You might think this title is a joke but it is actually quite serious. Volatile organic carbons (VOCs) are what give stool it’s characteristic and often very malodorous scent. These same VOCs though could serve as biomarkers for preemies at risk of NEC. In fact previous research using an artificial nose has suggested as much. In 2015 de Meij TGJ et al published a study looking at VOCs entitled Early detection of necrotizing enterocolitis by fecal volatile organic compounds analysis. They used an electronic nose to try and detect changes in VOCs before the onset of NEC. This study which included a small sample of 13 with NEC compared to 14 without found a different profile of VOCs starting about 2-3 days before diagnosis of NEC. The study was quite small though and may not have made the waves that a larger trial might have.
Along comes the bigger trial
This month the DOVE study was published by Probert C et al “Faecal volatile organic compounds in preterm babies at risk of necrotising enterocolitis: the DOVE study”. The study picks up where this last one left off by looking at a much larger sample of babies. They managed to recruit 1326 babies under the age of 34 weeks of whom 49 developed NEC vs 70 matched controls. Of the 49 with NEC only 32 had sufficient stool samples for analysis since not every infant stooled every day. For the study all babies in these units had each stool sample collected from birth and then frozen until ready for analysis. The samples were then analyzed from 6 days prior to the diagnosis of NEC in the cases vs a day equivalent of 6 days prior in the controls. NEC was defined as stage IIa or greater.
The Results
When looking at overall numbers of VOCs between cases and controls there was no difference (35.8 in cases and controls 36.4). When grouping VOCs into 9 different natural groupings (factors) though, some interesting findings emerged.
The five best VOCs for prediction had the following receiver operator curves. Not dramatic curves but acceptable for a relationship overall with NEC.
Each of these factors were found to be associated with different demographics. For example, factor 1 VOCs were correlated to gestational age. Factor 4 contained six correlated VOCs which are associated with formula milk feeds and age. The risk of NEC increases with the value of factor 4, raising the question of whether an elevated level of this factor could predict NEC. Another curious finding was the presence of VOCs in factors 8 that are protective against NEC. One of the VOCs is known to be produced by bifidobacteria and lactobacillus both of which are also associated with less NEC. It makes some sense then that factor 8 would be negatively correlated with NEC.
What’s next?
The results raise some questions for the future like how would units actually use this information? The lead time before NEC that these VOCs were identified were anywhere from about 3-4 days. Could a unit ready device be ready in the near future with point of care technology? It wouldn’t help to find out from an outside lab several days after NEC what the VOC profile was but if it was at your finger tips that might be helpful. The next issue as I see it is what if anything you can do about it. Is there a guarantee that if three to four days prior to NEC you find these VOCs rising as in factor 4 that you can prevent NEC? It is possible that the cascade towards NEC has already started and it is now unavoidable.
In spite of these questions I find it quite interesting that we would be able to utilize these VOCs in such a way. One never knows if in the future an electronic nose will show up in an NICU near you!
If you have been following this blog for awhile you may recall a post from a couple years back on Physiological based cord clamping. The premise of that paper was that rather than arbitrarily choosing a time to clamp the cord, one should look for the following three features that indicate adequate pulmonary blood flow has been established:
1. Establishment of adequate breathing(average tidal volume > 4 ml/kg) on CPAP – using a mask capable of measuring expired volumes
2. HR above 100 BPM
3. SpO2 above the 25th percentile using an FiO2 <0.4
In the original trial it was a proof of concept design that sought to determine if resuscitation on their “Concord” table was feasible and how long would it take for the above criteria to be met so the cord could be clamped.
The mean time for cord clamping in that trial was 4 minutes and 23 seconds. This is much longer than the typical delayed clamping of 30 -60 seconds and even longer than the few studies that have looked at delays of 1- 3 minutes.
The Next Phase
The same group now sought to compare DCC of 30 – 60 seconds with the PBCC approach for infants <32 weeks gestational age in the paper Physiological-based cord clamping in very preterm infants – Randomised controlled trial on effectiveness of stabilisation. This trial was set up as a non-inferiority trial to see if the pre-defined difference in time to stability of 75 seconds would be crossed. A power calculation was performed that indicated the authors would need to recruit 64 infants with 32 in each arm. Due to poor recruitment the authors chose to stop the trial early with only 17 infants in the DCC group and 22 infants in the PBCC arm. An analysis with those patients identified that the non-inferiority limit had been met already.
Difference in resuscitation
Infants randomised to the DCC group had their cords clamped at 30-60 seconds and had their resuscitation started on a resuscitation table. Infants in the PBCC arm were placed on the Concord after delivery and had their resuscitation performed there. Care afterwards would have been similar.
They found that the mean time to stabilisation was 5:54 +/- 2:27 in the PBCC group and 7:07 +/-2:54 in the DCC groups. The mean difference was 1:19 min (95% CI -3:04 to 0:27 min). The results clearly demonstrated a finding of shorter time to stabilisation in the PBCC arm as shown in the figure.
As the confidence interval crossed 0 though in the intention to treat analysis we can say that PBCC is no worse than DCC but can’t say it is superior as a strategy overall. Perhaps larger numbers may have shown something different but at least we know it isn’t worse.
Other Findings
One thing that I would imagine Obstetricians would be concerned with here is the potential for significant blood loss since uterotonics were not provided until the cord was clamped which in PBCC was quite a bit longer, Opposite to what one would have expected the mean blood loss in the DCC group was 450 mL compared to 300 mL in the PBCC arm. Not different statistically though given the small numbers.
There were almost twice the number of females in the PBCC group which could account for some of the findings here. Another difference worth noting was that respiratory support was initiated earlier on the concord than on the standard resuscitation table which the authors acknowledge may be due to familiarity with doing so from experience with the specialized set up. Earlier ventilation (1:11 min vs 2 min in the DCC) could indeed lead to earlier reaching of the end points of the stabilisation criteria.
Regardless of the last couple points, what is needed now is a much larger study to look at clinical outcomes. The numbers were so small here to really examine such clinical points but this is where I believe we are now headed. If the pattern continues I guess we will see another study coming from this group in a couple years so stay tuned!
If you are reading this and have a baby in the NICU with respiratory distress syndrome (RDS) otherwise known as hyaline membrane disease you might be surprised to know that it is because of the same condition that modern NICUs exist. The newspaper clipping from above sparked a multibillion dollar expansion of research to find a cure for the condition that took the life of President Kennedy’s preterm infant Patrick Bouvier Kennedy. He died of complications of RDS as there was nothing other than oxygen to treat him with. After his death the President committeed dollars to research to find a treatment and from that came surfactant and modern ventilators to support these little ones.
What is surfactant and what is it’s relationship to RDS?
When you take a breath (all of us including you reading this) oxygen travels down your windpipe (trachea) down into your lung and goes left and right down what are called your mainstem bronchi and then travels to the deep parts of the lung eventually finding its way to your tiny air sacs called alveoli (there are millions of them). Each alveolus has a substance in it called surfactant which helps to reduce the surface tension in the sac allowing it to open to receive oxygen and then shrink to get rid of carbon dioxide that the blood stream brings to these sacs to eliminate. Preterm infants don’t have enough surfactant and therefore the tension is high and the sacs are hard to open and easily collapse. Think of surface tension like blowing up those latex balloons as a child. Very hard to get them started but once those little balloons open a little it is much easier! The x-ray above shows you what the lungs of a newborn with RDS look like. They are described as having a “ground glass” appearance which if you recall is the white glass that you write on using a grease pencil when you are using a microscope slide. Remember that?
Before your infant was born you may have received two needles in your buttocks. These needles contain steroid that helps your unborn baby make surfactant so that when they are born they have a better chance of breathing on their own.
Things we can do after birth
Even with steroids the lungs may be “sticky” after birth and difficult to open. The way this will look to you is that when your baby takes a breath since it is so difficult the skin in between the ribs may seem to suck in. That is because the lungs are working so hard to take breath in that the negative pressure is seen on the chest. If your baby is doing that we can start them on something called CPAP which is a machine that uses a mask covering the nose and blows air into the chest. This air is under pressure and helps get oxygen into the lungs and gives them the assist they need to overcome the resistance to opening.
Some babies need more than this though and will need surfactant put into the lungs. The way this is done is typically by one of two ways. One option is to put a plastic tube in between the vocal cords and then squirt in surfactant (we get it from cow’s or pigs) and then typically the tube is withdrawn (you may hear people call it the INSURE technique – INtubate, SURfactant, Extubate). For some babies who still need oxygen after the tube is put in they may need to remain on the ventilator to help them breathe for awhile. The other technique is the LISA (Less Invasive Surfactant Administration). This is a newer way of giving surfactant and typically involves putting a baby on CPAP and then looking at the vocal cords and putting a thin catheter in between them. Surfactant is then squirted into the trachea and the catheter taken out. The difference between the two methods is that in the LISA method your baby is breathing on their own throughout the procedure while receiving CPAP.
Even if no surfactant is given the good news is that while RDS typically worsens over the first 2-3 days, by day 3-4 your baby will start to make their own surfactant. When that happens they will start to feel better and breathe easier. Come to think of it you will too.
I had the pleasure of being asked to speak to a Canadian audience of people working with newborns yesterday about the new CPS practice points for managing deliveries and newborns with suspected or proven COVID-19. Something fascinating happened over the course of the discussion and that was that we are a country divided. It didn’t help that the week prior to the CPS releasing their practice points the American Academy of Pediatrics released the following position:
“Precautions for birth attendants: Staff attending a birth when the mother has COVID-19 should use gown and gloves, with either an N95 respiratory mask and eye protection goggles or with an air-purifying respirator that provides eye protection. The protection is needed due to the likelihood of maternal virus aerosols and the potential need to perform newborn resuscitation that can generate aerosols.”
I don’t know how the Americans are going to deliver on bringing N95 masks to all deliveries and even acknowledge in their statement that this recommendation essentially holds as long as there are supplies. There are a lot of deliveries in the US and if every one requires all team members to have an N95 respirator (two nurses, RRT, MD) that will burn through supplies quickly!
The driver of this division in the country and the AAP I believe is fear butI am not in any way judging anyone for having it in these trying times. I think it is worth looking at what is being proposed for care of the newborn by the CPS and what may be motivating this fear. Who knows it may help someone work through their own feelings on this.
What has been recommended?
What the CPS recommendations boil down to is this. For attendance at a delivery in which the mother is not intubated or expected to be, providers of care for the newborn should use droplet precautions. Specifically, whether the infant is going to receive PPV, CPAP or be intubated the evidence strongly suggests the newborn is delivered uninfected so an N95 is not needed to protect health care providers. Even if the baby is born vaginally and is exposed to blood and stool, the viral load in the distal tracheobronchial tree will be low to non-existent so aerosolization would not be a concern. If the mother is going to be intubated then an N95 mask should be worn instead of a surgical mask. Outside of the delivery room in the NICU one should use an N95 mask for providing care to any newborns on CPAP or other non-invasive support as well as those who are intubated.
It is the last statement that I know has caused some confusion. Why is it that Dr. Narvey is suggesting that in the first 30 minutes of resuscitation we don’t need an N95 but then after the baby is moved to NICU we do? The issue is a pragmatic one. The earliest known case of a positive nasopharyngeal swab is 36 hours. This doesn’t mean of course that the earliest one can get horizontal transmission is 36 hours as this is when the health care providers decided to test. Presumably they were not lucky and timed it right so we have to expect at some point maybe hours or more earlier the baby became infected. As we get busier with more and more COVID suspect mothers there is a risk of people not “watching the clock” and therefore if we had said once 12 hours or 24 hours have elapsed use N95 masks for those on respiratory support we run the risk of someone losing track of time. There are a lot of babies who need PPV at birth though but not all eventually need CPAP so eliminating the need to use N95 masks when the evidence doesn’t support their use is a responsible way of preserving masks that are in short supply for those who truly need them based on true proven risk such as with adults with COVID pneumonia being intubated.
Why is there so much fear?
I blame the media to a great extent. They latch on to stories such as this one that made its way around twitter and facebook and yet there are no publications of this infant. Likely a positive infant no doubt but I suspect it was not detected minutes after birth. Then there is the case series in Jama Pediatrics that turned the world upside down a few weeks ago. I don’t know about you but my inbox was peppered with this paper from all over Canada and beyond. Looking at the paper in detail including the images is informative as what was initially touted as evidence of vertical transmission on closer inspection I think is far from it. Three out of thirty three infants tested positive on an NPA at 48 hours of age with a claim that all three had pneumonia. The authors included two x-rays for the two 40 week infants and a CT scan of the chest for the 31 week infant. Take a look at these films.
I am not a radiologist but I suspect we would have reported these films as normal. The CT scan of the chest is in a 31 week infant who had RDS and enterobacter sepsis. How would one differentiate RDS, enterobacter pneumonia or COVID19? It may be possible these three babies indeed were inoculated in the first day or two with COVID19 but I am not so sure they really had disease. If you agree with my argument here then we have multiple case series demonstrating no vertical transmission and this one case series indicating possible horizontal transmission. Why then are we hearing about care providers bring N95 masks to deliveries just in case CPAP is needed?
Fear is a great motivator
It likely comes down to the “what if” argument. What if everyone is wrong and babies can be born with COVID19? If we had an unlimited supply of N95 masks then my answer to everyone would be “if it makes you feel better then go for it and use away”. My argument for not using them at birth is twofold. Firstly, the evidence so far is that this is not a risk and secondly we don’t have an unlimited supply of N95 masks. This creates an issue for society as a whole that if we are guided by our fear we may deprive those who truly need this resource for evidence supported high risk procedures. I believe we all have a duty to provide the best care possible and working within a system with a finite amount of resources we need to really consider what happens if we let fear override what we know from evidence.
Having said all that (and this is not a cop out but reality), we are all fatigued and probably not at our best at the moment. We are fearful for our own heath and not just physicial but mental as well. I read this morning that suicide rates in the US are up 35% this year and extrapolating I would imagine that rates of depression and anxiety have gone up with it. These infants we care for deserve us to be at our very best. If fear of contracting COVID19 has reached a level for an individual that it may interfere with their ability to provide the proper steps of NRP if not wearing their “armor” in the form of an N95 mask this needs to be considered. I am not a psychiatrist nor am I pretending to be one but our mental state has a great impact on performance. I am not endorsing the use of N95 masks for everyone but I am suggesting that during this time we all take a moment and do a check in with yourself. Are you focused, are you able to think with a clear head when needed? We need to be at our best and for me I am confident that I can care for a newborn with a regular mask but I ask you since you know yourself to be truthful with yourself so we can provide the best care possible.
