Has permissive hypercapnia failed to deliver?

Positive pressure ventilation puts infants at risk of developing chronic lung disease (CLD). Chronic lung disease in turn has been linked many times over, as a risk for long term impacts on development.  So if one could reduce the amount of positive pressure breaths administered to a neonate over the course of their hospital stay, that should reduce the risk of CLD and by extension developmental impairment.  At least that is the theory.  Around the start of my career in Neonatology one publication that carried a lot of weight in academic circles was the Randomized Trial of Permissive Hypercapnia in Preterm Infants which randomized 49 surfactant treated infants to either a low (35-45) or high (45-55) PCO2 target with the thought being that allowing for a higher pCO2 should mean that lower settings can be used.  Lower settings on a ventilator would lead to less lung damage and therefore less CLD and in turn better outcomes.  The study in question did show that the primary outcome was indeed different with almost a 75% reduction in days of ventilation and with that the era of permissive hypercapnia was born.

The Cochrane Weigh in

In 2001 a systematic review including this and another study concluded that there was insufficient evidence to support the strategy in terms of a benefit to death or chronic lung disease. Despite this lack of evidence and a recommendation from the Cochrane group that permissive hypercapnia be used only in the context of well designed trials the practice persisted and does so to this day in many places.  A little lost in this discussion is that while the end point above was not different there may still be a benefit of shorter term ventilation.

A modern cohort

It would be unwise to ignore at this point that the babies of the late 90s are different that the ones in the current era.  Surfactant and antenatal steroid use are much more prevalent now.  Ventilation strategies have shifted to volume as opposed to pressure modes in many centres with a shift to early use of modalities such as high frequency ventilation to spare infants the potential harm of either baro or volutrauma.  Back in 2015 the results of the PHELBI trial were reported Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. This large trial of 359 patients randomized to a high or low target pCO2 again failed to show any difference in outcomes in terms of the big ones “death or BPD, mortality alone, ROP, or severe IVH”.  What was interesting about this study was that they did not pick one unified target for pCO2 but rather set different targets as time went on reflecting that with time HCO3 rises so what matters more is maintaining a minimum pH rather than targeting a pCO2 alone which als0 reflects at least our own centre’s practice. There is a fly in the ointment here though and that is that the control group has a fault (at least in my eyes)

Day of life Low Target High Target
1-3 40-50 55-65
4-6 45-55 60-70
7-14 50-60 65-75

In the original studies of permissive hypercapnia the comparison was of a persistent attempt to keep normal pCO2 vs allowing the pCO2 to drift higher.  Although I may get some argument on this point, what was done in this study was to compare two permissive hypercapnia ranges to each other.  If it is generally accepted that a normal pCO2 is 35-45 mmHg then none of these ranges in the low target were that at all.

How did these babies do in the long run?

The two year follow-up for this study was published in the last month; Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. At the risk of sounding repetitive the results of Bayley III developmental testing found no benefit to developmental outcome.  So what can we say?  There is no difference between two strategies of permissive hypercapnia with one using a higher and the other a lower threshold for pCO2.  It doesn’t however address the issue well of whether targeting a normal pCO2 is better or worse although the authors conclude that it is the short term outcomes of shorter number of days on ventilation that may matter the most.

The Truth is Out There

I want to believe that permissive hypercapnia makes a difference.  I have been using the strategy for 15 or so years already and I would like to think it wasn’t poor strategy.  I continue to think it makes sense but have to admit that the impact for the average baby is likely not what it once was.  Except for the smallest of infants many babies these days born at 27 or more weeks of gestation due to the benefits of antenatal steroids, surfactant and modern ventilation techniques spend few hours to days on the ventilator.  Meanwhile the number of factors such chorioamniotitis, early and late onset sepsis and genetic predisposition affect the risks for CLD to a great degree in the modern era.  Not that they weren’t at play before but their influence in a period of more gentle ventilation may have a greater impact now.  That so many factors contribute to the development of CLD the actual effect of permissive hypercapnia may in fact not be what it once was.

What is not disputed though is that the amount of time on a ventilator when needed is less when the strategy is used.  Let us not discount the impact of that benefit as ask any parent if that outcome is of importance to them and you will have your answer.

So has permissive hypercapnia failed to deliver?  The answer in terms of the long term outcomes that hospitals use to benchmark against one and other may be yes.  The answer from the perspective of the baby and family and at least this Neonatologist is no.

You don’t plan to fail. You fail to plan

I am fortunate to work with a group of inter-professionals who strive for perfection.  When you connect such people with those with skills in multimedia you create the opportunity for education.  I can’t say enough about the power of education and moreover the ability to improve patient outcomes when it is done well.

With this post I am going to be starting to share a collection of videos that I will release from time to time.  The hope with any release like this is that you the reader wherever you are may find some use from these short clips.  My thanks to the team that put these together as the quality is beyond compare and the HD quality is great for viewing on any device.

Placing A Chest Tube Can Be A Difficult Thing

As I said to a colleague in training the other day, a chest tube may seem daunting but once you see how it is done it loses some of its intimidation.  Having said that, once you see it placed it can be a long time between opportunities for you to view another.  That is where having a repository of videos comes in that you can watch prior to the next opportunity.  These very short clips are easy to access when needed and may calm the nerves the next time you are called to place a chest tube.

A Word About Chest Tubes

The videos in question demonstrate how to place a Thal quick chest tube. figure-1-the-thal-quick-chest-tube-set-including-introducer-needle-wire-guideIn case this looks foreign to you it may be because you are using the older generation style of chest tubes that come equipped with a trocar.  Even without the use of the trocar, these rigid tubes carry a significant risk of lung laceration or other tissue injury.  For a review of such complications related to chest tube insertion see Thoracostomy tubes: A comprehensive review of complications and related topics.

The jury as they say is still out with respect to the use of these softer chest tube sets.  There is no question that they are easier to place than the traditional thoracostomy tube.  Their pliability though does carry a significant risk of kinking or blockage as we have seen in some patients when the Thal chest tube set is used to drain fluid in particular.  Less of an issue with air leaks.

Start of a series

This post I suppose marks a slightly new direction for the blog.  While I thoroughly enjoy educating you with the posts about topics of interest I see an opportunity to help those who are more visual in their learning.  The videos will be posted over the next while with accompanying written posts such as this.  They can be accessed on my Youtube channel at

All Things Neonatal YouTube

To receive regular updates as new videos are added feel free to subscribe!

Lastly a big thank you to NS, RH and GS without whom none of this would have been possible!


Just how safe is feeding while on CPAP?

This is becoming “all the rage” as they say.  I first heard about the strategy of feeding while on CPAP from colleagues in Calgary.  They had created the SINC * (Safe Individualized Feeding Competence) program to provide an approach to safely introducing feeding to those who were still requiring CPAP.  As news of this approach spread a great deal of excitement ensued as one can only imagine that in these days when attainment of oral feeding is a common reason for delaying discharge, could getting an early start shorten hospital stay?  I could describe what they found with the implementation of this strategy but I couldn’t do it the same justice as the presenter of the data did at a recent conference in Winnipeg.  For the slide set you can find them here.  As you can imagine, in this experience out of Calgary though they did indeed find that wonderful accomplishment of shorter hospital stays in the SINC group.  We have been so impressed with the results and the sensibility of it all that we in fact have embraced the concept and introduced it here in both of our units.  The protocol for providing this approach is the following.eating-in-sinc-algorithm

I have to admit, while I have only experienced this approach for a short time the results do seem to be impressive.  Although anecdotal a parent even commented the other day that she felt that SINC was instrumental in getting her baby’s feeding going!  With all this excitement around this technique I was thrown a little off kilter when a paper came out suggesting we should put a full stop to feeding on CPAP!

Effect of nasal continuous positive airway pressure on the pharyngeal swallow in neonates

What caused my spirits to dampen? This study enrolled preterm infants who were still on CPAP at ≥ 34 weeks PMA and were taking over 50% of required feeding volumes by NG feeding.  The goal was to look at 15 patients who were being fed on CPAP +5 and with a mean FiO2 of 25% (21-37%) using video fluoroscopic swallowing studies to determine whether such patients aspirate when being fed.  The researchers became concerned when each of the first seven patients demonstrated abnormalities of swallowing function indicating varying degrees of aspiration.  As such they took each patient off CPAP in the radiology suite and replaced it with 1 l/min NP to achieve acceptable oxygen saturations and repeated the study again.  The results of the two swallow studies showed remarkable differences in risk to the patient and as such the recruitment of further patients was stopped due to concerns of safety and a firm recommendation of avoiding feeding while on CPAP was made.

Table 2. Percentage of all swallows identified with swallowing dysfunction
on-nCPAP off-nCPAP
Variable Mean ± s.d. Mean ± s.d. Median (q1–q3) Mean ± s.d. Median (q1–q3) P-value
Mild pen. % 20.1±16 20 (4.5–35) 15.4± 7.6 20 (9–20) 0.656
Deep pen. % 43.7±15.4 38.5 (30–59) 25.3± 8.8  25 (18.2–32) 0.031
Aspiration % 33.5±9.4 30 (27.3–44.4) 14.6± 7 15 (9.1–20) 0.016
Nasopharyngeal reflux   % 42.8±48.5 18.2 (0–100) 44.2± 45.4 18.2 (5–92) 0.875

Taking these results at face value it would seem that we should put an abrupt halt to feeding while on CPAP but as the saying goes the devil is in the details…

CPAP Using Ram Cannulae

Let me start off by saying that I don’t have any particular fight to pick with the RAM cannulae.  They serve a purpose and that is they allow CPAP to be delivered with a very simple set of prongs and avoid the hats, straps and such of more traditional CPAP devices. We have used them as temporary CPAP delivery when moving a patient from one area to another.  As the authors state the prongs are sized in order to ensure the presence of a leak.  This has to do with the need to provide a way for the patient to exhale when nasal breathing.  Prongs that are too loose have a large leak and may not deliver adequate pressure while those that are too tight may inadvertently deliver high pressure and therefore impose significant work of breathing on the patient.nonivasive-respiratory-support-niv-high-frequency-ventilation-hfv-63-638  Even with appropriate sizing these prongs do not allow one to exhale against a low pressure or flow as is seen with the “fluidic flip” employed with the infant flow interface. With the fluidic flip, exhalation occurs against very little resistance thereby reducing work of breathing which is not present with the use of the RAM cannula.

A comparison of the often used “bubble CPAP” to a variable flow device also showed lower work of breathing when variable flow is used.

The Bottom Line

Trying to feed an infant who is working against a constant flow as delivered by the RAM cannulae is bound to cause problems.  I don’t think it should be a surprise to find that trying to feed while struggling to breathe increases the risk of aspiration.  Similarly, under treating a patient by placing them on nasal prongs would lead to increased work of breathing as while you may provide the needed O2 it is at lower lung volumes.  Increasing work of breathing places infants at increased risk of aspiration.  That is what I would take from this study.  Interestingly, looking at the slide set from Calgary they did in fact use CPAP with the fluidic flip.  Smart people they are.  It would be too easy to embrace the results of this study and turn your nose to the SINC approach to feeding on CPAP.  Perhaps somewhere out there someone will read this and think twice about abandoning the SINC approach and a baby will be better for it.

* SINC algorithm and picture of the fluidic flip courtesy of Stacey Dalgleish and the continued work of Alberta Health Services


Autopilot Non-Invasive Ventilation

I had a chance recently to drive a Tesla Model S with autopilot. Taking the car out on a fairly deserted road near my home I flicked the lever twice to activate the autopilot feature and put my hands behind my head while the vehicle took me where I wanted to go.  Tesla Introduces Self-Driving Features With Software UpgradeAs I cruised down the road with the wheel automatically turning with the curves in the road and the car speeding up or slowing down based on traffic and speed limit notices I couldn’t help but think of how such technology could be applied to medicine.  How far away could the self driving ventilator or CPAP device be from development?

I have written about automatic saturation adjustments in a previous post but this referred to those patients on mechanical ventilation.  Automatic adjustments of FiO2. Ready for prime time? Why is this goal so important to attain?  The reasoning lies in the current design trends in modern NICUs.  We are in the middle of a large movement towards single patient room NICUs which have many benefits such as privacy which may lead to enhanced breastfeeding rates and increased parental visitation.  The downside, having spoken to people in centres where such designs are already in place is the challenge nursing faces when given multiple assignments of babies on O2.  If you have to go from room to room and a baby is known to be labile in their O2 saturations it is human nature to turn the O2 up a little more than you otherwise would to give yourself a “cushion” while you are out of the room.  I really don’t fault people in this circumstance but it does pose the question as to whether in a few years we will see a rise in oxygen related tissue injury such as CLD or ROP from such practice.  In the previous post I wrote about babies who are ventilated but these infants will often be one to one nursed so the tendency to overshoot the O2 requirements may be less than the baby on non- invasive ventilation.

A System For Controlling O2 Automatically For Infants on Non-Invasive Ventilation

This month in Archives Dr. Dargaville and colleagues in Australia provide two papers, the first demonstrating the validation of the mathematical algorithm that they developed to control O2 and the second a clinical report outlining how well the system actually performed on patients.  The theoretical paper Development and preclinical testing of an adaptive algorithm for automated control of inspired oxygen in the preterm infant. is a challenge to comprehend although validates the approach in the end while the clinical paper at least for me was easier to digest Clinical evaluation of a novel adaptive algorithm for automated control of oxygen therapy in preterm infants on non-invasive respiratory support.

The study was really a proof of concept with 20 preterm infants (mean GA 27.5 weeks, 8 days of age on average) included who each underwent two hours of manual control by nursing to keep saturations between 90-94% and then 4 hours of automated control (sats 91 – 95%) then back to manual for two hours.  The slightly shifted ranges were required due to the way in which midpoint saturations are calculated. The essential setup was a computer equipped with an algorithm to make adjustments in FiO2 using an output to a motor that would adjust the O2 blender and then feedback from an O2 saturation monitor back to the computer.  The system was equipped with an override to allow nursing to adjust in the event of poor signal or lack of response to the automatic adjustment.

The results though demonstrate that the system works and moreover does a very good job!  The average percentage of time that the saturations were in the target range were significantly better with automated control (81% automated, 56% manual).  As well as depicted in the following figure the amount of time spent in both hypoxic and hyperoxic ranges was considerable with manual control but non-existent on either tail with automated control (defined as < 85% or > 98% where black bars are manual control and white automatic).


From the figure you can see that the amount of time the patients are in target range are much higher with automatic control but is this simply because in addition to automatic control, nurses are “grabbing the wheel” and augmenting the system here?  Not at all.

“During manual control epochs, FiO2 adjustments of at least 1% were made 2.3 (1.33.4) times/hour by bedside staff. During automated control, the minimum alteration to FiO2 of 0.5% was being actuated by the servomotor frequently (9.9 alterations/min overall), and changes to measured FiO2 of at least 1% occurred at a frequency of 64 (4998) /hour. When in automated control, a total of 18 manual adjustments were made in all 20 recordings (0.24 adjustments/hour), a reduction by 90% from the rate of manual adjustments observed during manual control (2.3/hour).”

From the above quote from the paper it is clear that automated control works to keep the saturation goal through roughly 7 X the number of adjustments than nursing makes per hour.  It is hard to keep up with that pace when you have multiple assignments but that is what you need I suppose!  The use of the auto setting here reduced the amount of nursing interventions to adjust FiO2 by 90% and yields tighter control of O2 saturations.

Dare to Dream

Self driving oxygen administration is coming and this proof of concept needs to be developed and soon into a commercial solution.  The risk of O2 damage to developing tissues is too great not to bring this technology forward to the masses.  As we prepare to move into a new institution I sincerely hope that this solution arrives in time but regardless I know our nurses and RRTs will do their best as they always do until such a device comes along.  When it does imagine all of the time that could be devoted to other areas of care once you were able to move away from the non-invasive device!

Does High Flow Really Have A Place in the NICU At All?

This may sound familiar as I wrote about this topic in the last year but the previous post was restricted to infants who were under 1000g.  High Flow Nasal Cannula be careful out there had a main message that suggested the combined outcome of BPD or death was more prevalent when HFNC is used alone or with CPAP than when CPAP is used alone.  The question remains though whether this applies to larger infants.  Without looking at the evidence for that combined outcome most people would say there is unlikely to be a difference.  Larger more mature babies have a much lower risk of BPD or death so proponents of HFNC would say it is simpler to use and helps prevent nasal breakdown as well.  The question remains as to whether all outcomes are the same in larger infants and that is the point of this post.

A Non-Inferiority Trial

First off it is important to understand what this type of trial is.  The first requirement is that the two treatments have both been compared to a placebo and found to be both effective.  Once you establish that you have a choice between two treatment options then you eliminate the placebo and compare them head to head.  What you are looking for in this type of trial is to determine not whether one is better than the other but that there is no difference in a clinical outcome of interest.  If you find no difference then the next step is to look at other outcomes that might be of interest and see if there are any benefits to picking one versus the other.  In the case of CPAP vs HNFC, if a non-inferiority trial showed no difference in an important outcome such as length of stay but nasal breakdown was less with HFNC it might lead a unit to use HFNC for their infants.  Okay, now that we have that cleared up we can move on to an actual study examining this very subject.

Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants.

This was an interesting study with a great name (The HIPSTER trial) that enrolled infants > 28 weeks and 0 days with none of the infants receiving surfactant but either being randomized to HFNC or CPAP after delivery.  These infants were your typical modern day cohort of babies who may avoid intubation and surfactant by establishing FRC early with positive pressure applied to the nose through one of these devices.  The end point for the study was treatment failure within 72 hours.  If an infant failed in the HFNC they could have a trial of CPAP whereas in the CPAP group they were intubated.  For each infant in the HFNC group flow was set from 6-8 l/min and for CPAP 6-8 cmH2O.

Treatment was considered to have failed if an infant receiving maximal support (high-flow therapy at a gas flow of 8 liters per minute or CPAP at a pressure of 8 cm of water) met one or more of the following criteria:

  1. FiO2 of 0.4 or higher
  2. Arterial or free flowing cap gas with a pH of 7.2 or less plus a pCO2 > 60 mm Hg obtained at least 1 hour after starting treatment
  3. Two or more episodes of apnea requiring positive-pressure ventilation within a 24-hour period or six or more episodes requiring any intervention within a 6-hour period.
  4. Infants with an urgent need for intubation and mechanical ventilation.

So what happened?

The trial randomized 583 infants (278 HFNC, 286 CPAP) but was halted by the data and safety monitoring committee after an analysis of the first 515 revealed that the outcome was worse in the HFNC group (25.5% failure rate vs 13.3 for CPAP).  Interestingly treatment failures were more common in babies below and above 32 weeks so it was not just the smallest infants who failed.

table-2Another interesting finding was that the most common reason for treatment failure was criteria 1 (FiO2 > 40%) while intubation was higher for all infants but did not reach statistical significance.  Curiously what did reach a significant difference was criteria #4 (18.4% urgent intubations in the CPAP group vs 5.6% in the HFNC group). You might be tempted to therefore ponder which is worse, a little O2 or being intubated but you need to recall the trial design which was set up to provide this kind of result.  If you failed HFNC you were placed on CPAP whereas if you failed CPAP you were intubated.  In the HFNC group, 78 infants were deemed to have failed but 28 of them were in fact “rescued by CPAP”.  It therefore isn’t a fair comparison when it comes to urgent intubation since if you failed CPAP there wasn’t another option.

Not a total loss

Nasal trauma was indeed much lower in the HFNC group, occurring only 8.3% vs 18.5% of the time with CPAP.  Pneumothorax was also found to be significantly different with none of the patients in the HFNC group having that complication vs 2.1% in the CPAP group.  What this study tells us is that as a primary modality to treat newborns with RDS who have not received surfactant it is preferable to use CPAP in the first 72 hours.  Some of you may say it might not say that at all but consider the impact of having more babies exposed to high FiO2.  We know from other studies that high FiO2 can be quite damaging to preterm infants and this study was certainly not powered to look at all those important outcomes such as ROP, PVL and BPD.  The authors report them and found no difference but without adequate power to show a difference I wouldn’t take much comfort in those findings.

I think were things may settle out though is what to do in more mature infants.  There is no question that for those on chronic respiratory support there is some risk of nasal breakdown.  Although I don’t have much experience with HFNC I would think that for the older patient who either already has BPD at 36 weeks or is close to that point but reliant on +4 or +5 CPAP that HFNC might help “give them a break”.  As such I don’t see this as a total loss but rather an option to try when CPAP for whatever reason is not tolerated.

As a primary therapy for non-invasive management RDS I will keep my CPAP for all babies thank you.


High Flow Nasal Cannula: Be Careful Out There

As the saying goes the devil is in the details.  For some years now many centres worldwide have been publishing trials pertaining to high flow nasal cannulae (HFNC) particularly as a weaning strategy for extubation.  The appeal is no doubt partly in the simplicity of the system and the perception that it is less invasive than CPAP.  Add to this that many centres have found less nasal breakdown with the implementation of HFNC as standard care and you can see where the popularity for this device has come from.

This year a contact of mine Dominic Wilkinson@NeonatalEthics on twitter (if you don’t follow him I would advise having a look!) published the following cochrane review, High flow nasal cannula for respiratory support in preterm infants.  The review as with most cochrane systematic reviews is complete and comes to a variety of important conclusions based on 6 studies including 934 infants comparing use of HFNC to CPAP.

1.  No differences in the primary outcomes of death (typical RR 0.77, 95% CI 0.43 to 1.36; 5 studies, 896 infants) or CLD.

2.  After extubation to HFNC no difference in the rate of treatment failure (typical RR 1.21, 95% CI 0.95 to 1.55; 5 studies, 786 infants) or reintubation (typical RR 0.91, 95% CI 0.68 to 1.20; 6 studies, 934 infants).

3.  Infants randomised to HFNC had reduced nasal trauma (typical RR 0.64, 95% CI 0.51 to 0.79; typical risk difference (RD) -0.14, 95% CI -0.20 to -0.08; 4 studies, 645 infants).

4. Small reduction in the rate of pneumothorax (typical RR 0.35, 95% CI 0.11 to 1.06; typical RD -0.02, 95% CI -0.03 to -0.00; 5 studies 896 infants) in infants treated with HFNC but the RR crosses one so this may be a trend at best.

If one was to do a quick search for the evidence and found this review with these findings it would be very tempting to jump on the bandwagon.  Looking at the review a little closer though there is one line that I hope many do not miss and I was happy to see Dominic include it.

“Subgroup analysis found no difference in the rate of the primary outcomes between HFNC and CPAP in preterm infants in different gestational age subgroups, though there were only small numbers of extremely preterm and late preterm infants.”

In his conclusion he further states:

Further evidence is also required for evaluating the safety and efficacy of HFNC in extremely preterm and mildly preterm subgroups, and for comparing different HFNC devices.

With so few ELBW infants included and with these infants being at highest risk of mortality and BPD our centre has been reluctant to adopt this mode of respiratory support in the absence of solid evidence that it is equally effective to CPAP in these smallest infants.  A big thank you to our Respiratory Therapy Clinical Specialist for harping on this point over the years as the temptation to adopt has been strong as other centres turn to this strategy.

Might Not Be So Safe After All

Now do not take what I am about to say as a slight against my twitter friend.  The evidence to date points to exactly what he and his other coauthors concluded but with the release of an important paper in May by Taka DK et al, I believe caution is needed when it comes to our ELBW infants.

High Flow Nasal Cannula Use Is Associated with Increased Morbidity and Length of Hospitalization in Extremely Low Birth Weight Infants

This paper adds to the body of literature on the topic as it truly focuses on the outcome of infants < 1000g.  While this study is retrospective in nature it does cover a five year period and examines important outcomes of interest to this population.

The primary outcome in this case was death or BPD and whether HFNC was used alone or with CPAP, this was more frequent than when CPAP was used alone.  Other important findings were the need for multiple and longer courses of ventilation in those who received at least some HFNC.  In these times of overburdened health care systems with goals of improving patient flow, it is also worth noting that there was a significant prolongation of length of stay with use of HFNC or HFNC and CPAP.

One interesting observation was that the group that fared the worst across the board was the combination of CPAP and HFNC rather than HFNC alone.

CPAP (941) HFNC (333) HFNC +/- CPAP (1546)
CPAP d (median, IQR) 15(5-28) 7 (1-19)
HFNC d (median, IQR) 14(5-25) 13 (6-23)
HFNC +/- CPAP 15 (5-28) 14(5-25) 26 (14-39)
BPD or death % 50.40% 56.80% 61.50%
BPD % 42.20% 52.20% 59.00%
Multiple ventiation courses 51.10% 53.10% 64.70%
More than 3 vent courses 17.60% 21.00% 29.40%
Ventilator d (median, IQR) 18(5-42) 25 (6-52) 30 (10-58)

I believe the finding may be explained by the problem inherent with retrospective studies.  This is not a study in which patients were randomized to either CPAP, HFNC or CPAP w/HFNC.  If that were the case one would expect lung pathologies and severity of illness to even ou,t such that differences between groups might be explained by the difference in treatments.  In this study though we are looking though the rearview mirror so to speak.  How could we account for the combination being worse than the HFNC alone?  I suspect it relates to the severity of lung disease.  The babies who were placed on HFNC and did well on it might have had less severe chronic changes.  What might be said about those that had the combination?  Well, one could postulate that there might be some who were extubated to HFNC and collapsed needing escalation to CPAP and then failing that therapy were reintubated.  Another explanation could be those babies who were placed on CPAP after extubation and transitioned before their lungs were ready to HFNC may have failed and lost FRC thereby going back to CPAP and possibly intubation.  Exposure in either circumstance to HFNC would therefore put them at risk of further positive pressure ventilation and subsequent further lung injury.  The babies who could tolerate transition to HFNC without CPAP might be intermediary in their outcomes (as they were found to be) as they lost FRC but were able to tolerate it but consumed more calories leaving less for growth and repair of damaged tissue leading to prolonged need for support.

Either way, the use of HFNC was found to lead to worse outcomes and in the ELBW infant should be avoided as routine practice pending the results of a prospective RCT on the subject.

Is it a total ban though?

As with many treatments that one should not consider standard of care there may be some situations where there may be benefit.  The ELBW infant with nasal breakdown from CPAP that despite excellent nursing and RRT attention continues to demonstrate tissue damage is one patient that could be considered.  The cosmetic implications and potential for surgical correction at a later date would be one reason to consider a trial of HFNC but only in the patient that was close to being able to come off CPAP.  In the end I believe that if a ELBW infant needs non invasive pressure support then it should be with CPAP but as there saying goes there may be a right time and a place for even this modality.



Is It Time To Use Sustained Lung Inflation In NRP?

As I was preparing to settle in tonight I received a question from a reader on my Linkedin page  in regards to the use of sustained inflation (SI) in our units.  We don’t use it and I think the reasons behind it might be of interest to others.  The concept of SI is that by providing a high opening pressure of 20 – 30 cm H2O for anywhere from 5 to 15 seconds one may be able to open the “stiff” lung of a preterm infant with RDS and establish an adequate functional residual capacity.  Once the lung is open, it may be possible in theory to keep it open with ongoing peep at a more traditional level of 5 – 8 cm of H20.

The concept was tested 25 years ago by Vyas et al in their article Physiologic responses to prolonged and slow-rise inflation in the resuscitation of the asphyxiated newborn infant.  In this study, 9 newborn infants were given a relatively short 5 second sustained inflation and led to earlier and larger lung volumes with good establishment of FRC.  Like many trials in Neonatology though sceptics abound and here we are 25 years later still discussing the merits of this approach.

As I have a warm place in my heart for the place that started my professional career whenever I come across a paper published by former colleagues I take a closer look.  Such is the case with a systematic review on sustained inflation by Schmolzer et al.  The inclusion criteria were studies of infants born at <33 weeks. Their article provides a wonderful assessment of the state of the literature on the topic and I would encourage you to have a look at it if you would like a good reference to keep around on the topic.  What it comes down to though is that there are really only four randomized human studies using the technique and in truth they are fairly heterogeneous in their design.  They vary in the length of time an SI was performed (5 – 20 seconds), the pressures used (20 – 30 cm H2O), single or multiple SIs and lastly amount of oxygen utilized being 21 – 100%.  In fact three of the four studies used either 100% or in one case 50% FiO2 when providing such treatments.

What Did They Show?

This is where things get interesting.  SI works in the short term by reducing the likelihood that an infant will need mechanical ventilation at 72 hours with a number needed to treat of only 10!  In medicine we normally would embrace such results but sadly the results do not translate into long term benefits as the rate of BPD, mortality and the combined outcome do not remain significant.  Interestingly, the incidence of a symptomatic PDA needing treatment with either a medical or surgical approach had a number needed to harm of 11; an equally impressive number but one that gives reason for concern.  PDAAs the authors speculate, the increased rate of PDA may be in fact related to the good job that the SI does in this early phase.  By establishing an open lung and at an earlier time point it may well be that there is an accentuation in the relaxation of the pulmonary vasculature and this leads to a left to right shunt that by being hemodynamically significant helps to stent the ductus open at a time when it might otherwise be tending to close.  This outcome in and of itself raises concern in my mind and is the first reason to give me reason to pause before adopting this practice.

Any other concerns?

Although non-significant there was a trend towards increased rates of IVH in the groups randomized to SI.  There is real biologic plausibility here.  During an SI the increased positive pressure in the chest could well simulate a similar effect to a pneumothorax and impede the passive drainage of blood from the head into the thorax.  In particular, longer durations and/or frequent SIs could increase such risk.  Given the heterogeneous nature of these studies it is difficult to know if they all had been similar in providing multiple SIs could we have seen this cross over to significant?

I believe the biggest concern in all of this though is that I would have a very hard time applying the results of these studies to our patient population.  The systematic review addresses the question about whether SI is better than IPPV as a lung recruitment strategy in the preterm infant with respiratory distress.  I have to say though we have moved beyond IPPV as an initial strategy in favour of placement of CPAP on the infant directly after birth.  The real question in my mind is whether providing brief periods of SI followed by CPAP of +6 to +8 is better than placement on CPAP alone as a first strategy to establish good lung volumes.

If I am to be swayed by the use of SI someone needs to do this study first.  The possibility of increasing the number of hemodynamically significant PDAs and potentially worsening IVH without any clear reduction in BPD is definitely placing me firmly in the camp of favouring the CPAP approach.  Having said all that, the work by the Edmonton group is important and gives everyone a glimpse into what the current landscape is for research in this field and opens the door for their group or another to answer my questions and any others that may emerge as this strategy will no doubt be discussed for years to come.

Building A Better Mask For PPV

Ask almost anyone who has worked in the field of Neonatology for some time and they will tell you that babies are not as sick as they once were. We can give a lot of credit to better antenatal steroid use, maternal nutrition and general management during pregnancy.  Additionally, after birth we now rush to place infants on CPAP and achieve adequate expansion of the lungs which in many cases staves off intubation.

The downside to our success though is that the opportunities to provide positive pressure ventilation (PPV) and moreover intubation are becoming less and less.  How then do we perform when we are asked to do such procedures on an infrequent basis?  The answer as you might expect is not that well.  Dr. Schmolzer et al studied the ability of people to keep a good seal and found a 29% leak on average with as high as 63% in one patient.  As this was a study in which people were being observed one might think the Hawthorne Effect might artificially decrease the percentage leak compared to real world scenarios when you know you aren’t being watched.

What is the cause of the leak?

Leaks most commonly occur on either side of the nasolabial folds.  Although at least in my experience we educate trainees about this issue it remains a problem.  I would also speculate that at the times when we need to be at our best during an advanced resuscitation involving chest compressions we may well function at our worst.  This is the effect of the adrenalin rushing through our system as our sympathetic system turns into overdrive.  The question therefore is one of getting around human error in particular when we need to minimize such inefficiency the most.

The Solution?

If the masks are prone to leaking and with it the ability to properly ventilate compromised, how could we minimize such human error.  The answer may lie in what I consider to be an ingenious way to apply a mask. The concept and it is just that at the moment is to use suction to apply the mask to the face without risk of leak.  UntitledLorenz L et al have just published a proof of concept study utilizing a mannequin with a “seal skin” layer applied to the face to simulate human skin.  The article is entitled A new suction mask to reduce leak during neonatal resuscitation: a manikin study.

In this study, the mask was applied to the face of the mannequin and 100 cm H2O pressure was applied through a side port on the mask.  There is an inner and outer ring such that the internal 41 mm diameter mask is surrounded by a double wall in which the suction is applied to the space between the two walls leading to the mask seating itself firmly against the face.  The authors then studied the amount of leak found when using a Neopuff set to deliver 40 – 60 breaths per minute at pressures of 25/5.  For this study 60 courses were tested.

How did it do compared to PPV through a traditional mask?

As you might expect (since you can feel my excitement!) it did very well. The average leaks using a conventional approach were quite good at 12.1% but the suction mask was only 0.7% leak.  Importantly the ranges were quite different.   PPV through a conventional mask had a range of 0.6 – 39% leak while with the suction version it was 0.2 – 4.6%.  These results were statistically different.

What does the future hold?

As mentioned this study is what one would consider a proof of concept study.  We do not know how this would fare in the real world and that of course is the next step.  In terms of harm, the authors did note that when applied to the forearm of an adult it caused some mild redness from the suction that vanished quickly on breaking of the seal but we do not know if there could be greater harm in a newborn in particular one who is quite small.  Such testing will be needed as part of any further study.

Having said that I think this rethink of the mask for PPV could be transformative to those who perform neonatal resuscitation infrequently.  If this mask is found not only to be effective in a clinical trial but safe as well I would suggest a change to this type of mask could quite literally be life saving.  Placed in the hands of those who are inexperienced in keeping a seal, PPV would become much more effective and in particular for rural sites the infants being transported in much more stable than some are at present.

Keep your eyes peeled for future work using this mask.  Something tells me if it proves to be efficacious outside of a seal skin covered mannequin, your toolkit for providing NRP may be in for a change.

High Frequency Nasal Ventilation: What Are We Waiting For?

I will admit it.  I resist change at times just like many others.  This may come as a surprise to some of you who have worked with me and accused me of bringing too much change at times to the units.  The truth though is that when one understands something and is enthusiastic about implementation the change does not seem so difficult.  When it isn’t your idea though we may find ourselves a little uneasy about adopting this unfamiliar practice.

Such has been my experience with nasal HFOV.  It is a strategy that has been around for over five years but has seen slow adoption among centres in Canada and has trickled into practice in Winnipeg on a few occasions.  In each occasion when I have been asked about either continuing or perhaps starting this therapy I have shrugged my shoulders and confessed my inexperience with the modality.  Sure I have used HFOV through an ETT but through prongs or a mask?!  How would it work?  Could it cause harm?  What would the actual indications be?  How would our in house physicians and NNPs respond to abnormal gases overnight even if I felt comfortable with using it?  These sorts of questions have led to virtual inertia in my acceptance of the strategy.

Before I go on it would be good to see an example of how it is set up.  The MedinCNO device is capable of delivering such non-invasive HFOV and can be seen in this short video.

One could use the strategy either prophylactically to extubate an infant or as rescue to prevent reintubation if trials of either CPAP or NIPPV were unsuccessful.  HFOV is known to be very effective at clearing CO2 when used through an ETT so perhaps nasal application could also lower pCO2 and achieve a similar effect.  This was tested using a neonatal lung simulator by Mukeji A et al Nasal high-frequency oscillation for lung carbon dioxide clearance in the newborn.  In this study CO2 was introduced into the manequin and the amount of exhaled CO2 determined while on CPAP, NIPPV and nasal HFOV.  Interestingly during CPAP no exhaled CO2 could be detected while CO2 clearance occurred during NIPPV and nasal HFOV although it was three-fold greater with HFOV.  In theory then CO2 clearance would appear to be better so in the case of ventilatory failure as evidenced by CO2 retention this modality would seem to win out.

Clinical Evidence for Use

There is one RCT in term infants with TTN to support the practice while the rest are unblinded case series with no controls. Four Canadian NICUs recently described their experience however using a retrospective analysis.  Included were 79 instances of HFOV distributed as follows; 73% utilized as rescue from another mode and in 27% used as the primary mode for extubation.  The outcomes are shown in the table:Table 2

In 45% of cases the patients needed  intubation after first trialing CPAP or NIPPV while in 33% of cases following extubation the infants needed replacement of the endotracheal tube.  The numbers here are small so it is difficult to truly compare them to other studies with confidence but reintubation rates of 40-44% have been noted recently when using NIPPV or CPAP so the numbers are at least consistent.

One aspect though that caught my eye was the duration of use for HFOV across these 79 patients.  The median use was 57 hours with the longest duration being just over 400 hours.  It would seem that the use of this modality for the most part is as a bridge to something else.  The median duration of 2.5 days is much shorter than the weeks that some of our smallest infants remain on CPAP/NIPPV for.  Whether for rescue or prophylaxis this is not a long term option.

Another point worth noting though is the question of whether it is the pressure or oscillatory wave that is leading to success.  As the authors note, there were a wide range in applications of MAP, delta P and frequency.

MAP ranges from 8 – 24 cm H2O while frequency from 6 – 14 hz and amplitude varied widely depending on the device used but was as high as 100%.  While high MAP has been used invasively though an ETT I can’t help but wonder if in some cases the real benefit was the high MAP.  What would happen for example if the centres had simply raised the CPAP to 10, 12 or even higher?

In the end it would seem that in principal it is an effective therapy that may be able to remove CO2 more efficiently than the other modes.  What we don’t have are RCTs in the smallest babies comparing HFOV to NIPPV or CPAP with adequate power to detect differences.  I suspect these will come soon enough but what do we do in the meantime?   The main reservation I have has to do with safety.  We truly have little if any data on this without proper trials to ease such worry.  When a patient is in front of us though and is failing CPAP or NIPPV what are we to do?  Should we intubate or trial this modality based on the evidence thus far?

I might be tempted to trial HFOV in this circumstance but as with any new therapy we need education for all staff.  Everyone caring for our infants need to understand what they are using and how to respond based on clinical findings.  This is the real issue with safety that I see and until such time that we have widespread education across RRT, nursing and medicine I would suggest we use this with trepidation.  This is not a rejection of the modality in the least but rather a call to come together as a team and see how implement this in such a way that will provide direction to caregivers, provide a consistent approach with respect to length of use, indications and when to change direction entirely.  Time to call a meeting of the minds I think.


Extubation failure is not a failure itself

The decision to extubate an extremely low birthweight infant is one of the most common sources of disagreement and anxiety in the NICU.  As a resident, I recall an unwritten rule that “no baby under 750g will have a trial of extubation as they will most certainly fail”.  As time went on however, studies suggested that not only is this a false statement but also that the duration of intubation was directly correlated with risk of BPD. As Danan described, for infants less than a 1000g, delaying extubation when they had reached minimal settings did not result in lower rates of BPD. Moreover 60 – 70% of infants who have such extubation attempts are not reintubated within a week, so it is possible to have success.

The detractors however express concern about the 30-40% who do require reintubation and worry that harm will be caused by such acts.  Frequent concerns are voiced with respect to potential trauma to the airway leading to subglottic stenosis; potentially increasing the risk of BPD and finally the belief that attempts are futile so why put parents through the stress in the midst of perceived near certain failure.  The problem with these perceptions however is that they are mostly the culmination of confirmation bias.  Patients that have multiple failed extubations are remembered especially when they develop significant complications, while the ones who extubate successfully are quickly forgotten.  This is not intentional in any way but simply a human tendency to follow the pattern of “the squeaky wheel getting the grease”.  The preemies who do poorly are front and centre as they take up a great deal of our time & attention while the ones who do very well while celebrated, are not as easily remembered for the success they demonstrated when extubated.

Being someone who believes in extubating as soon as possible though I was surprised several months ago to find a paucity of data demonstrating that there was in fact support for the practice in terms of better outcomes being associated with early extubation.  While small studies certainly pointed in that direction the real question was about to be answered in the study that follows.

Is it better to fail multiple times or be intubated once for the duration of ventilation.

This is the central question that I believe has been answered as good as it will ever be by EA Jensen et al in JAMA this past month “Effects of Multiple Ventilation Courses and Duration of Mechanical Ventilation on Respiratory Outcomes in Extremely Low-Birth-Weight Infants.”  This retrospective review included 3343 infants below 1000g and examined the primary outcome of BPD and secondary outcomes of death, continued supplemental oxygen use at the time of discharge, and tracheostomy among survivors.  As you might expect, regardless of whether one compared duration of ventilation or number of reintubations, variables such as need for surfactant, postnatal dexamethasone, PDA treatment and NEC became more common as exposure to either outcome increased.  poi150060t4When a logistic regression model was applied though it became evident that the odds ratio for BPD increased to a much greater degree with increasing duration of ventilation than the number of attempts.

To quote the authors:

“After adjustment for the cumulative duration of mechanical ventilation, a greater number of ventilation courses was not associated with an increase in the risk-adjusted odds of supplemental oxygen use at discharge. The number of ventilation courses remained associated with increased risk of BPD only among infants exposed to 4 or more courses.”

The Needs of The Many Outweigh The Needs of The Few

In other words, for an infant to have an increased risk of BPD they would need to have failed extubation four or more times!  It is not easy to predict with certainty who these children will be but if we take these findings as accurate (since I believe we will not see an RCT of this magnitude anytime soon) is it ethical to keep a child intubated due to the belief that they might fail?  On the contrary, how can we not try when failure is not associated with adverse outcome?  In fact none of the secondary outcomes were found to be increased either. Importantly, there was no difference in the need for a tracheostomy in this population which may serve as a proxy for lack significant airway injury from multiple intubations. The goal of this post is to provide all of us who care for these preemies with the reassurance that if they fail extubation, once, twice and even three times that is still a good thing.  For the ones that fail more than that, if only we had a crystal ball we might have spared them that risk but given that we live in a world without this ability, we owe it to our patients to try.  Moreover, we owe it to the parents of these children to educate them that failure can still be a good thing.

May I never have a near 100% success at extubating my patients on the first try.  If I truly care for them I will embrace my failures and know that I have done the right thing.