This post is special to me. A redemption of sorts. When I was a fellow in Edmonton in the early 2000s my fellowship project was to see whether heliox (helium/oxygen) given to piglets with meconium aspiration syndrome (MAS) would improve ventilation and measures of pulmonary hypertension vs controls. Why heliox? There had been work done with this gas for other conditions and the lower viscosity of the gas (who hasn’t sucked on a helium balloon to see the effect of helium) means that the flow of the gas in a tube is more linear that regular air. Turbulent flow as with air/oxygen mixtures creates more resistance to flow than linear flow with heliox. Imagine if you will this linear flow slipping more easily past particles of meconium partially blocking airways and you get the idea of why heliox might work. One thing to bear in mind though is that as your FiO2 goes up the percentage of helium drops so the properties described work best at low FiO2 so flow is more linear.
I collected meconium from diapers in the NICU and created a NS slurry of meconium and then instilled it into the trachea’s of these piglets through a tracheostomy (they were too small to intubate for me at least). A flow probe was put around the pulmonary artery to look for evidence of pulmonary hypertension. We saw some interesting trends but the paper never saw the light of day for a variety of reasons that I won’t go in to here. Originally I had wanted to do the study as a small RCT in humans but I was advised that although heliox is an inert gas I should do the animal study first. That was the end of the heliox story as far as I was concerned as I hadn’t thought much about it since that time. I will admit though that anytime I had a baby with bad meconium aspiration syndrome though the thought did pop into my head.
The Study Has Arrived
Imagine my surprise when this week an RCT from China entitled A randomized single‐center controlled trial of synchronized intermittent mandatory ventilation with heliox in newborn infants with meconium aspiration syndrome came across my inbox. The authors used a power calculation based on some previous work in RDS using heliox to determine they needed 28 neonates in each arm to show a difference. In the end they managed 71 total with 35 in the heliox and 36 in the control arm. Inclusion criteria were a diagnosis of MAS on x-ray, GA ≥37 weeks and ≤42 weeks, need for intubation due to a pH <7.2/PCO2 >60 mmHg. The study could not be blinded as one would not be able to hide the large tanks for heliox so for any study like this it would be unavoidable. One thing that differs in terms of management from my own practice is that the authors in this study used SIMV pressure limited ventilation as the ventilatory strategy as opposed to AC/VG that my unit would typically use. Initial ventilator PIP of 15–28 cmH2O, PEEP of 4–10 cmH2O, and RR of 15–45 breaths/min; FiO2 of 0.21 to 1 to reach the target oxygen saturation (SpO2) of 90%–95%. The intervention group received heliox for 6 hours and then switched over to air/oxygen while the control group was ventilated with air/oxygen from the start. The extubation criteria included PIP ≤15 cmH2O, gradually enhanced effective spontaneous breathing, a ventilator breathing frequency ≤10/min, and normal blood gas analysis results. The main outcomes were PaO2/FiO2 (P/F), the extubation time and the hospital length of stay in the NICU. Aside from measuring the ventilatory responses and time of extubation the authors also examined the effect of heliox as an anti-inflammatory agent based on previous results demonstrating markers of inflammation can be attenuated by use of the gas.
To start with, the babies in both arms were equivalent at the start of the study in terms of inflammatory markers and some clinical variables.
As you will see from the following figures a number of important findings are noted. The main marker of oxygenation used for this study was the PaO2/FiO2 ratio and this was statistically different (301 ± 22 vs. 260.64 ± 24.83, p < .001). Secondly, extubation time (78 ± 30 vs. 114 ± 28.07, p < .001 and length of hospital stay in days were also shorter 15.3 ± 4.2 vs. 19.11 ± 4.01, p < .001.
The authors state that the following markers of pO2, pH and pCO2 shown in the graphs were all significantly improved in the heliox group but looking at the first two I find that hard to believe as the curves look almost superimposed. pCO2 however could be different in particular given the linear flow described above so ventilation might be improved.
Finally, across the board, markers of inflammation were noted to improve with administration of heliox as well as markers of myocardial injury. The gas may have done what it was supposed to do.
I wish the conclusions were that easy
I want to like this paper so badly. Sadly, I have some pretty significant reservations. It is helpful to see that the two groups began at a similar PaO2/FiO2 ratio. What is missing though is the ventilatory requirements to get to that point. There is no information provided as to the mean airway pressures or PIP/PEEP for each group over time to get a sense of whether the two groups in terms of severity of illness were the same. Yes we know that the inflammatory markers at the start were similar but could the difference in changes of inflammation relate to a progressive rise in the control group that were just sicker rather than a protective effect of heliox to reduce inflammation? Also when one looks at the change in pCO2 how do you interpret that without knowing the minute ventilation to achieve those data points? It is really unfortunate that the authors did not use oxygenation index (MAP X FiO2/PaO2) as this would have taken the ventilation component at least into account. Would be helpful as well to know the weaning strategy in each group as without blinding might the authors have reacted more aggresively with weaning of the ventilator to get to extubatable settings knowing that the babies were receiving the intervention. As there was no weaning strategy planned out from the start we can only guess. Lastly, one could have possibly gotten around the inability to hide the heliox tanks by having a Neonatologist not on service take each blood gas data and sight unseen suggest changes to ventilation without being able to see which arm a baby was in.
I will end on a positive note though. It has been almost twenty years since I did the piglet study using heliox. I had always hoped that this research would see the light of day in a human model although my piglet data didn’t show much benefit however the intervention was shorter than this study. I think this study is worthy of being repeated using a different mode of ventilation that does not rely on manual changes to PIP but rather by using a VG mode the baby would be gradually weaned as compliance improves. Any further study needs to address differences that were missing from this paper as well. I don’t think this is the last we will see of heliox and I look forward to seeing another paper although if it takes another twenty years I may be out of this line of work.
In July 2016 I published a blog post No more intubating for meconium? Not quite. In this post I highlighted the recent recommendations to modify the approach to the non vigorous infant born through meconium. The traditional approach of electively intubating such infants for tracheal suctioning before beginning PPV was replaced by provision of PPV first. The rationale here was that delaying the establishment of ventilation while trying to intubate for most situations was more risky than just trying to establish a functional residual capacity (FRC). The naysayers pointed out that while this recommendation is possibly warranted for less experienced intubators, perhaps in the hands of those with more skill, tracheal suctioning would be the better option if it could on average be done quickly.
It has been over two years since that recommendation and change in practice. Isn’t it about time someone looked at whether or not this was a good thing to do?
A Comparison of Two Time Periods
Chiruvolu A et al published Delivery Room Management of Meconium-Stained Newborns and Respiratory Support in this month’s Pediatrics. In this paper the authors compared 4 hospitals with a retrospective period of one year before the NRP changes (October 1, 2015, to September 30, 2016) to a one year prospective period (October 1, 2016, to September 30, 2017) after implementation of the new guidelines. In the retrospective cohort there were 11163 mothers delivered at ≥35 weeks’ gestation. Meconium stained amniotic fluid (MSAF) was present in 1303 (12%) deliveries with 130 (10%) of newborns who were nonvigorous. During the prospective time period, a total of 10 717 mothers delivered at ≥35 weeks’ gestation. MSAF was noted in 1282 (12%) deliveries, yielding 101 (8%) newborns who were nonvigorous. Therefore the study compared these 130 newborns in the retrospective cohort to the 101 in the prospective time period. The authors note that aside from the approach to MSAF there were no changes in care during this time in the delivery room.
A few differences exist though in the cohorts that are worth mentioning that were statistically significant. Firstly, the incidence of preterm and post-term infants were both higher in the prospective cohort (both 6% vs 1%). Secondly, the incidence of fetal distress was higher in the prospective cohort 57% vs 43%. All of these factors would tend to favour the retrospective cohort doing better than the prospective and so the authors in their results controlled for these differences. Not surprisingly the rate of intubation in the retrospective group was 70% vs 2% in the prospective arm.
What were the results?
The results shown in table 3 in terms of the Odds ratios have been adjusted for the aforementioned differences of preterm post-term and fetal distress. There are several things here worth noting. The risk of admission was significantly higher for respiratory distress.
Oxygen needs and mechanical ventilation along with surfactant therapy were also notably higher. One things that showed no difference at all was the mean apgar score at 1 and 5 minutes. This is an interesting finding given the hypothesis that drove the change in practice. If establishing an FRC is the goal of the intervention to provide earlier PPV then shouldn’t the retrospective group have worse apgars due to less effective resuscitation? Maybe or maybe not. This really depends on the staff in the resuscitation room at the 4 hospitals. It might be that the staff were quite skilled so the intubations may have gone smoothly with minimal reductions in FRC compared to the prospective group. What would this study look like if done in a centre with less experienced people capable of intubation.
Also interesting in this study is that when isolating comparisons to those admitted to the NICU and those specifically diagnosed with MAS there were no differences between groups for such outcomes as length of stay, oxygen therapy, mechanical ventilation (MV) or days of MV. Given that the group sizes though were quite small (7 and 11 for MAS) we do have to take this data with a grain of salt as it really is too small to make any certain conclusions. A larger study would need to be done looking at these types of outcomes to really get a better handle on whether the approach to MSAF matters to these individual outcomes.
What this study does for me is raise an eyebrow. The change in practice does not seem to yield “better babies”. Secondly what we do see even when controlling for differences that would affect hospital admissions for respiratory distress is an increase in admission rate. In times when beds are becoming increasingly precious as census for many units swell one has to ask whether this approach is truly the better way to go. Perhaps it was wrong for the NRP to declare that for all practitioners it is best to provide PPV rather than intubate. This may have been too simplistic. If you have experienced intubators perhaps it would be best to continue to intubate first in this setting rather than provide PPV. What this study does is certainly raise questions and begs for a larger study to be done to determine whether these results can be replicated. If they are then I suspect the NRP may be headed down a different path for recommendations yet again.
After the recent CPS meeting I had a chance to meet with an Obstetrical colleague and old friend in Nova Scotia. It is easy to get lost in the beauty of the surroundings which we did. Hard to think about Neonatology when visits to places like Peggy’s Cove are possible. Given out mutual interest though in newborns our our conversation eventually meandered along the subject of the new NRP. What impact would the new recommendations with respect to meconium have on the requirements for providers at a delivery. This question gave me reason to pause as I work in a level III centre and with that lens tend to have a very different perspective than those who work in level I and II centres (I know we don’t label them as such anymore but for many of you that has some meaning). Every delivery that is deemed high risk in our tertiary centre has ready access to those who can intubate so the changes in recommendations don’t really affect our staffing to any great degree. What if you are in a centre where the Pediatrician needs to be called in from home? Do you still have to call in people to prepare for a pending delivery of a baby through meconium stained fluid?
What does the new recommendation actually say?
These recommendations are from the American Heart Association and are being adopted by the NRP committees in the US and Canada. The roll-out for this change is coming this fall with all courses required to teach the new requirements as of September 2017.
“However, if the infant born through meconium-stained amniotic fluid presents with poor muscle tone and inadequate breathing efforts, the initial steps of resuscitation should be completed under the radiant warmer. PPV should be initiated if the infant is not breathing or the heart rate is less than 100/min after the initial steps are completed. Routine intubation for tracheal suction in this setting is not suggested, because there is insufficient evidence to continue recommending this practice. (Class IIb, LOE C-LD)“
The rationale for the change is that is that there is a lack of evidence to demonstrate that routine suctioning will reduce the incidence of meconium aspiration syndrome and its consequences. Rather priority is placed on the establishment of adequate FRC and ventilation thereby placing a priority on teaching of proper bag-valve mask or t-piece resuscitator. Better to establish ventilation than delay while atempting to intubate and run the risk of further hypoxia and hypercarbia causing pulmonary hypertension.
Does this mean you don’t need to have a person skilled in intubation at such deliveries?
This question is the real reason for the post. At least from my standpoint the answer is that you do in fact still require such people. This may seem to be in conflict with the new position but if you move past that recommendation above you will see there is another line that follows afterwards that is the basis for my argument.
“Appropriate intervention to support ventilation and oxygenation should be initiated as indicated for each individual infant. This may include intubation and suction if the airway is obstructed.”
While we should not routinely perform such intubations there may be a time and a place. If one has intiated PPV with a mask and is not obtaining a rising heart rate, MRSOPA should be followed and attempts made to optimize ventilation. What if that is unsuccessful though and heart rate continues to be poor. You could have a plug of meconium distal to the vocal cords and this is the reason that intubation should be considered. In order to remove such a plug one would need to have an intubator present.
Where do we go from here?
As much as I would like to tell my colleague that he doesn’t need to have this skill set at a delivery for meconium I am afraid the skill still needs to be present. It will be interesting to see how instructors roll this out and answer such questions. It is a little concerning to me that in our world of wanting the “skinny” or “Coles’ Notes” version of things, the possibility of still needing the intubator on short notice may be lost. Having someone on call who is only “5 minutes away” may seem to be alright but at 3 AM I assure you the 5 minutes will become 15 as the person is woken, dresses, gets to the car and parks. Whether it is 5 or 15 minutes each centre needs to ask themselves if the baby is in need of urgent intubation are you willing to wait that amount of time for that to happen?
We live in a world at the moment where the public has become increasingly aware of the dangers of antibiotic overuse. Parents are more than ever requesting no erythromycin for the eyes after birth, and even on occasion questioning the need for antibiotics after delivery for the infant with risk factors for sepsis. The media has latched on to the debate as well by publishing the sensational articles about superbugs and medicine running out of the last lines of defence such as this article from the CBC.
As teams caring for newborns both preterm and term we are also increasingly aware of the dangers of altering the microbiome of these vulnerable infants with antibiotic overuse. Some babies robbed of the vaginal microbiome when delivery occurs by C-section, have their parents swabbing their newborn with vaginal secretions to populate their child with the “good bacteria” that come through a “natural” delivery although recent commentary questions the safety of such practice.
Infants born through meconium stained amniotic fluid can certainly become sick after delivery. Inhalation of meconium in the sickest infants often occurs during gasping episodes in utero after hypoxic stress causes evacuation of the rectal contents. The fetuses who inhale this material may go on to develop, inflammatory changes, areas of atelectasis and hyperinflation and pulmonary hypertension; the so called meconium aspiration syndrome. These infants of course may be extremely sick and need high frequency ventilation to manage their CO2 retention and in some cases may go on to ECMO although with inhaled nitric oxide this has become less common. As another consideration, could infection such as chorioamnionitis be the inciting event to cause passage of meconium in utero?
The health care team though for as long as I have been in practice would add to the treatment plan a course of antibiotics. In fact I would guess that many Neonatologists the world over have uttered the phrase “They are REALLY sick, please start antibiotics”. The real question though is whether the baby is in fact infected. Meconium is certainly a good growth medium for bacteria but with the short time from passage to delivery in most cases I doubt there is much time for significant growth. Moreover, I have found myself saying many times that such infants have a chemical pneumonitis and have often questioned whether antibiotics are really needed. Nonetheless it would take nerves of steel in some cases to not use antibiotics in these patients.
Then along came this study
Role of prophylactic antibiotics in neonates born through meconium-stained amniotic fluid (MSAF)—a randomized controlled trial by Goel A et al. This study was done prospectively by randomizing newborns born through meconium stained amniotic fluid to either antibiotics (N=121) for three days or no antibiotics (N=129) after diagnosis. In each case blood and CRP were drawn and if the infant was symptomatic (presence of respiratory distress, lethargy, abdominal distension, temperature or hemodynamic instability, hypoglycemia, apnea, or any other systemic abnormalities) a lumbar puncture and chest x-ray were added. The primary outcome variable was defined as ” the incidence of early (within first 72 h of birth) or late onset (after 72 h of birth) suspect sepsis (clinical symptoms or positive sepsis screen defined as ≥2 positive parameters) and confirmed sepsis (positive blood culture).”
Clinicians in the study were allowed to continue antibiotics past the 72 hours or start antibiotics in the no antibiotic group if they considered an infant to have suspected sepsis or in fact were found to be proven. The outcomes for those possibilities are shown below.
Taking it all together whether you started antibiotics or not the primary outcomes were no different. Furthermore there is no apparent harm based on outcomes that matter including the most important; death (3 in each group) that it does give one reason to pause when considering whether to treat prophylactically with antibiotics for babies born through meconium stained fluid.
What About The Sickest of The Sick
When attempting to answer this question the authors noted the following.
“On doing a subgroup analysis on incidence of sepsis in symptomatic babies (presenting with respiratory distress), both groups were found to have comparable incidence of suspect sepsis (p=0.084). The incidence of confirmed sepsis was more in symptomatic babies, although the total numbers was very few (p=0.01)”
Herein lies the challenge in declaring once and for all that we don’t need antibiotics at all in MAS. While the study was powered to adequately answer the primary outcome, the subgroups are so small that declaring with any confidence that one can stand by and watch infants with severe MAS without starting antibiotics is a tough conclusion to come to. The child though who is born through MSAF and has mild tachypnea as the only symptom I suspect is another story. I might even argue that the baby who is in need of CPAP could be watched and if they deteriorate have antibiotics started. As much as I would love to say none of these babies need antibiotics I would have to admit that I would cave once the baby was ventilated. It is better to provide a couple of days of antibiotics while awaiting blood cultures than to have a patient with sepsis left untreated or at least that is my opinion.