If you work in Neonatology you no doubt have listened to people talk in rounds or at other educational sessions about the importance of opening the lung. Many units in the past were what you might call “peepaphobic” but over time and with improvements in technology many centers are adopting an attitude that you use enough PEEP to open the lung. There are some caveats to this of course such as there being upper limits to what units are comfortable and not just relying on PEEP but adding in surfactant when necessary to improve pulmonary compliance.
When we think about giving nitric oxide the importance of opening the lung can’t be stressed enough. I have heard it said many times when a baby has been found to be a “non responder” to inhaled nitric oxide that they may have been so because the lung wasn’t open. What we mean by this is that the distal alveoli are open. One can administer all the iNO in the world but if the majority of alveoli are collapsed the drug can’t get to the pulmonary vasculature and cause the pulmonary vasodilation that is so sorely needed in the presence of hypoxemic respiratory failure. Surfactant and inhaled nitric oxide in the presence of hypoxemic respiratory failure could be a great combo as one would help open the alveoli and then the iNO could address any pulmonary vasoconstriction which might be exacerbating the hypoxemic state.
Study Tests This Theory
Researchers in Chile led by Gonzalez A published Early use of combined exogenous surfactant and inhaled nitric oxide reduces treatment failure in persistent pulmonary hypertension of the newborn: a randomized controlled trial in the Journal of Perinatology. The concept of this study was to compare in a double blind RCT for 100 patients (based on a power calculation looking for a 25% reduction in treatment failure) whether provision of surfactant as up to 2 doses and iNO would be better than just iNO alone. Included infants needed an oxygenation index (OI = MAPXFiO2/pO2) of 20 or more to qualify and treatment failure was an OI of 40 or more. The patients recruited were similar in common characteristics including types of conditions that would benefit from iNO. RDS, meconium aspiration syndrome and pneumonia certainly have been shown to benefit from surfactant before while in the PPHN category that is questionable. In order to ensure that it was not just the primary disease but pulmonary hypertension that was present as well, all patients required confirmation of pulmonary hypertension prior to enrollment via ECHO with either a TR jet indicating a pulmonary pressure at least 2/3 of systemic or right to left shunting at the ductal or atrial level.
The results of the study demonstrated a clear difference in the primary outcome.
Patients receiving the combination of surfactant prior to starting iNO showed a faster reduction in OI than those receiving iNO alone. In fact the reduction in primary outcome of treatment failure was over 50% different while the power calculation had been based on only a 25% difference. That’s ok as this means there were more than enough patients to demonstrate a difference. As a secondary outcome the rate of ECMO or death was also different between the groups favouring use of surfactant.
It works so now what?
Who doesn’t like seeing a study that confirms what you have long believed. I feel that this study validates the teaching I received throughout the years about ensuring the lung is open before giving iNO. There are some caveats to this however. About 90% of the patients studied had conditions present (RDS, MAS, pneumonia) for which surfactant would have been indicated anyway. If this study had been done let’s say in patients with asphyxia induced pulmonary hypertension and clear lungs the surfactant may have made no difference as the lungs were already open. I mention this as I don’t think readers of this analysis need to jump to the conclusion that every time there is a patient with PPHN that you MUST give surfactant. What I think this illustrates though is the importance of first asking the question if iNO is being considered “Have I opened the lungs?”. The next time you encounter such a patient consider whether you are using enough PEEP and whether surfactant is indicated. The bottom line is if the lung isn’t open then all the iNO in the world isn’t going to make much difference!
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.
The Canadian Pediatric Society has a statement on the use of premedication before non-emergent intubation which was written in 2011 and reaffirmed in 2018. After reviewing available medications for use the recommended strategy was atropine, fentanyl and succinylcholine. This combination does involve three different medications, the first being to prevent bradycardia, the second to sedate and the third to paralyze. With the use of three medications however there is always room for error so it is very alluring to try and use one medication to provide optimal conditions for intubation. As a matter of fact I once tried thiopental as a single agent as a fellow (unpublished) which never saw the light of day due to difficulties with recruitment. Nonetheless I was after a simpler solution to providing good conditions for intubation so it is not surprising that others are also looking at single agents as well.
Propofol Would Seem Like a Good Contender
Propofol has been used in the adult and Pediatric world for some time. It causes a decreased level of conciousness and amnesia surrounding the events for which it was given. It is short acting often wearing off within minutes which would seem perfect for procedural sedation. On the downside one of its side effects is hypotension so in a fragile neonate this might be something to be watch for.
Dose finding study
de Kort et al published Propofol for endotracheal intubation in neonates: a dose-finding trial this month. It is an interesting study design for those unfamiliar with dose finding studies. The goal was to begin with a low but starting dose for propofol at 1 mg/kg/dose and escalate by 0.5 mg/kg/dose until adequate sedation was reached WITHOUT signficant adverse side effects. Moreover the authors built on previous work in this area to attempt to break the patients into 8 groups as shown in this figure.
All patients were less than 28 days so allocation was based on gestational age and whether a patient was greater or less than 10 days of age at dosing. Level of intubation readiness was evaluated using a standardized tool called the Intubation Readiness Score.
Side effects were hypotension, myoclonus, chest wall rigidity, persistent respiratory and/or circulatory failure and bronchospasm. Blood pressure was assessed via an indwelling catheter if available or by cuff if not available. Importantly any mean blood pressure after provision of propofol less than the gestational age met the criteria for declaring hypotension.
The study was terminated early due to low inclusion in some groups after 91 total patients had been enrolled. In the end there were only enough patients in Groups 3 (26 – 29 weeks and <10 days) and 5 (30 – 36 weeks and < 10 days) enrolled to analyze fully. The results of the dose finding analysis are shown below.
Walking through group 3, there were 5 patients enrolled at the 1 mg/kg level and based on poor levels of sedation in all the dosing for next 5 were increased to 1.5 mg/kg. As intubating conditions improved, the authors found that at a dose of 2 mg/kg while conditions were optimal, hypotension became a significant problem with 59% being hypotensive. The management of hypotension included 54% needing volume resuscitation and inotropes in 10%. Curiously the hypotension often did not appear until 2 hours or more after drug delivery. When the authors did a step down to 1.75 mg/kg as a intubation dose they found it was inadequate for providing good conditions for intubation albeit with less hypotension.
Not the right drug
The goal of this study was to find the optimal dose that provided good intubation conditions without significant side effects. The strength of this study was that it included babies across a wide range of gestational ages from 26+0 to 36+6 weeks gestational age. While the authors were unable to recruit enough patients to fill each group the stoppage of the study made sense as it was clear that the goal of the study would not be met. Propofol would be a great single agent if it weren’t for the issues found in this study. This is not to say that the drug is a poor choice for Pediatrics but in the Neonatal world I just don’t think it has a place. I would welcome further testing on other single agent drugs but that of course is an analysis for another post!
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.