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.
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!
It’s Father’s Day so why not put out a post about a role for father’s in resuscitation. Given that we are talking about a parent being present for resuscitation after delivery and the mother will have just delivered, what follows is a discussion about having the other parent present at the ensuing resuscitation if needed. This will of course not always be a father as in female same sex parenting so what follows could apply to any situation in which there are two parents present and one has just delivered.
Since I was a resident this question has been batted around. During a resuscitation is it better to have families present or not? Certainly work has been done in this area which has demonstrated that from the families perspective this is a worthwhile pursuit. Families wish to be present and as a parent myself I would say it would be far more frightening to be kept out of the room than invited in to see what is going on. A mind can often conjure up scenarios that are far worse than actually exist if left to ourselves. I think in many centres now this is the case that families are invited into the room when their infant is being resuscitated but looking at things from another standpoint the question becomes what effect this has on the team doing the work? Does the team perceive that their workload is increased and if so could this affect performance?
An Answer to this question?
Dr. Schmölzer and his team in Edmonton (my former place of work) have atttempted to answer this question by looking at initial resuscitations in the delivery suite. Their study Does parental presence affect workload during neonatal resuscitation? used a tool I was unfamiliar with called the multidimensional National Aeronautics and Space Administration Task Load Index (TLX) survey to assess workload. After a resuscitation team members were invited to fill out the survey anonymously and in total 204 submissions were done. Degree of intervention after delivery included requiring stimulation 149 (73%) and suction 130 (64%), 120 (59%) continuous positive airway pressure, 105 (52%) positive pressure ventilation, 33 (16%) intubation, 10 (5%) chest compression, and 4 (2%) reported administration of epinephrine during resuscitation.
Results and Thoughts
Looking at the raw scores on the TLX the difference was highly significant in favour of having a parent present.
When further subdividing by apgar scores an interesting finding emerges in that as the apgar score increases the workload decreases. Even in the lowest apgar range the workload though appears to be equivalent.
I wonder if the finding results from being able to kill two birds with one stone? Part of the duty for any health care provider performing a resuscitation is to inform the parent of what is happening. When a patient is not doing well a provider might feel distracted and torn between providing the immediate care required and keeping the family abreast of what is happening. Having the family member present to see exactly what is going on reduces the amount of communication using descriptions and having to explain what they mean. Being able to point at an infant on CPAP and having respiratory distress for example is far easier with the parent present to point at the finding of indrawing than taking the time to explain it. I suppose the number of questions might even be lower in that circumstance. If a baby is quite ill at birth though and receiving chest compressions or epinephrine I would imagine it would be difficult to educate the family concurrently so explaining in detail what has been happening might be deferred to a later time point and hence the workload might be no different. What the data does suggest to me though is that in addition to previous research demonstrating benefits of families being part of the resuscitation for themselves, the team is no worse off in terms of workload and might even benefit from having them there as well.
The next logical study will look at resuscitations on the unit rather than in the case room but I think the question that was talked about as a resident can be put to rest.
If you have been following this blog for awhile you may recall a post from a couple years back on Physiological based cord clamping. The premise of that paper was that rather than arbitrarily choosing a time to clamp the cord, one should look for the following three features that indicate adequate pulmonary blood flow has been established:
1. Establishment of adequate breathing(average tidal volume > 4 ml/kg) on CPAP – using a mask capable of measuring expired volumes
2. HR above 100 BPM
3. SpO2 above the 25th percentile using an FiO2 <0.4
In the original trial it was a proof of concept design that sought to determine if resuscitation on their “Concord” table was feasible and how long would it take for the above criteria to be met so the cord could be clamped.
The mean time for cord clamping in that trial was 4 minutes and 23 seconds. This is much longer than the typical delayed clamping of 30 -60 seconds and even longer than the few studies that have looked at delays of 1- 3 minutes.
The Next Phase
The same group now sought to compare DCC of 30 – 60 seconds with the PBCC approach for infants <32 weeks gestational age in the paper Physiological-based cord clamping in very preterm infants – Randomised controlled trial on effectiveness of stabilisation. This trial was set up as a non-inferiority trial to see if the pre-defined difference in time to stability of 75 seconds would be crossed. A power calculation was performed that indicated the authors would need to recruit 64 infants with 32 in each arm. Due to poor recruitment the authors chose to stop the trial early with only 17 infants in the DCC group and 22 infants in the PBCC arm. An analysis with those patients identified that the non-inferiority limit had been met already.
Difference in resuscitation
Infants randomised to the DCC group had their cords clamped at 30-60 seconds and had their resuscitation started on a resuscitation table. Infants in the PBCC arm were placed on the Concord after delivery and had their resuscitation performed there. Care afterwards would have been similar.
They found that the mean time to stabilisation was 5:54 +/- 2:27 in the PBCC group and 7:07 +/-2:54 in the DCC groups. The mean difference was 1:19 min (95% CI -3:04 to 0:27 min). The results clearly demonstrated a finding of shorter time to stabilisation in the PBCC arm as shown in the figure.
As the confidence interval crossed 0 though in the intention to treat analysis we can say that PBCC is no worse than DCC but can’t say it is superior as a strategy overall. Perhaps larger numbers may have shown something different but at least we know it isn’t worse.
One thing that I would imagine Obstetricians would be concerned with here is the potential for significant blood loss since uterotonics were not provided until the cord was clamped which in PBCC was quite a bit longer, Opposite to what one would have expected the mean blood loss in the DCC group was 450 mL compared to 300 mL in the PBCC arm. Not different statistically though given the small numbers.
There were almost twice the number of females in the PBCC group which could account for some of the findings here. Another difference worth noting was that respiratory support was initiated earlier on the concord than on the standard resuscitation table which the authors acknowledge may be due to familiarity with doing so from experience with the specialized set up. Earlier ventilation (1:11 min vs 2 min in the DCC) could indeed lead to earlier reaching of the end points of the stabilisation criteria.
Regardless of the last couple points, what is needed now is a much larger study to look at clinical outcomes. The numbers were so small here to really examine such clinical points but this is where I believe we are now headed. If the pattern continues I guess we will see another study coming from this group in a couple years so stay tuned!
This post has the potential to be polarizing as sustained inflations while common as an approach after delivery in Europe has not been widely adopted in Canada and the United States. Some time ago I wrote about sustained inflations and a reader commented that I should wait for the results of the The Sustained Aeration for Infant Lungs (SAIL) trial before forming a final opinion on whether this is a good strategy or not. The previous blog post on this topic was Is It Time To Use Sustained Lung Inflation in NRP? and was followed by Is expired CO2 the key to making sustained inflation a standard in resuscitation? The first post concluded that there was a concerning trend towards more IVH in those who received sustained inflations (SI) while the second showed both a reduction in BPD and duration of mechanical ventilation with this approach. I suggested that maybe we were really onto something here and then I was asked to wait before coming to a conclusion until the SAIL trial was done. Well that day has come.
The SAIL trial
This trial led by Dr. H. Kirpalani and involving 18 NICUs in 9 countries was a big endeavour. The paper was just published and is entitled Effect of Sustained Inflations vs Intermittent Positive Pressure Ventilation on Bronchopulmonary Dysplasia or Death Among Extremely Preterm Infants The SAIL Randomized Clinical Trial. The trial compared SI of 15 seconds at a peak pressure of 20 cmH2O, followed if needed by a second SI of 15 seconds
at a peak of 25 cmH2O to traditional PPV for infants who after initial 30 seconds of CPAP required further intervention to establish breathing. These were provided via facemask or nasopharyngeal tune attached to a t-piece resuscitator. In both groups after the initial intervention standard resuscitation steps were carried out. The primary outcome was death or BPD at 36 weeks PMA. A data safety monitoring board (DSMB) was formed as well and it is this group that became very important to the conclusions of the study and led to its early termination. All infants were 23 weeks 0 days’ to 26 weeks 6 days’ GA. Before the study was terminated the final totals were 215 patients in the SI arm and 211 in the traditional PPV group.
The trial was stopped after the DSMB identified an excessive number of early deaths within 48 hours in the SI group. The findings were “11 of 16 early deaths in the sustained inflation group vs 1 of 3 in the standard
resuscitation group were considered possibly related to allocation group”. A number of these deaths occurred in the highest risk group of those born at 23-24 weeks but it was enough to stop recruitment.
With respect to the primary outcome the results showed no difference between the two approaches. In saying this however, if the study did not recruit enough patients as planned to demonstrate a difference one has to question whether the study had enough power to find a benefit.
To answer this question the authors performed a Bayesian Analysis to determine the probability that adding more patients would have led to a different conclusion. That is to determine if they would have found a difference favouring SI. In the end they found that their conclusions would not have changed. Sustained inflations in infants from 23 weeks 0 days’ to 26 weeks 6 days’ GA do not confer a benefit and may be associated with a higher likelihood of death within 48 hours of birth.
What do we do with these results?
I think this is it. I can’t see a research ethics board allowing another study at this point. This by neonatal standards was a big study given the relative scarcity of infants at these gestational ages. The fact that no difference was found in rates of death or survival with BPD for those at highest risk of these outcomes suggests to me that looking at older GA at birth will not produce different results. Sustained inflation to establish FRC and initiate respiration was a good concept backed by animal research. Moreover, clinical work out of Edmonton in recent years suggested potential benefits but with the publication of this study I suspect we will need as a neonatal community to look at other strategies to decrease rates of BPD. Concerns over increased risk of death in my opinion mean this ship has SAILed,
Just about all of our preterm infants born at <29 weeks start life out the same in terms of neurological injury. There are of course some infants who may have suffered ischemic injury in utero or an IVH but most are born with their story yet to be told. I think intuitively we have known for some time that the way we resuscitate matters. Establishing an FRC by inflating the lungs of these infants after delivery is a must but as the saying goes the devil is in the details.
One hundred and sixty five infants comprised this cohort. Overall, 124 (75%) infants were in the high volume group compared to 41 (25%) with a mean VT<6 mL/kg. Median Vt were 5.3 (4.6-5.7) ml/kg for the low group and 8.7
(7.3-10.6) mL/kg which were significantly different.
When looking at the rates of IVH and the severity of those affected the results are striking. Hydrocephalus, following IVH developed in 7/49 (14%) and 2/16 (13%) in the >6 mL/kg and <6 mL/kg VT groups. Looking at other factors that could affect the outcome of interest the authors noted the following physiologic findings. Oxygen saturations were lower in the low volume group at 6, 13 and 14 min after birth while tissue oxygenation as measured by NIRS was similarly lower at 7,8 and 25 min after birth (P<0.001). Conversely, heart rate was significantly lower in the VT>6 mL/kg group at 5, 20 and 25 min after birth (P<0.001). Fraction of inspired oxygen was similar in both groups within the first 30 min. Systolic, diastolic and mean blood pressure was similar between the groups. What these results say to me is that despite having lower oxygen saturations and cerebral oxygen saturation at various time points in the first 25 minutes of life the infants seem to be better off given that HR was lower in those given higher volumes despite similar FiO2. Rates of volume support after admission were slightly higher in the high volume group but inotrope usage appears to be not significantly different. Prophylactic indomethacin was used equally in the two cohorts.
Thoughts for the future
Once a preterm infant is admitted to the NICU we start volume targeted ventilation from the start. In the delivery room we may think that we do the same by putting such infants on a volume guarantee mode after intubation but the period prior to that is generally done with a bag and mask. Whether you use a t-piece resuscitator or an anesthesia bag or even a self inflating bag, you are using a pressure and hoping not to overdistend the alveoli. What I think this study demonstrates similar to the previous work by this group is that there is another way. If we are so concerned about volutrauma in the NICU then why should we feel any differently about the first few minutes of life. Impairment of venous return from the head is likely to account for a higher risk of IVH and while a larger study may be wished for, the results here are fairly dramatic. Turning the question around, one could ask if there is harm in using a volume targeted strategy in the delivery room? I think we would be hard pressed to say that keeping the volumes under 6 mL/kg is a bad idea. The challenge as I see it now is whether we rig up devices to accomplish this or do the large medical equipment providers develop an all in one system to accomplish this? I think the time has come to do so and will be first in line to try it out if there is a possibility to do a trial.