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
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.
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. In 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!
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. As 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 (1.3–3.4) 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 (49–98) /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!
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 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.
||HFNC +/- CPAP (1546)
|CPAP d (median, IQR)
|HFNC d (median, IQR)
|HFNC +/- CPAP
|BPD or death %
|Multiple ventiation courses
|More than 3 vent courses
|Ventilator d (median, IQR)
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.
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. As 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.