This is one of the most difficult things to determine. Families being given a diagnosis of asphyxia in their baby often ask the question when did this happen? For sure this is not an exact science and in my opinion it is often difficult to answer the question with certainty. There are of course situations in which we can offer an educated guess such as if there is a witnessed acute cord compression such as with a cord presentation. In many other instances though it is more difficult to ascertain.
When meconium is passed in utero it is attributed to a hypoxic insult leading to internal anal sphincter relaxation. Depending on the length of exposure to this green amniotic fluid we also know that some babies may have a green or yellow hue to them from exposure of tissues to the pigments in meconium. What do we know about exposure of tissue to meconium? It turns out not too much but I will share with you a couple of interesting papers that help to give us a clue with a window into the past to provide a best estimate of how many hours have passed since a baby passed meconium. By knowing that we can then get a better guess as to when a hypoxic event may have happened.
Going way back in time
It was almost 70 years ago that Desmond MM et al published a paper trying to establish the answer to this question. The paper published in 1956 was called Meconium Staining of Newborn Infants. This paper out of Houston Texas did something that while on the surface seems disturbing was actually a creative way of determining how long exposure to meconium really takes. The authors took meconium stained fluid from 6 babies and put the fluid into sterile gloves. They then placed the feet of babies who had not been exposed to meconium into the meconium filled gloves to determine how long it took for nails to discolor and secondarily for vernix (the cheesy coating on the skin of newborns) to change color as well. The authors also created meconium slurries in normal saline of various percentages of 1 and 5% to get an idea in an artificial way with simulated meconium how long staining took. In order to determine timing of staining, at regular intervals the authors washed the baby’s feet under running water, removed the moisture with with absorbent paper, and the nails were checked for yellow staining under natural light.
As you can see from Table 1 of the paper surprisingly for natural meconium stained amniotic fluid the time it takes to stain the nails of a baby yellow ranged from 4-6 hours. This occurred faster with meconium in normal saline but for run of the mill meconium you are looking at least 4-6 hours of exposure time.
Curiously for vernix in one case it took 10 hours to turn it yellow and 12 hours in another infant.
What About Umbilical Cords and Placenta
To answer this question we need to look at another study By Miller PW et al from 1985 entitled Dating the Time Interval From Meconium Passage to Birth. in this study meconium was collected from pregnancies experiencing passage before birth and similar to the 1950s study a slurry was created in normal saline. The placenta and umbilical cord were collected from pregnancies without meconium and exposed to the slurry while being incubated at 37 degrees Celsius.
The authors in this case demonstrated that over a period of 1-3 hours the tissues subjected to the meconium slurry became stained. One might come to the conclusion that this means at least 1-3 hours is needed to stain the tissues but in all likelihood it is probably longer. We know from the previous study that an artificial slurry in normal saline seems to stain faster than meconium in amniotic fluid so it would not surprise me if the authors were to have done the study using the meconium filled glove technique the tissues might need 4-6 hours as we saw in the last study. Regardless however the point is that it takes time.
What might this mean for timing a hypoxic episode
In the absence of any meconium staining it would suggest that a baby born with meconium likely had some distress that is less than 4 hours in duration. A baby who has a stained umbilical cord, yellow nails and discolored skin has likely been exposed to meconium for greater than 4 hours. To be sure this is not an exact science but let’s say there was a labor in which 8 hours prior to delivery there were some late decelerations and practitioners were questioning could there have been a significant hypoxic injury at that time. If the infant was born with meconium staining one might argue that indeed those decelerations may have contributed to the passage of meconium. If however a baby was born through meconium and there was no staining of the tissues it might lead one to conclude that if there were a significant hypoxic event it may have occurred after that time points since there should have been staining present.
I continue to say that in these cases one cannot determine exactly when a hypoxic event occurred most of the time but the degree of meconium staining and the information provided in this piece just might help give you some added information to try and make that educated guess a little more sophisticated.
I recall the shock waves through the neonatal community when ILCOR changed its recommendation to stop routine intubation of non-vigorous infants born through meconium. The rationale again was that for most practitioners it would be better to give bag valve mask ventilation and establish a functional residual capacity than try and intubate and start with a collapsed lung.
Oommen VI et al wrote a brief report on their experience in the UK with the change as recommended for these infants. Their brief publication has a large cohort that is looked at and one result in particular I found interesting enough to share with you today. The publication is Resuscitation of non-vigorous neonates born through meconium-stained amniotic fluid: post policy change impact analysis. The authors looked prospectively at the “new approach” group from October 2016-September 2017 and compared their outcomes to the retrospecitve cohort in the same hospital from August 2015-July 2016 as the “old approach” group.
As you can see in Table 1 they saw a lot of deliveries during this time that were complicated by meconium. This gives us a good before and after comparison and while not all prospective and ensuring that practices were otherwise the same it is a pretty decent sample to look at. I like seeing that 7% of the group in the new approach still received endotracheal suctioning. It is worth remembering that what the recommendation says is to not do this routinely but if the resuscitation is not going well and the baby not responding to ventilation it is reasonable to apply suctioning as they would have done to see if there is any obstructive material in the airway.
It is the last comparison in Table 1 though that drew my attention. Over 50% of the non-vigorous babies needing routine suctioning in the retrospective arm needed NICU admission compared to 19.1% of the new approach group which was quite significant. More on this later.
In Table 2 the authors compare the respiratory morbidities showing no difference in rates of ventilation, HFOV, surfactant or iNO. What they are demonstrating is that to the best of their abilities the babies were similar in terms of respiratory morbidiites in a binary sense. What I mean here is that when you ask the question did they need any of these aforementioned things it is a yes or no. What is not easy to pick up from the table is the quality of the respiratory disease. In the table they make it clear that severe respiratory disease was the same at 56% pre and 40% post and of course all of these babies would have needed admission. What we don’t know is what happened to the mild to moderate group.
The whole point of giving PPV for the non-vigorous infant is to establish FRC. In the old approach it is conceivable that some of the infants could have lost volume during attempted intubation. The resultant delay in oxygenation could exacerabate any tendency to pulmonary hypertension. It could also turn a baby from one that could have had mild grunting to one that needed CPAP. Put another way it could have changed the outcome from a baby that needed observation and some prone positioning for a few hours to one that is committed to admission.
What these results show is basically what the intent of doing away with routine suctioning was supposed to do. The vast majority of severe disease in meconium aspiration syndrome is acquired in-utreo. Hypoxia and acidosis contribute to pulmonary hypertension while gasping respirations lead to inhalation of meconium deep into the airways. Suctioning after birth is not really going to help this cohort much. Providing positive pressure ventilation to the more mildly affected infants however may help open their lungs whereas delays in initiating would have the opposite effect.
In the end routine suctioning was a dogma that was in need of a challenge. The authors in the body of the paper go through other similar studies and in all but one the findings are similar. I commend the authors here for their humility as they do add at the end of the report all the potential shortcomings of the research. I for one don’t think it was necessary, as well designed research and thought went into taking down the dogma of routine suctioning. There is complete biological plausability for the findings presented here and I for one am glad to see that research in this case informed practice change that I believe was for the better.
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?