterial overgrowth and malabsorption.
Now all of this is speculative I will admit and to throw out one dark green aspirate is not going to lead to much harm I would think. What if this was systematic though over 24 or 48 hours that such aspirates were being found and discarded. Might be something there, What I do think the finding of such aspirates should trigger however is a thorough examination of the patient as dark green aspirates can be found in serious conditions such as NEC or bowel perforation. In the presence of a normal examination with or without laboratory investigations what I take from this study is that we should question are tendency to find and discard. Maybe the time has come to replace such fear with a practice of closing our eyes and putting that dark green aspirate right back where it came from.
