It seems so simple doesn’t it. Shouldn’t we just be able to feed milk whether it be from humans or cows and our preemies will just adapt? I have often written about human milk diets vs those with bovine but this week an intriguing article came my way that really gave me some pause to say hmmm. Human milk diets have been shown to reduce the risk of necrotizing enterocolitis (NEC) compared to use of formula. The use of bovine human milk fortifiers falls somewhere in the middle I suppose as the diet in that case is mostly human milk with some bovine sprinkled in so to speak. If NEC is something that these infants are at increased risk of then what might be going at a tissue level when infants are exposed to human milk alone vs other bovine ingestions?
Near Infrared Spectroscopy May Tell Us the Answer
Dani C et from Italy just published an elegant study entitled EFFECT ON SPLANCHNIC OXYGENATION OF BREAST MILK, FORTIFIED BREASTMILK, AND FORMULA MILK IN PRETERM INFANTS. The study looked at the use of two particular measurements from regional splanchnic NIRS application. One is called splanchnic regional oxygenation (rSO2S) and the other splanchnic fractional oxygen extraction ratio (FOES). The rSO2S tells you how much oxygen is in the gut at a tissue level and FOES which is calculated by using systemic oxygenation (SpO2) using the formula (SpO2-rSO2S)/SpO2). So FOES will be high when rSO2S is low meaning the gut relative to the rest of the body is consuming more oxygen. For this study, increments in feedings were standardized for all infants. The study was done once patients were on full bolus feedings for one week.
The authors designed a study that needed 15 infants in three different groups with the first being human milk, then human milk + bovine fortifier and then the last formula fed infants. NIRS data was recorded 30 minutes before a feed (T0), 30 minutes after a bolus feed (T1) and then 2 hours after a bolus feed (T2). In the end the authors recruited 18 per arm. What the authors found is what I am having trouble not running with in terms of its meaning.
Looking at the data, babies who were fed exclusively mothers own milk experienced no change at all in rSO2S at any time points. Interestingly the value even trended higher after a feed. Infants who received fortified human milk experienced a decrease in this value from before the feed to 30 minutes afterwards but then recovered by 2 hours. Formula fed infants though simply dropped from exposure to formula after 30 minutes through 2 hours and the FOES rose over that time demonstrating a greater amount of oxygen extraction by the gut.
What is the meaning of all this?
Bovine sources of nutrition in the form of fortifier seem to cause the gut to become more metabolically active and consume more oxygen at least for the first 30 minutes after a feeding. Formula tends to have a progressive increase in oxygen extraction over the first two hours post feed. This may be reflective of stress in the gut as it works harder to absorb and process nutrients from a bovine source and perhaps in a dose response fashion, a little bovine content as in fortifier causes some short term increase in oxygen demand vs pure bovine formula causing a sustained increase in oxygen need.
This situation sets up an interesting concept. The NIRS results if you recall are from babies who have reached full feeds for one week. What if these same studies had been done in babies who were just in the process of increasing feeds? If infants consuming bovine sources of nutrition need more oxygen in the gut, might this explain why in the presence of acidosis, congenital heart defects or even with a PDA causing changes in end diastolic flow that they don’t tolerate in many cases anything other than human milk?
I am not aware of any such studies looking at feeding advancement but it does really make me wonder what we would see as we advance feedings using our protocols? It is tempting to place abdominal NIRS sensors on the bellies of preterm infants who are just starting out on HMF and see what happens? If the rSO2S was going down and/or the FOES was rising, would you stop the bovine fortification if it reached a certain point? What would happen if a human milk fortifier was used instead of a bovine source? Any difference?
So many questions and in my mind a great area for research. I can’t wait to see where this all goes.
I was reluctant to wade into what has in the past been a quagmire. The anti-vax (or as some like to be called vaccine-risk aware” movement pops up from time to time with sensational claims. Let me state as well up front that I do not believe those who are anti-vaccination are bad people or poor parents but I do believe that they are unfortunately susceptible to false claims. They want to believe and defend their position so badly that when articles come out suggesting there is conspiracy at work they are really hard to ignore. The one that caught my eye today was a piece from the website Vaccine Impact called “Nurse Whistleblower Confirms NICU Pre-term Babies Being Injured by Vaccines“.
Given that I work in this field and myself have ordered thousands of vaccines for preterm babies over the years I wanted to check it out and see where this claim is coming from.
Who doesn’t love a credible witness! The “whistleblower” in this case is a neonatal nurse who retires due to her inability to continue seeing preterm babies “injured” by vaccines! This person is clearly “in the know” and should be trusted. She is on the inside and has the “evidence”. Interestingly the news story is coming out now yet her claims are from back in 2015. Here is what she said.
“I’ve sat in a room with our on-call staff of physicians and practitioners (when they say) “Oh wow, this is so embarrassing this 25 weeker never actually required a breathing tube and going on the vent after he was born, he was so strong. But we gave him his two month vaccinations and he got intubated last night ha ha, oops how embarrassing. The step-down units are calling the NICU’s and saying “hey we’re going to go ahead and give these four babies their two month shots today, make sure you have beds ready because we all know they’re going to have increased breathing difficulties, feeding and digestion difficulties, apnea, and bradycardia. This is what goes on.”
Does this happen?
It may happen that an infant has increased numbers of bradycardias and apneic events after vaccination. This was shown in the large research study that the article quotes. The article is quick to point out this part of the conclusion from the paper.
“All ELBW infants in the NICU had an increased incidence of sepsis evaluations and increased respiratory support and intubation after routine immunization. “
What did the authors of this anti-vaccination piece leave out (I am sure it was intentional).
The title of the article is completely misleading as it says “pre-term babies”. Preterm babies run the gamut from 22 weeks to 36 weeks and from 400+ grams to 3000g or so. The research that the author is quoting is the following paper. Adverse Events After Routine Immunization of Extremely Low-Birth-Weight Infants. It is right in the title. We are talking about ELBW infants and not all preterm infants. ELBW infants are under 1000g at birth so it is a very select group of infants.
Who was affected by vaccination in this study of 13926 ELBW infants? The greatest impact was in the infants born at 23 to 24 weeks and a prior history of sepsis evaluations where it was found that they had an increased rate of intubation and sepsis evaluations after vaccination. If you look at prevalence of such babies the 23 and 24 week infants would be only a tiny number of babies per year. In our instititution we would see less than 10 compared to about 1500 babies born prior to 37 weeks. It is completely irresponsible to generalize the findings to all “preterm babies”
Overall the following findings were identified. Infants had a higher incidence of sepsis evaluations (adjusted rate ratio [ARR], 3.7; 95% CI, 3.2-4.4), need for increased respiratory support (ARR, 2.1; 95% CI, 1.9-2.5), and intubation (ARR, 1.7; 95% CI, 1.3-2.2) in the 3 days after immunization relative to the 3 days before immunization. These rates are still VERY low.
The conclusion that anti-vaccine article didn’t want you to see
Right after the part of the conclusion that was quoted in the article supporting this “whistleblower” commentary the authors of the JAMA Pediatrics paper concluded with this statement.
Our findings provide no evidence to suggest that physicians should not use combination vaccines in ELBW infants.
Can very fragile babies get a septic work-up after a vaccine? Absolutely! Working in the NICU for nearly 20 years I can tell you that the babies who we worry about the most do get more evaluations for sepsis and may get intubated more readily. The issue is that if there are even mild deteriorations in an infant who was already on the cusp of being intubated or worked up for sepsis it takes very little to tip the scales and do such a workup. What is the evidence presented in the anti-vaccination piece that injury has occurred to these infants? Nothing. Just the words of a nurse who believes this to be the case. Those who don’t want to vaccinate will embrace articles like this and hold them close and use the word conspiracy to suggest that what I have written here is just all part of the game that doctors are playing.
Let me put it plainly though.
I have seen injury from hemophilus influenza type B, steptococcus pneumoniae and neisseria meningititis among other infectious disease. Meningitis and pneumonia are real and and preventible with vaccination. These are real injuries and can threaten the life of a child. The minimal increase risk of sepsis evaluations and potential intubation for babies born under 1000g is well worth the risk.
As the familiar saying goes, “when the U.S sneezes Canada catches a cold”. This post will be the most political one I have ever written I suppose but before I get too far into it let me say that I do not intend to write a pro or con piece about the President of the United States. What I do intend is to alert you all to a very interesting trend that occurred in the months following the election in November 2016 of Donald Trump.
A Shocking Result
It is fair to say that the election provided the US with a right leaning president and also fair to say that in Ontario the political leanings tend to be more to the middle or left of centre. When you have that disparity it could lead to stress in such left leaning areas of the Province as people would begin to worry about the impact of right leaning policies on their fortunes. Prior work had noted that in times of significant stress the ratio of male to female births can be affected. Interestingly on average there are almost always slightly more males born than females. Many theories abound as to why this might be with one theory being that we males fetuses tend to be more fragile (some women would say this is for life) so we need more of us to start in order to balance the population out. As seen in global catastrophes such as war this ratio can move closer to 1:1 for a period of a few months after the significant event but then recovers a few months later.
Study in Ontario
Outcome of the 2016 United States presidential election and the subsequent sex ratio at birth in Canada: an ecological study was published this year by Retnakaran and Yi using the Better Outcomes Registry & Network (BORN) in Ontario to capture data on birth ratios from 2010 to 2017. The authors were able to control for birth seasonality and looked at the change in birth ratio in left leaning health regions in particular between the months leading up to the election in November 2016 and then the 12 months afterwards. Their findings I found fascinating and like much research probably creates further questions. As has been seen in other situations like this a trough in the ratio occurred about 5 months after the election. A gradual but consistent increase in the ratio back to baseline came about close to 6 months later. This effect is seen in the figure below demonstrating that on the far right of the graph recovery was brisk and unidirectional. In the end it would appear that much like previous psychologically dramatic situations the impact in Ontario with a markedly different political viewpoint than their neighbours to the south had a similar effect.
Perhaps equally interesting is what happened in right leaning health regions with respect to birth ratio. No increase in ratio was seen in the months after the election. The trend was really reversed as shown below.
The Next Question is Why and How?
The answer to this question is likely a sad one that at this point is speculative. Five months after the election the die was cast so to speak as women were already pregnant so the answer cannot be that people were having less pregnancies or selecting out female fetuses through IVF. The most likely answer is that there was an disproportionate loss of male fetuses after this political moment in history. We teach often in medicine that the female sex is the stronger one and it is for this reason that in times of trauma the male fetuses might be expected to be lost in a higher frequency than female.
I can’t help but think if people knew of this phenomenon and could anticipate that it could happen that an opportunity for intervention would exist. Maybe the next time an election involves such polarizing candidates (such as now) part of the antenatal visit could be reminding families about programs for grief counseling or help with stress relief. I have to confess I had no idea this phenomenon existed but I must confess I am sold that it is real and if fetal loss is a risk there is something that we can do before the next US election and help maybe save a few lives along the way.
Intubate-Surfactant- Extubate or INSURE has been around for awhile. The concept is to place an ETT while an infant is first on CPAP and then after pushing surfactant in quickly remove the ETT and put back on CPAP. This does not always go as planned though. If after surfactant the FiO2 remains above 30% many people would keep the ETT in place as they would surmise that the infant would fail if the tube was removed. They would probably be right.
Sustained inflations have fallen out of favour ever since the SAIL trial results were published and written about here . Having said that, the concept of using sustained inflation is to open the lung and expand closed alveoli to improve both oxygenation and gas exchange. Much like giving inhale nitric oxide to a collapsed lung is unlikely to make much difference, the question could be asked whether giving surfactant to a lung that is most collapsed will fail to deliver this compliance improving medication to the areas of the lung that most sorely need it. Our Italian colleagues therefore decided to undertake a study to look at providing surfactant to lungs after a recruitment manouver and see if this made a difference to the meaningful outcome of extubation failure after surfactant provision. The results are intriguing and as such here we go in looking at the study.
Optimizing Lung Expansion
The trial is the Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial and involved 35 NICUs in Italy. All infants enrolled were born from 24 + 0 weeks to 27 6/7 weeks gestational age at birth and all < 24 hours of age at enrollment. Each baby had to be on CPAP at the time of randomization and meet prespecified failure criteria of FiO2 of 0·30 or greater for target SpO2 of 87% to 94% for at least 30 min or in 10 Infants for rapid deterioration of clinical status or if pCO2 was > 65 mm Hg with a pH less than 7·20. Regardless of which arm they were randomized to all infants received 1-2 sustained inflation breaths using 25 cm H2O for 10-15 secs using a t-piece resuscitator after being started on CPAP as was the practice at the time. After randomization which could not be blinded, patients were then either given surfactant via INSURE without any further strategy for opening the lung or received the IN-REC-SUR-E approach. The latter involved putting the infant on high frequency oscillation starting with settings of mean airway pressure 8 cm H2O; frequency 15 Hz; ΔP15 cm H2O; and inspiration to expiration ratio of 1:2. Using this modality infants underwent stepwise recruitment methods prior to administering surfactant (poractant). The primary outome was the need for mechanical ventilation within the first 72 h of life. Infants met the primary outcome if they were not extubated within 30 min after surfactant administration or required reintubation before 72 h of life.
Based on a power calculation the authors needed 103 infants in each arm and they recruited 107 in the treatment and 111 in the control arm. In the per-protcol allocation 101 received the treatment and 111 the contol. While the strategies for extubation were not set out to be equal (units were allowed to extubate to anywhere from +6 to +8 for pressure levels), the groups were not different 7·0 cm H2O, SD 0·4 for the experimental group and control arms. Given the steps taken to open the lung in the lung recruitment arm, the FiO2 was lower at 28% prior to surfactant provision in the treatment group than in the usual INSURE approach at 42% prior to surfactant provision. All infants were extubated within 30 minutes of receiving surfactant. As the results demonstrate, whether there was an intention to treat analysis or per-protocol analysis the babies who received the intervention were more likely to remain extubated. The number needed to treat was 7 which is a pretty powerful measure. Interestingly, looking at secondary outcomes there are some interesting trends as well including less mortality which on a per-protocol analysis was significant but also a trend towards more PVL at 9% in the treatment arm and 4% in the control. The mean times to surfactant administration were 4 hours in the treatment group and 3 hours in the control but the high frequency manoeuvre had a mean duration of only 30 minutes. It is possible that the use of high frequency could have blown off CO2 to very low levels but I am uncertain if the short reduction in pCO2 could have contributed significantly to reduced cerebral perfusion if that trend is representative of something. Interestingly, pneumothroaces were not different between groups as no doubt as a reader you might wonder if use of high pressures to recruit the lungs when they are non compliant might have led to air leaks.
So it worked, now what?
First of all, the results to me make a lot of sense. Opening the lung before delivering surfactant and then seeing better chances of staying extubated doesn’t really surprise me. Some questions that come up now for me would be how this strategy would fare in those who are older at birth. I suspect given the greater chest wall support and lower likelihood of severe RDS this strategy might be even more effective at reducing FiO2 or perhaps CPAP need in terms of duration after extubation. I would think it unlikely to make a difference in reintubation though as most would remain extubated regardless. That is for another study though with a different outcome.
There will be centres that don’t like the use of HFOV for recruitment so what other strategies could be used in lieu of this? I hate to say it but there will also be calls to have a much larger study specifically designed to look at the secondary outcomes. Would a larger study find a significant increase in PVL or demonstrate that it was just a random finding? Might mortality be proven to be lower and even more so?
Regardless of the above what I think this paper does is give us reason to pause before giving INSURE and ask ourselves if we have done what we can to open the lung after intubating before rushing to squirt the surfactant in. Maybe increasing the provided PEEP and lowering the FiO2 somewhat before giving surfactant will help with distribution and increase your chances of first being able to extubate and secondly when you do keeping the tube out!
I recently had the honour of being asked to present grand rounds at the University of Manitoba. My former Department Head during the question period stumped me when he asked me what role angiotensin converting enzyme 2 receptor (ACE2) has in pediatric COVID19. Like all great teachers, after I floundered and had to confess that while I was aware there is a role in COVID19 I wasn’t sure of the answer, he sent me a paper on the subject. The reality is that a very small percentage of COVID19 illness is found in children. Some estimates have it at 2%. Why might that be?
It’s what’s in the nose that matters
What has been known for some time know is that the point of entry for SARS-CoV-2 is the nasal epithelium. What is also known is that the receptor that the virus binds to in order to gain access to the host. Such binding and what happens after the virus gains entry to the body is shown in this figure depicting the life cycle of SARS-CoV-2.
I think the results somewhat speak for themselves. The younger you are the less receptors you have. If you have less receptors maybe you are less likely to contract the virus!
What we don’t know
This research leads to some interesting questions. Drugs such as losartan and valsartan already exist and function by blocking he ACE2 receptor. Could blockade help to limit the spread of infection? I am not aware of any such trials going on at the moment but something worth looking at.
The other point that needs to be raised is that the most vulnerable group of ages >60 were not looked at in this study. The trend would certainly indicate that with age we would expect the receptor numbers to increase but since we don’t actually have the data in the older groups we don’t know if receptor numbers start to fall again with age. Similarly we don’t know below the age of 4 what receptor numbers are like. In examining risk of vertical transmission it is worth noting that the recent placental positive RT-PCRs as in Detection of SARS-COV-2 in Placental and Fetal Membrane Samples. In that study while 3 of 11 placental membranes tested positive, none of the newborns were infected. Could it be the fetus and newborn is protected by having very little density of ACE2 receptors? Something to look at and will be no doubt.
Regardless, in the fight against COVID19 maybe one direction for therapeutic targeting should be addressing this receptor and seeing if there is something we can’t do to make it less susceptible to binding.
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