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.
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.