Can’t intubate to give surfactant? Maybe try this!

Can’t intubate to give surfactant? Maybe try this!

Intubation is not an easy skill to maintain with the declining opportunities that exist as we move more and more to supporting neonates with CPAP.  In the tertiary centres this is true and even more so in rural centres or non academic sites where the number of deliveries are lower and the number of infants born before 37 weeks gestational age even smaller.  If you are a practitioner working in such a centre you may relate to the following scenario.  A woman comes in unexpectedly at 33 weeks gestational age and is in active labour.  She is assessed and found to be 8 cm and is too far along to transport.  The provider calls for support but there will be an estimated two hours for a team to arrive to retrieve the infant who is about to be born.  The baby is born 30 minutes later and develops significant respiratory distress.  There is a t-piece resuscitator available but despite application the baby needs 40% oxygen and continues to work hard to breathe.  A call is made to the transport team who asks if you can intubate and give surfactant.  Your reply is that you haven’t intubated in quite some time and aren’t sure if you can do it.  It is in this scenario that the following strategy might be helpful.

Surfactant Administration Through and Laryngeal Mask Airway (LMA)

Use of an LMA has been taught for years in NRP now as a good choice to support ventilation when one can’t intubate.  The device is easy enough to insert and given that it has a central lumen through which gases are exchanged it provides a means by which surfactant could be instilled through a catheter placed down the lumen of the device.  Roberts KD et al published an interesting unmasked but randomized study on this topic Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial. Due to size limitations (ELBWs are too small to use this in using LMA devices) the eligible infants included those from 28 0/7 to 35 6/7 weeks and ≥1250 g.  The infants needed to all be on CPAP +6 first and then fell into one of two treatment groups based on the following inclusion criteria: age ≤36 hours,
(FiO2) 0.30-0.40 for ≥30 minutes (target SpO2 88% and 92%), and chest radiograph and clinical presentation consistent with RDS.
Exclusion criteria included prior mechanical ventilation or surfactant administration, major congenital anomalies, abnormality of the airway, respiratory distress because of an etiology other than RDS, or an Apgar score <5 at 5 minutes of age.

Procedure & Primary Outcome

After the LMA was placed a y-connector was attached to the proximal end.  On one side a CO2 detector was placed and then a bag valve mask in order to provide manual breaths and confirm placement over the airway.  The other port was used to advance a catheter and administer curosurf in 2 mL aliquots.  Prior to and then at the conclusion of the procedure the stomach contents were aspirated and the amount of surfactant determined to provide an estimate of how much surfactant was delivered to the lungs.  The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life.  Treatment failure was defined upfront and required 2 of the following: (1) FiO2 >0.40 for >30
minutes (to maintain SpO2 between 88% and 92%), (2) PCO2 >65 mmHg on arterial or capillary blood gas or >70 on venous blood gas, or (3) pH <7.22 or 1 of the following: (1)  recurrent or severe apnea, (2) hemodynamic instability requiring pressors, (3) repeat surfactant dose, or (4) deemed necessary by medical provider.

Did it work?

It actually did. Of the 103 patients enrolled (50 LMA and 53 control) 38% required intubation in the LMA group vs 64% in the control arm.  The authors did not reach their desired enrollment based on their power calculation but that is ok given that they found a difference.  What is really interesting is that they found a difference in the clinical end point despite many infants clearly not receiving a full dose of surfactant as measured by gastric aspirate. Roughly 25% of the infants were found to have not received any surfactant, 20% had >50% of the dose in the stomach and the other 50+% had < 10% of the dose in the stomach meaning that the majority was in fact deposited in the lungs.  I suppose it shouldn’t come as a surprise that among the secondary outcomes the duration length of mechanical ventilation did not differ between two groups which I presume occurred due to the babies needing intubation being similar.  If you needed it you needed it so to speak. Further evidence though of the effectiveness of the therapy was that the average FiO2 30 minutes after being treated was significantly lower in the group with the LMA treatment 27 vs 35%.  What would have been interesting to see is if you excluded the patients who received little or no surfactant, how did the ones treated with intratracheal deposition of the dose fare?  One nice thing to see though was the lack of harm as evidenced by no increased rate of pneumothorax, prolonged ventilation or higher oxygen.

Should we do this routinely?

There was a 26% reduction in intubations in te LMA group which if we take this as the absolute risk reduction means that for every 4 patients treated with an LMA surfactant approach, one patient will avoid intubation.  That is pretty darn good!  If we also take into account that in the real world, if we thought that little of the surfactant entered the lung we would reapply the mask and try the treatment again.  Even if we didn’t do it right away we might do it hours later.

In a tertiary care centre, this approach may not be needed as a primary method.  If you fail to intubate though for surfactant this might well be a safe approach to try while waiting for a more definitive airway.  Importantly this won’t help you below 28 weeks or 1250g as the LMA is too small but with smaller LMAs might this be possible.  Stay tuned as I suspect this is not the last we will hear of this strategy!

Automated control of FiO2; one step closer

Automated control of FiO2; one step closer

It has been over two years since I have written on this subject and it continues to be something that I get excited about whenever a publication comes my way on the topic.  The last time I looked at this topic it was after the publication of a randomized trial comparing in which one arm was provided automated FiO2 adjustments while on ventilatory support and the other by manual change.  Automated adjustments of FiO2. Ready for prime time? In this post I concluded that the technology was promising but like many new strategies needed to be proven in the real world. The study that the post was based on examined a 24 hour period and while the results were indeed impressive it left one wondering whether longer periods of use would demonstrate the same results.  Moreover, one also has to be wary of the Hawthorne Effect whereby the results during a study may be improved simply by being part of a study.

The Real World Demonstration

So the same group decided to look at this again but in this case did a before and after comparison.  The study looked at a group of preterm infants under 30 weeks gestational age born from May – August 2015 and compared them to August to January 2016.  The change in practice with the implementation of the CLiO2 system with the Avea ventilator occurred in August which allowed two groups to be looked at over a relatively short period of time with staff that would have seen little change before and after.  The study in question is by Van Zanten HA The effect of implementing an automated oxygen control on oxygen saturation in preterm infants. For the study the target range of FiO2 for both time periods was 90 – 95% and the primary outcome was the percentage of time spent in this range.  Secondary outcomes included time with FiO2 at > 95% (Hyperoxemia) and < 90, <85 and < 80% (hypoxemia). Data were collected when infants received respiratory support by the AVEA and onlyincluded for analysis when supplemental oxygen was given, until the infants reached a GA of 32 weeks

As you might expect since a computer was controlling the FiO2 using a feedback loop from the saturation monitor it would be a little more accurate and immediate in manipulating FiO2 than a bedside nurse who has many other tasks to manage during the care of an infant.  As such the median saturation was right in the middle of the range at 93% when automated and 94% when manual control was used. Not much difference there but as was seen in the shorter 24 hour study, the distribution around the median was tighter with automation.  Specifically with respect to ranges, hyperoxemia and hypoxemia the following was noted (first number is manual and second comparison automated in each case).

Time spent in target range: 48.4 (41.5–56.4)% vs 61.9 (48.5–72.3)%; p<0.01

Hyperoxemia  >95%: 41.9 (30.6–49.4)% vs 19.3 (11.5–24.5)%; p<0.001

< 90%: 8.6 (7.2–11.7)% vs 15.1 (14.0–21.1)%;p<0.0001

< 85%: 2.7 (1.4–4.0)% vs 3.2 (1.8–5.1)%; ns

Hypoxemia < 80%: 1.1 (0.4–1.7)% vs 0.9 (0.5–2.1)%; ns

What does it all mean?

I find it quite interesting that while hyperoxemia is reduced, the incidence of saturations under 90% is increased with automation.  I suspect the answer to this lies in the algorithmic control of the FiO2. With manual control the person at the bedside may turn up a patient (and leave them there a little while) who in particular has quite labile saturations which might explain the tendency towards higher oxygen saturations.  This would have the effect of shifting the curve upwards and likely explains in part why the oxygen saturation median is slightly higher with manual control.  With the algorithm in the CLiO2 there is likely a tendency to respond more gradually to changes in oxygen saturation so as not to overshoot and hyperoxygenate the patient.  For a patient with labile oxygen saturations this would have a similar effect on the bottom end of the range such that patients might be expected to drift a little lower then the target of 90% as the automation corrects for the downward trend.  This is supported by the fact that when you look at what is causing the increase in percentage of time below 90% it really is the category of 85-89%.

Is this safe? There will no doubt be people reading this that see the last line and immediately have flashbacks to the SUPPORT trial which created a great deal of stress in the scientific community when the patients in the 85-89% arm of the trial experienced higher than expected mortality.  It remains unclear what the cause of this increased mortality was and in truth in our own unit we accept 88 – 92% as an acceptable range.  I have no doubt there are units that in an attempt to lessen the rate of ROP may allow saturations to drop as low as 85% so I continue to think this strategy of using automation is a viable one.

For now the issue is one of a ventilator that is capable of doing this.  If not for the ventilated patient at least for patients on CPAP.  In our centre we don’t use the Avea model so that system is out.  With the system we use for ventilation there is also no option.  We are anxiously awaiting the availability of an automated system for our CPAP device.  I hope to be able to share our own experience positively when that comes to the market.  From my standpoint there is enough to do at the bedside.  Having a reliable system to control the FiO2 and minimize oxidative stress is something that may make a real difference for the babies we care for and is something I am eager to see.

Is  expired CO2 the key to making sustained inflation a standard in resuscitation?

Is expired CO2 the key to making sustained inflation a standard in resuscitation?

We can always learn and we can always do better.  At least that is something that I believe in.  In our approach to resuscitating newborns one simple rule is clear.  Fluid must be replaced by air after birth and the way to oxygenate and remove CO2 is to establish a functional residual capacity.  2000px-Lungvolumes.svgThe functional residual capacity is the volume of air left in the lung after a tidal volume of air is expelled in a spontaneously breathing infant and is shown in the figure. Traditionally, to establish this volume in a newborn who is apneic, you begin PPV or in the spontaneously breathing baby with respiratory distress provide CPAP to help inflate the lungs and establish FRC.

Is there another way?

Something that has been discussed now for some time and was commented on in the most recent version of NRP was the concept of using sustained inflation (SI) to achieve FRC. I have written about this topic previously and came to a conclusion that it wasn’t quite ready for prime time yet in the piece Is It Time To Use Sustained Lung Inflation In NRP?

The conclusion as well in the NRP textbook was the following:

“There are insufficient data regarding short and long-term safety and the most appropriate duration and pressure of inflation to support routine application of sustained inflation of greater than 5 seconds’ duration to the transitioning newborn (Class IIb, LOE B-R). Further studies using carefully designed protocols are needed”

So what now could be causing me to revisit this concept?   I will be frank and admit that whenever I see research out of my old unit in Edmonton I feel compelled to read it and this time was no different.  The Edmonton group continues to do wonderful work in the area of resuscitation and expand the body of literature in such areas as sustained inflation.

Can you predict how much of a sustained inflation is needed?

This is the crux of a recent study using end tidal CO2 measurement to determine whether the lung has indeed established an FRC or not.  Dr. Schmolzer’s group in their paper (Using exhaled CO2 to guide initial respiratory support at birth: a randomised controlled trial) used end tidal CO2 levels above 20 mmHg to indicate that FRC had been established.  If you have less CO2 being released the concept would be that the lung is actually not open.  There are some important numbers in this study that need to be acknowledged.  The first is the population that they looked at which were infants under 32 6/7 weeks and the second is the incidence of BPD (need for O2 or respiratory support at 36 weeks) which in their unit was 49%.  This is a BIG number as in comparison for infants under 1500g our own local incidence is about 11%.  If you were to add larger infants closer to 33 weeks our number would be lower due to dilution.  With such a large number though in Edmonton it allowed them to shoot for a 40% reduction in BPD (50% down to 30%).  To accomplish this they needed 93 infants in each group to show a difference this big.

So what did they do?

For this study they divided the groups in two when the infant wouldn’t breathe in the delivery room.  The SI group received a PIP of 24 using a T-piece resuscitator for an initial 20 seconds.  If the pCO2 as measured by the ETCO2 remained less than 20 they received an additional 10 seconds of SI.  In the PPV group after 30 seconds of PPV the infants received an increase of PIP if pCO2 remained below 20 or a decrease in PIP if above 20.  In both arms after this phase of the study NRP was then followed as per usual guidelines.

The results though just didn’t come through for the primary outcome although ventilation did show a difference.

Outcome SI PPV p
BPD 23% 33% 0.09
Duration of mechanical ventilation (hrs) 63 204 0.045

The reduction in hours of ventilation was impressive although no difference in BPD was seen.  The problem though with all of this is what happened after recruitment into the study.  Although they started with many more patients than they needed, by the end they had only 76 in the SI group and 86 in the PPV group.  Why is this a problem?  If you have less patients than you needed based on the power calculation then you actually didn’t have enough patients enrolled to show a difference.  The additional compounding fact here is that of the Hawthorne Effect. Simply put, patients who are in a study tend to do better by being in a study.  The observed rate of BPD was 33% during the study.  If the observed rate is lower than expected when the power calculation was done it means that the number needed to show a difference was even larger than the amount they originally thought was needed.  In the end they just didn’t have the numbers to show a difference so there isn’t much to conclude.

What I do like though

I have a feeling or a hunch that with a larger sample size there could be something here.  Using end tidal pCO2 to determine if the lung is open is in and of itself I believe a strategy to consider whether giving PPV or one day SI.  We already use colorimetric devices to determine ETT placement but using a quantitative measure to ascertain the extent of open lung seems promising to me.  I for one look forward to the continued work of the Neonatal Resuscitation–Stabilization–Triage team (RST team) and congratulate them on the great work that they continue doing.

Is our approach to ventilation harming babies?

Is our approach to ventilation harming babies?

A grenade was thrown this week with the publication of the Australian experience comparing three epochs of 1991-92, 1997 and 2005 in terms of long term respiratory outcomes. The paper was published in the prestigious New England Journal of Medicine; Ventilation in Extremely Preterm Infants and Respiratory Function at 8 Years. This journal alone gives “street cred” to any publication and it didn’t take long for other news agencies to notice such as Med Page Today. The claim of the paper is that the modern cohort has fared worse in the long run. This has got to be alarming for anyone reading this! As the authors point out, over the years that are being compared rates of antenatal steroid use increased, surfactant was introduced and its use became more widespread and a trend to using non-invasive ventilation began. All of these things have been associated with better short term outcomes. Another trend was declining use of post-natal steroids after 2001 when alarms were raised about the potential harm of administering such treatments.

Where then does this leave us?

I suppose the first thing to do is to look at the study and see if they were on the mark. To evaluate lung function the study looked at markers of obstructive lung disease at 8 years of age in survivors from these time periods. All babies recruited were born between 22-27 completed weeks so were clearly at risk of long term injury. Measurements included FEV1, FVC, FVC:FEV1 and FEF 25-75%. Of the babies measured the only two significant findings were in the FEV1 and ratio of FEV1:FVC. The former showed a drop off comparing 1997 to 2005 while the latter was worse in 2005 than both epochs.

Variable 1991-92 1997 2005
%predicted value N=183 N=112 N=123
FEV1 87.9+/-13.4 92.0+/-15.7 85.4+/-14.4
FEV1:FVC 98.3+/-10 96.8+/-10.1 93.4+/-9.2

This should indeed cause alarm. Babies born in a later period when we thought that we were doing the right things fared worse. The authors wonder if perhaps a strategy of using more CPAP may be a possible issue. Could the avoidance of intubation and dependence on CPAP for longer periods actually contribute to injury in some way? An alternative explanation might be that the use of continuous oximetry is to blame. Might the use of nasal cannulae with temporary rises in O2 expose the infant to oxygen toxicity?

There may be a problem here though

Despite everyone’s best efforts survival and/or BPD as an outcome has not changed much over the years. That might be due to a shift from more children dying to more children living with BPD. Certainly in our own centre we have seen changes in BPD at 36 weeks over time and I suspect other centres have as well. With concerted efforts many centres report better survival of the smallest infants and with that they may survive with BPD. The other significant factor here is after the extreme fear of the early 2000s, use of postnatal steroids fell off substantially. This study was no different in that comparing the epochs, postnatal glucocorticoid use fell from 40 and 46% to 23%. One can’t ignore the possibility that the sickest of the infants in the 2005 cohort would have spent much more time on the ventilator that their earlier counterparts and this could have an impact on the long term lung function.

Another question that I don’t think was answered in the paper is the distribution of babies at each gestational age. Although all babies were born between 22-27 weeks gestational age, do we know if there was a skewing of babies who survived to more of the earlier gestations as more survived? We know that in the survivors the GA was not different so that is reassuring but did the sickest possible die more frequently leaving healthier kids in the early cohorts?

This bigger issue interestingly is not mentioned in the paper. Looking at the original cohorts there were 438 in the first two year cohort of which 203 died yielding a survival of 54% while in 1997 survival increased to 70% and in 2005 it was 65%. I can’t help but wonder if the drop in survival may have reflected a few more babies at less than 24 weeks being born and in addition the holding of post natal steroids leading to a few more deaths. Either way, there are enough questions about the cohorts not really being the same that I think we have to take the conclusions of this paper with a grain of salt.

It is a sensational suggestion and one that I think may garner some press indeed. I for one believe strongly though as I see our rates of BPD falling with the strategies we are using that when my patients return at 8 years for a visit they will be better off due to the strategies we are using in the current era. Having said that we do have so much more to learn and I look forward to better outcomes with time!

It’s possible! Resuscitation with volume ventilation after delivery.

It’s possible! Resuscitation with volume ventilation after delivery.

I know how to bag a baby.  At least I think I do.  Providing PPV with a bag-valve mask is something that you are taught in NRP and is likely one of the first skills you learned in the NICU.  We are told to squeeze the bag at a rate of 40-60 breaths a minute.  According to the Laerdal website, the volume of the preterm silicone bag that we typically use is 240 mL.  Imagine then that you are wanting to ventilate a baby who is 1 kg.  How much should you compress the bag if you wish to delivery 5 mL/kg.  Five ml out of a 240 mL bag is not a lot of squeeze is it?  Think about that the next time you find yourself squeezing one.  You might then say but what about a t-piece resuscitator?  A good choice option as well but how much volume are you delivering if you set the initial pressures at 20/5 for example?  That would depend on the compliance of the lung of course.  The greater the compliance the more volume would go in. Would it be 5 mL, 10 ml or even 2.5 mL based on the initial setting?  Hard to say as it really depends on your seal and the compliance of the lung at the pressure you have chosen.  If only we had a device that could deliver a preset volume just like on a ventilator with a volume guarantee setting!

Why is this holy grail so important?

It has been over 30 years since the importance of volutrauma was demonstrated in a rabbit model. Hernandez LA et al published Chest wall restriction limits high airway pressure-induced lung injury in young rabbits. The study used three models to demonstrate the impact of volume as opposed to pressure on injuring the lung of preterm rabbits.  Group 1 were rabbit ventilated at pressures of 15/30/45 cm H2O for one hour, group 2 rabbits with a cast around their thorax to limit volume expansion and group 3 sets of excised lungs with no restriction to distension based on the applied pressures.  As you might expect, limitation of over distension by the plaster cast led the greatest reduction in injury (measured as microvascular permeability) with the excised lungs being the worst.  In doing this study the authors demonstrated the importance of over distension and made the case for controlling volume more than pressure when delivering breaths to avoid excessive tidal volume and resultant lung injury.

The “Next Step” Volume Ventilator BVM

Perhaps I am becoming a fan of the Edmonton group.  In 2015 they published A Novel Prototype Neonatal Resuscitator That Controls Tidal Volume and Ventilation Rate: A Comparative Study of Mask Ventilation in a Newborn Manikin.  The device is tablet based and as described, rather than setting a PIP to deliver a Vt, a rate is set along with a volume to be delivered with a peep in this case set at +5.  fped-04-00129-g002_figure2This study compared 5 different methods of delivering PPV to a 1 kg preterm manikin.  The first was a standard self inflating bag, the next three different t-piece resuscitators and then the Next Step.  For the first four the goal was to deliver a pressure of 20/5 at a rate of 40-60 breaths per minute.  A test lung was connected to the manikin such that each device was used for a one minute period at three different levels of compliance (0.5 ml/cmH2O, 1.0 ml/cmH2O and then 2.0 ml/cm H2O representing increasing compliance.  The goal of the study was to compare the methods in terms of delivering a volume of 5 mL to this 1 kg model lung.  The order in which the devices were used was randomized for the 25 participants in the study who were all certified in NRP and included some Neonatologists.

Some Concerning Findings

As I said at the beginning, we all like to think we know how to ventilate a newborn with BVM.  The results though suggest that as compliance increases our ability to control how much volume we deliver to a lung based on a best guess for pressures needed is lacking.  One caveat here is that the pressures set on the t-piece resucitators were unchanged during the 1 minute trials but then again how often during one minute would we change settings from a starting point of 20/5?

Vt (mL)
0.5 mL/cmH20 1.0 mL/cmH20 2.0mL/cmH20
Self inflating 11.4 17.6 23.5
Neo-Tee 5.6 11.2 19.3
Neopuff 6.1 10 21.3
Giraffe 5.7 10.9 19.8
Next Step 3.7 4.9 4.5

Without putting in all the confidence intervals I can tell you that the Next Step was the tightest.  What you notice immediately (or at least I did) was that no matter what the compliance, the self inflating bag delivers quite an excessive volume even in experienced hands regardless of compliance.  At low compliance the t-piece resuscitators do an admirable job as 5-6 ml/kg of delivered Vt is reasonable but as compliance improves the volumes increase substantially.  It is worth pointing out that at low compliance the Next Step was unable to deliver the prescribed Vt but knowing that if you had a baby who wasn’t responding to ventilation I would imagine you would then try a setting of 6 ml/kg to compensate much like you would increase the pressure on a typical device. How might these devices do in a 29 week infant for example with better compliance than say a 24 week infant?  You can’t help but wonder how many babies are given minutes of excessive Vt after birth during PPV with the traditional pressure limited BVM setup and then down the road how many have BPD in part because of that exposure.

I wanted to share this piece as I think volume resuscitation will be the future.  This is just a prototype or at least back then it was.  Interestingly in terms of satisfaction of use, the Next Step was rated by the participants in the study as being the easiest and most comfortable to use of all the devices studied.  Adding this finding to the accuracy of the delivered volume and I think we could have a winner.