Endotracheal and IV epinephrine go head to head

Endotracheal and IV epinephrine go head to head

For some time the Neonatal Resuscitation Program has recommended IV epinephrine preferentially over the endotracheal route. I have written about epinephrine twice before with the last one being Is epinephrine via the ETT really so bad? Previous studies looking at epinephrine has really asked the question “How likely am I to get return of spontaneous circulation (ROSC) if I give endotracheal epinephrine and follow this with IV epinephrine?” This really doesn’t address the question on which the recommendation for IV epinephrine has been made which is if you actually give the first dose of epinephrine IV to you get a a faster ROSC.

Why might one better than the other?

It probably makes sense to start here. In a patient with poor cardiac output or asystole, injecting epinephrine into the heart via the intravascular route (at birth through a UVC most likely) leads to deposition of the drug within the heart. With cardiac compressions blood passes through the right ventricle to the lung and then back to the left side with eventual passage of blood containing epinephrine to the coronary arteries. Epinephrine then can stimulate the heart to begin pumping or with more vigour leading to increased carotid blood flow which is the all important need for perfusing the brain. In the case of endotracheal epinephrine one is relying on the absorption of the drug from the alveolar capillary interface and for this to be effective, ideally the whole dose of the drug provided would need to be distributed to the terminal airways. If you don’t have great blood flow in the case of asystole and compressions are not effective it stands to reason that there are multiple reasons why the drug might not get to the coronaries in the same way as if given directly into the venous return to the heart.

Let’s go head to head

It should come as no surprise that given the push to give the first dose IV there would over time be a shift to having a large enough sample to look at a direct comparison vs looking at IV AFTER ETT. There will of course still be those that give the fist dose via ETT as it really is just much easier. As you move through the steps of NRP you reach placement of the ETT faster than placement of a UVC and having been there it really is tempting since you have the option to give the first dose via the ETT. Remember the speed with which you can give the first dose as that will come up again later in this piece.

Halling et al published Use of Initial Endotracheal Versus Intravenous Epinephrine During Neonatal Cardiopulmonary Resuscitation in the Delivery Room: Review of a National Database. The article is as described wherein the authors examined in a retrospective fashion the responses to a first dose via IV vs ETT to see how they differ. Their sample size was fairly decent for a neonatal study. Their group under study were taken from a larger pool of 1288 patients who had received chest compressions. Of those 538 had both chest compressions and epinephrine and after excluding 130 for various reasons this left 408 patients for study. The newly born infants were on average about 31-32 weeks gestational age and about 55% in both groups were under 34 weeks at birth. There were 281 patients with an initial dose via the ETT and 127 with dosing first via the IV route. Looking at Table II from the study reveals some surprising findings.

Those who received their first dose via the endotracheal route had a statistically higher chance of having ROSC at 70.11% vs 58.27%. Additional doses to achieve ROSC could have been again via the ETT or IV and in the Initial ETT group, of the 281 patients, 169 received only ETT epinephrine of whom 132 had ROSC while 113 received IV epinephrine after ETT of which 65 achieved ROSC. If you look at secondary outcomes the chance of ROSC after only the first dose was also equal in both groups at 34.16 and 36.22% with a trend towards greater survival with an initial dose of ETT epinephrine. This would seem to fly in the face of prior studies would it not? Are the drugs equally efficacious or is something else going on here?

I believe the difference in outcomes relates to the final line in the above table. Patients who were given ETT epinephrine as the first dose had a median time to first dose of 2 minutes shorter. As I mentioned above the placement of the ETT comes before UVC placement in the stepwise progression of NRP so you just have an opportunity to get the epinephrine in faster. As shown in the next figure, the relationship between timing of dosing and ROSC can be seen.

Final Thoughts

There isn’t anything wrong with giving IV epinephrine but the question is can you really give it at the same time as you would through the ETT? If a myocardium is stunned from hypoxia and is either beating very slowly or asystolic it may be that the extra two minutes of inadequate perfusion matters in terms of getting the heart muscle to respond. I suspect this is the reason why if you compare ETT vs IV dosing and look at the response to a first dose to achieve ROSC there is no difference. I could argue that the IV dose is actually superior as it can achieve the same chance of ROSC after one dose even if given two minutes later. If you look at the overall effect though of starting with an earlier dose via ETT your chances of successful resuscitation and survival may be better if you start with the ETT. The purists out there will no doubt point out that the trial here is retrospective so it is possible that there are factors that have not been taken into account that are unbalanced between groups. My counter to that however is that this may be the near best evidence we will get. I am not sure if a true RCT will ever be done as it would be very difficult I suspect for practitioners to follow NRP and delay giving epinephrine via the ETT when it is right there and a patient is doing quite poorly. There would be some of course who would but I could see many breaches in protocol from nervous team members.

I think what the study really says is that if you choose to start with ETT epinephrine it doesn’t preclude you from trying to place a UVC quickly following the first dose and following up with an IV dose. This sort of research is quite reassuring to those who still give the first dose via the ETT but doesn’t negate efforts that should be made to establish IV access in those most severely compromised.

Endotracheal and IV epinephrine go head to head

What is the optimal depth of chest compressions to achieve return of spontaneous circulation (ROSC)

If you work in Neonatology or in Pediatrics for that matter there is no doubt that at some point you took the neonatal resuscitation program (NRP). Ideally you should be recertified every year or two years depending on your profession. In the course you are taught that the depth of chest compressions required to achieve the best chances of ROSC is 1/3 the diameter of the chest. The evidence to support this comes from a CT evaluation of neonatal thoraces in the paper Evaluation of the neonatal resuscitation program’s recommended chest compression depth using computerized tomography imaging. In this study the authors found that using a mathematic model the 1/3 chest compression recommendation should in theory yield the best hemodynamic outcome.

What about ROSC?

Hemodynamics is one thing in a model but what about real life? I don’t think you could reasonably do an RCT these days with the outcome of interest being ROSC in humans. What research ethics board would allow you to randomize to the outcome of death in babies and deviate from an international organizations recommendations for best practice? My former colleagues in Edmonton had an answer to this issue though by using a piglet model to test the hypothesis that 33% is indeed better than either 12.5%, 24% or 40% chest compression depth. Their paper Assessment of optimal chest compression depth during neonatal cardiopulmonary resuscitation: a randomised controlled animal trial tackles just that question.

How did they do it? In an animal lab that is equipped with a mechanical device to simulate chest compressions they were able to instrument piglets and after asphyxiating them with an occluded ETT they began the process of trying to revive them. After being asphyxiated they initiated a combination of PPV with a neopuff and gave epinephrine (0.02 mg/kg/dose) intravenously2 min after the start of positive pressure ventilation and every 3 min until ROSC with a maximum of three doses, with a maximum resuscitation time of 10 min. The groups were divided in the following manner.

What did they find?

Two very interesting things came out of the study. The first was that they abandoned the 12.5% group early in the study when it became apparent that no piglet would survive using this depth. The other thing they found in support of greater depths of 33 and 40% compression depth is shown in the following graph.

The authors found that in terms of systolic and diastolic blood pressure the best chances in particular for systolic blood pressure were the 33 and 40% compression depths. Looking at the bottom right figure it is also evident that cerebral blood flow increases with increasing depth of compression.

With respect to the primary outcome they found this:

The median (IQR) time to ROSC was 600 (600–600) s, 135 (90–589) s, 85 (71–158)* s and 116 (63–173)* s for the 12.5%, 25%, 33% and 40% AP depth groups, respectively (p<0.001 vs 12.5% AP depth group). The number of piglets that achieved ROSC was 0 (0%), 6 (75%), 7 (88%)** and 7 (88%)** in the 12.5%, 25%, 33% and 40% AP depth groups, respectively (*p<0.05 and **p<0.005 vs 12.5% AP depth group).

Of note, one of the piglets randomized to 40% depth of compression had pulmonary contusions at autopsy.

Putting it all together

The article supports the use of 33-40% chest compression but it raises an important point in my mind. The study used a mechanical device to ensure the percentage compression and it is clear that if you fall below these numbers the ROSC and hemodynamics is impaired while if you go to high you run the risk of damaging the lungs (I know it was just one but a previous study demonstrated harm at 50% compression depth as well).

This raises the question about failed resuscitations. Do we know how deep we are actually compressing during these situations? Sure, everyone can recite that we should be compressing to 1/3 of the chest diameter but what are we actually doing? In some cases are we not doing enough and in other cases doing way to much? I would imagine the answer to this question is yes. I do wonder as we continue to automate so much in our world through advances in technology if doing the same in neonatal resuscitation is not that far off. When our hands are sweaty and tremulous with adrenaline coursing through our veins how good are we really at controlling the precise depth of compression. Time will tell what happens but what is clear to me is that precision matters and really how precise can we be?

Say what!? Applying a mask to resuscitate preterm infants causes apnea.

Say what!? Applying a mask to resuscitate preterm infants causes apnea.

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!

Put me in! Care provider workload reduced when parents are present for resuscitations.

Put me in! Care provider workload reduced when parents are present for resuscitations.

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.

SAIL away. The death of sustained inflations for resuscitation.

SAIL away. The death of sustained inflations for resuscitation.

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,

 

High tidal volume during PPV for infants

High tidal volume during PPV for infants <29 weeks GA linked to IVH

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.

The Edmonton group led by Dr. Schmolzer has had several papers examined in these blogs and on this occasion I am reviewing an important paper that really is a follow-up study to a previous one looking at the impact of high tidal volume delivery after birth.  I have written on this previous paper before in It’s possibile! Resuscitation with volume ventilation after delivery.  On this occasion the authors have published the following paper; Impact of delivered tidal volume on the occurrence of intraventricular haemorrhage in preterm infants during positive pressure ventilation in the delivery room.This observational study had a simple enough premise.  Will the use of Vt > 6 mL/kg in infants given PPV for at least two minutes lead to worse rates of IVH?  All infants were < 29 weeks and if they had chest compressions or epinephrine were excluded.  All infants were treated equally in terms of delayed cord clamping and antenatal steroid provision.  Ventilation was done with a t-piece resuscitator and Vt measured with an NM3 monitor connected to the face mask.  First ultrasounds were done for all at 3 days of age.

What did the authors find?

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.

IVH in the high VT group was diagnosed in 63 (51%) infants compared with 5 (13%) infants in the normal VT group (P=0.008).Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the high VT group and 2/41 (6%) in the normal VT group (P=0.01)

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.