It’s time to approach nutrition in extreme preemies as if it were a drug

It’s time to approach nutrition in extreme preemies as if it were a drug

One of the benefits of operating this site is that I often learn from the people reading these posts as they share their perspectives.  On a recent trip I was reunited with Boubou Halberg a Neonatologist from Sweden whom I hadn’t seen in many years.  I missed him on my last trip to Stockholm as I couldn’t make it to Karolinska  University but we managed to meet each other in the end.  As we caught up and he learned that I operated this site he passed along a paper of his that left an impact on me and I thought I would share with you.

When we think about treating an infant with a medicinal product, we often think about getting the right drug, right dose and right administration (IV, IM or oral) for maximum benefit to the patient.  When it comes to nutrition we have certainly come a long way and have come to rely on registered dieticians where I work to handle a lot of the planning when it comes to getting the right prescription for our patients.  We seem comfortable though making some assumptions when it comes to nutrition that we would never make with respect to their drug counterparts.  More on that later…

A Swedish Journey to Ponder

Westin R and colleagues (one of whom is my above acquaintance) published a seven year retrospective nutritional journey in 2017 from Stockholm entitled Improved nutrition for extremely preterm infants: A population based observational study.  After recognizing that over this seven year period they had made some significant changes to the way they approached nutrition, they chose to see what effect this had on growth of their infants from 22 0/7 to 26 6/7 weeks over this time by examining four epochs (2004-5, 2006-7, 2008-9 and 2010-11.  What were these changes?  They are summarized beautifully in the following figure.

Not included in the figure was a progressive change as well to a more aggressive position of early nutrition in the first few days of life using higher protein, fat and calories as well as changes to the type of lipid provided being initially soy based and then changing to one primarily derived from olive oil.  Protein targets in the first days to weeks climbed from the low 2s to the mid 3s in gram/kg/d while provision of lipid as an example doubled from the first epoch to the last ending with a median lipid provision in the first three days of just over 2 g/kg/d.

While figure 3 from the paper demonstrates that regardless of time period there were declines in growth across all three measurements compared to expected growth patterns, when one compares the first epoch in 2004-2005 with the last 2010-11 there were significant protective effects of the nutritional strategy in place.  The anticipated growth used as a standard was based on the Fenton growth curves.

What this tells us of course is that we have improved but still have work to do.  Some of the nutritional sources as well were donor breast milk and based on comments coming back from this years Pediatric Academic Society meeting we may need to improve how that is prepared as growth failure is being noted in babies who are receiving donated rather than fresh mother’s own milk.  I suspect there will be more on that as time goes by.

Knowing where you started is likely critical!

One advantage they have in Sweden is that they know what is actually in the breast milk they provide.  Since 1998 the babies represented in this paper have had their nutritional support directed by analyzing what is in the milk provided by an analyzer.  Knowing the caloric density and content of protein, carbohydrates and fats goes a long way to providing a nutritional prescription for individual infants.  This is very much personalized medicine and it would appear the Swedes are ahead of the curve when it comes to this.  in our units we have long assumed a caloric density of about 68 cal/100mL.  What if a mother is producing milk akin to “skim milk” while another is producing a “milkshake”.  This likely explains why some babies despite us being told they should be getting enough calories just seem to fail to thrive.  I can only speculate what the growth curves shown above would look like if we did the same study in units that actually take a best guess as to the nutritional content of the milk they provide.

This paper gives me hope that when it comes to nutrition we are indeed moving in the right direction as most units become more aggressive with time.  What we need to do though is think about nutrition no different than writing prescriptions for the drugs we use and use as much information as we can to get the dosing right for the individual patient!

Capnography or colorimetric detection of CO2 in the delivery suite.  What to choose?

Capnography or colorimetric detection of CO2 in the delivery suite. What to choose?

For almost a decade now confirmation of intubation is to be done using detection of exhaled CO2. The 7th Edition of NRP has the following to say about confirmation of ETT placement “The primary methods of confirming endotracheal tube placement within the trachea are detecting exhaled CO2 and a rapidly rising heart rate.” They further acknowledge that there are two options for determining the presence of CO2 “There are 2 types of CO2 detectors available. Colorimetric devices change color in the presence of CO2. These are the most commonly used devices in the delivery room. Capnographs are electronic monitors that display the CO2 concentration with each breath.” The NRP program stops short of recommending one versus the other. I don’t have access to the costs of the colorimetric detectors but I would imagine they are MUCH cheaper than the equipment and sensors required to perform capnography using the NM3 monitor as an example. The real question though is if capnography is truly better and might change practice and create a safer resuscitation, is it the way to go?

Fast but not fast enough?

So we have a direct comparison to look at. Hunt KA st al published Detection of exhaled carbon dioxide following intubation during resuscitation at delivery this month. They started from the standpoint of knowing from the manufacturer of the Pedicap that it takes a partial pressure of CO2 of 4 mm Hg to begin seeing a colour change from purple to yellow but only when the CO2 reaches 15 mm Hg do you see a consistent colour change with that device. The capnograph from the NM3 monitor on the other hand is quantitative so is able to accurately display when those two thresholds are reached. This allowed the group to compare how long it took to see the first colour change compared to any detection of CO2 and then at the 4 and 15 mm Hg levels to see which is the quicker method of detection. It is an interesting question as what would happen if you were in a resuscitation and the person intubates and swears that they are in but there is no colour change for 5, 10 or 15 seconds or longer? At what point do you pull the ETT? Compare that with a quantitative method in which there is CO2 present but it is lower than 4. Would you leave the tube in and use more pressure (either PIP/PEEP or both?)? Before looking at the results, it will not shock you that ANY CO2 should be detected faster than two thresholds but does it make a difference to your resuscitation?

The Head to Head Comparison

The study was done retrospectively for 64 infants with a confirmed intubation using the NM3 monitor and capnography.  Notably the centre did not use a colorimetric detector as a comparison group but rather relied on the manufacturers data indicating the 4 and 15 mm Hg thresholds for colour changes.  The mean age of patients intubated was 27 weeks with a range of 23 – 34 weeks.  The results I believe show something quite interesting and informative.

Median time secs (range)
Earliest CO2 detection 3.7 (0 – 44s)
4 mm Hg 5.3 (0 – 727)
15 mm Hg 8.1 (0 – 727)

I wouldn’t worry too much about a difference of 1.6 seconds to start getting a colour change but it is the range that has me a little worried.  The vast majority of the patients demonstrated a level of 4 or 15 mm Hg within 50 seconds although many were found to take 25-50 seconds.  When compared to a highest level of 44 seconds in the first detection of CO2 group it leads one to scratch their head.  How many times have you been in a resuscitation and with no CO2 change you keep the ETT in past 25 seconds?  Looking closer at the patients, there were 12 patients that took more than 30 seconds to reach a threshold of 4 mm Hg.  All but one of the patients had a heart rate in between 60-85.  Additionally there was an inverse relationship found between gestational age and time to detection.  In other words, the smallest of the babies in the study took the longest to establish the threshold of 4 and 15 mm Hg.

Putting it into context?

What this study tells me is that the most fragile of infants may take the longest time to register a colour change using the colorimetric devices.  It may well be that these infants take longer to open up their pulmonary vasculature and deliver CO2 to the alveoli.  As well these same infants may take longer to open the lung and exhale the CO2.  I suppose I worry that when a resuscitation is not going well and an infant at 25 weeks is bradycardic and being given PPV through an ETT without colour change, are they really not intubated?  In our own centre we use capnometry in these infants (looks for a wave form of CO2) which may be the best option if you are looking to avoid purchasing equipment for quantitative CO2 measurements.  I do worry though that in places where the colorimetric devices are used for all there will be patients who are extubated due to the thought that they in fact have an esophageal intubation when the truth is they just need time to get the CO2 high enough to register a change in colour.

Anyways, this is food for thought and a chance to look at your own practice and see if it is in need of a tweak…

Perhaps it is time to change the way we use caffeine in the NICU.

Perhaps it is time to change the way we use caffeine in the NICU.

This has been a question that has befuddled Neonatologists for years.  Get ten of us in a room and you will get a variety of responses ranging from (talking about caffeine base) 2.5 mg/kg/day to 10 mg/kg/day.  We will espouse all of our reasons and question the issue of safety at higher doses but in the end do we really know?  As I was speaking to a colleague in Calgary yesterday we talked about how convinced we are of our current management strategies but how we both recognize that half of what we think we know today we will be questioning in 10 years.  So how convinced should we really be about caffeine?

Even the Cochrane Review Suggests There Is Something Amiss

Back in 2010 the Cochrane Collaboration examining 6 trials on caffeine for treating apnea of prematurity concluded “Methylxanthine is effective in reducing the number of apnoeic attacks and the use of mechanical ventilation in the two to seven days after starting treatment.” Notice the bolded section.  Two to seven days.  Interesting that we don’t see the effect last in perpetuity.  Why might that be?  Do babies become resistant with time or is there a change in the way these infants metabolize the drug such that levels in the bloodstream drop after that time point.  It is almost certainly the latter and in the last 7 years have we really seen any response to this finding?  I would say no for the most part although I don’t work in your unit so hard to say for sure. At least where I practice we pick a dose somewhere between 2.5-5 mg/kg/day and give a load of 10 mg/kg when we start the drug.  From time to time we give a miniload of 5 mg/kg and may or may not increase the dose of maintenance based on the number of apneic events the babies are having.  What if we could be proactive instead of reactive though.  Do the babies need to have multiple events before we act or could we prevent the events from happening at all?

Proactive Treatment With Caffeine

We have known that caffeine clearance increases with postnatal age.  The half-life of the drug shortens from about a week at the earliest gestational ages to 2-2.5 days by term equivalent age.  For those infants who are older such as 32 weeks and above we expect them to be off caffeine (if they need it) within 2-3 weeks so I am not really talking about them but what about the babies born earlier than that or certainly MUCH earlier at 23 and 24 weeks who will be on caffeine possibly till term.  Should one size (dose) fit all?  No it really shouldn’t and some crafty researchers led by Koch G have published a paper that demonstrates why entitled Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.

In this paper the authors armed with knowledge of the half life of caffeine at different gestational ages were able to calculate the clearance of the drug at different postnatal ages to demonstrate in a model of a 28 week male infant weighing 1150g. The authors further took into account predicted weight changes and were able to calculate what the expected caffeine levels would be in the fictional infant at various time points.  The target caffeine levels for this patient were a trough level of 15 -20 mg/L which are the currently acceptable ranges in the literature.  The testing was first done using a standard load of 10 mg/kg (base) followed by 2.5 mg/kg/d (base) and demonstrated levels which yielded the following graph over time. What this demonstrates is that if the dose is unchanged over the first 7 weeks, this hypothetical infant will only achieve effective concentrations for the first week.  Interesting isn’t it that the Cochrane review found clinical effect over the first 2-7 days? What if you were to double the dose to really “hit” the infant with a good dose of caffeine from the start and maintain at that level based on their weight gain as shown next. Well, you will get what you are hoping for and keep the trough level above 15 mg/L but you will hit 30 mg/L that some have said is too high and can lead to adverse effects (ever seen SVT with these high doses? I have).  Like Goldilocks and the Three Bears could there be a dosing strategy that might be just right?  The authors put in another model based on the knowledge of caffeine clearance over time and suggested a strategy in which after the first week the adjusted maintenance doses would be 3 mg/kg/day and 3.5 mg/kg/day in the third to fourth weeks and lastly 4 mg/kg/d in the 5th to 8th week.  Using that dosing schedule the model produced this curve. As you can see, the infant would have a therapeutic target without reaching levels above 30 mg/L and potential for side effects. As many of you read this however you may ask the obvious question. Each of us have seen infants who require higher doses than this to rid themselves of significant apnea and escape reintubation.  Given that this is a mathematical model it assumes that this fictional infant will respond beautifully to a trough level of 15 to 20 mg/L but some will not. Even in the curve shown it is clear that there is some room to go higher in the dosing as the curve is just touching 20 mg/L.

A Suggestion For The Future

What grabbed my attention here is the possibility that we could take a proactive rather than reactive approach to these infants.  Once a small baby is controlled on their dose of caffeine whether it is 2.5, 3, 5 or even 6 mg/kg/d of caffeine should we wait for more events to occur and then react by increasing caffeine?  What if we are too late to respond and the patient is intubated.  What effect does this have on the developing lung, what about the brain that is subjected to bradycardic events with resultant drops in cardiac output and cerebral perfusion.  Perhaps the solution is to work with our pharmacists and plan to increase dosing at several time points in the infants journey through the NICU even if they aren’t showing symptoms yet.  No doubt this is a change in approach at least for the unit I work in but one that should start with a conversation!

Hydrocortisone after birth may benefit the smallest preemies the most!

Hydrocortisone after birth may benefit the smallest preemies the most!

This must be one of my favourite topics as I have been following the story of early hydrocortisone to reduce BPD for quite some time. It becomes even more enticing when I have met the authors of the studies previously  and can see how passionate they are about the possibilities. The PREMILOC study was covered on my site twice now, with the first post being A Shocking Change in Position. Postnatal steroids for ALL microprems? and the second reviewing the 22 month outcome afterwards /2017/05/07/early-hydrocortisone-short-term-gain-without-long-term-pain/.

The intervention here was that within 24 hours of birth babies born between 24-27 weeks gestational age were randomized to receive placebo or hydrocortisone 1 mg/kg/d divided q12h for one week followed by 0.5 mg/kg/d for three days. The primary outcome was rate of survival without BPD at 36 weeks PMA. The finding was a positive one with a 9% reduction in this outcome with the use of this strategy. Following these results were the two year follow-up which reported no evidence of harm but the planned analysis by gestational age groupings of 24-25 and 26-27 weeks was not reported at that time but it has just been released this month.

Is there a benefit?

Of the original cohort the authors are to be commended here as they were able to follow-up 93% of all infants studied at a mean age of 22 months. The methods of assessing their neurological status have been discussed previously but essentially comprised standardized questionnaires for parents, assessment tools and physical examinations.

Let’s start off with what they didn’t find. There was no difference between those who received placebo vs hydrocortisone in the 26-27 week group but where it perhaps matters most there was. The infants born at 24-25 weeks are certainly some of our highest risk infants in the NICU. It is in this group that the use of hydrocortisone translated into a statistically significant reduction in the rate of neurodevelopmental impairment. The Global Neurological Assessement scores demonstrated a significant improvement in the hydrocortisone group with a p value of 0.02. Specifically moderate to severe disability was noted in 18% compared to 2% in the group receiving hydrocortisone.They did not find a difference in the neurological exam but that may reflect the lack of physical abnormalities with cognitive deficit remaining.  It could also be explained perhaps by the physical examination not being sensitive enough to capture subtle differences.

 

Why might this be?

Adding an anti-inflammatory agent into the early phase of a preemies life might spare the brain from white matter damage. Inflammation is well known to inflict injury upon the developing brain and other organs (think BPD, ROP) so dampening these factors in the first ten days of life could bring about such results via a mechanism such as that. When you look at the original findings of the study though, a couple other factors also pop up that likely contribute to these findings as well. Infants in the hydrocortisone group had a statistical reduction in the rate of BPD and PDA ligations. Both of these outcomes have been independently linked to adverse neurodevelopmental outcome so it stands to reason that reducing each of these outcomes in the most vulnerable infants could have a benefit.

In fact when you add everything up, is there much reason not to try this approach? Ten days of hydrocortisone has now been shown to reduce BPD, decrease PDA ligations and importantly in the most vulnerable of our infants improve their developmental outcome. I think with this information at our fingertips it becomes increasingly difficult to ignore this approach. Do I think this will become adopted widely? I suspect there will be those who take the Cochrane approach to this and will ask for more well designed RCTs to be done in order to replicate these results or at least confirm a direction of effect which can then be studied as part of a systematic review. There will be those early adopters though who may well take this on. It will be interesting to see as these centres in turn report their before and after comparisons in the literature what the real world impact of this approach might be.

Stay tuned as I am sure this is not the last we will hear on this topic!

Treating newborn drug withdrawal by getting back to nature

Treating newborn drug withdrawal by getting back to nature

I wish it were otherwise, but in my practice, I have seen a growing number of pregnancies complicated by signs of substance withdrawal in newborn babies. Print, online, and broadcast news sources include regular reports on the “opioid crisis”. Data from the Canadian Institute for Health Information indicate that in 2016-17, about 1 in 200 newborns in Canada were affected by symptoms of drug withdrawal after birth. As this represents an average, there are no doubt some centres with much higher rates, while others may seem far lower depending on local usage patterns. Wherever you practice, if you care for newborns, you must learn how to treat this.

If you ask a physician in training how best to treat such conditions, their first response is often to use a medication such as morphine, thinking that it is best to treat an opioid withdrawal with the same class of drug. While this may be true, it is important to note that beginning with something much simpler, if not more natural, may reap tremendous benefits.

The Canadian Pediatric Society (CPS) released a new practice point this week, Managing infants born to mothers who have used opioids during pregnancy. While the document addresses the use of medical treatment, it highlights something far more important. Think of managing such pregnancies as a pyramid, with substance avoidance (the best strategy) on the bottom. The next level would be to manage newborns by keeping mothers and babies together. The top of the pyramid—that is, the fewest number of cases—would be treating these babies with medications.

For many families, avoidance is just not possible. Whether mothers use opioids due to addiction or chronic pain, it is simply unsafe to quit cold turkey. In October 2017, the Society of Obstetricians and Gynaecologists (SOGC) recommended against opioid detoxification in pregnancy because of the high risk of relapse. We should commend pregnant women who take responsibility for their health and seek care to stabilize on medications such as methadone or buprenorphine to manage their symptoms. After delivery, though, taking these babies and placing them on medications in a special care nursery should be a last resort.

Getting back to nature

Medications do work, but giving them means admitting babies to special care nurseries. This forced separation from families and, in particular, their mothers, actually leads to longer stays in hospital. Skin-to-skin care and breastfeeding contribute to better bonding between mother and child and have been associated with shortened hospital stays. In our centre, we have seen great success with many infants managed for up to seven days on the post-partum ward with their families. While this may seem like a long time, it is less than half of the average 15-day stay when babies are admitted to a special care unit.

Provided a mother is HIV-negative, the benefits of breastfeeding may go well beyond the bonding and closeness associated between mother and newborn. As most of these women continue to use a substance to ease their own withdrawal or pain, the small quantities of opioid that enter the breastmilk are in turn passed on to the newborn, which helps ease them through this transitional period in their life.

As the saying goes, sometimes less is more. In the case of caring for newborns exposed to opioids in pregnancy, getting back to nature and promoting skin-to-skin care and breastfeeding is just what this doctor ordered.

Can’t intubate to give surfactant? Maybe try this!

Can’t intubate to give surfactant? Maybe try this!

Intubation is not an easy skill to maintain with the declining opportunities that exist as we move more and more to supporting neonates with CPAP.  In the tertiary centres this is true and even more so in rural centres or non academic sites where the number of deliveries are lower and the number of infants born before 37 weeks gestational age even smaller.  If you are a practitioner working in such a centre you may relate to the following scenario.  A woman comes in unexpectedly at 33 weeks gestational age and is in active labour.  She is assessed and found to be 8 cm and is too far along to transport.  The provider calls for support but there will be an estimated two hours for a team to arrive to retrieve the infant who is about to be born.  The baby is born 30 minutes later and develops significant respiratory distress.  There is a t-piece resuscitator available but despite application the baby needs 40% oxygen and continues to work hard to breathe.  A call is made to the transport team who asks if you can intubate and give surfactant.  Your reply is that you haven’t intubated in quite some time and aren’t sure if you can do it.  It is in this scenario that the following strategy might be helpful.

Surfactant Administration Through and Laryngeal Mask Airway (LMA)

Use of an LMA has been taught for years in NRP now as a good choice to support ventilation when one can’t intubate.  The device is easy enough to insert and given that it has a central lumen through which gases are exchanged it provides a means by which surfactant could be instilled through a catheter placed down the lumen of the device.  Roberts KD et al published an interesting unmasked but randomized study on this topic Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial. Due to size limitations (ELBWs are too small to use this in using LMA devices) the eligible infants included those from 28 0/7 to 35 6/7 weeks and ≥1250 g.  The infants needed to all be on CPAP +6 first and then fell into one of two treatment groups based on the following inclusion criteria: age ≤36 hours,
(FiO2) 0.30-0.40 for ≥30 minutes (target SpO2 88% and 92%), and chest radiograph and clinical presentation consistent with RDS.
Exclusion criteria included prior mechanical ventilation or surfactant administration, major congenital anomalies, abnormality of the airway, respiratory distress because of an etiology other than RDS, or an Apgar score <5 at 5 minutes of age.

Procedure & Primary Outcome

After the LMA was placed a y-connector was attached to the proximal end.  On one side a CO2 detector was placed and then a bag valve mask in order to provide manual breaths and confirm placement over the airway.  The other port was used to advance a catheter and administer curosurf in 2 mL aliquots.  Prior to and then at the conclusion of the procedure the stomach contents were aspirated and the amount of surfactant determined to provide an estimate of how much surfactant was delivered to the lungs.  The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life.  Treatment failure was defined upfront and required 2 of the following: (1) FiO2 >0.40 for >30
minutes (to maintain SpO2 between 88% and 92%), (2) PCO2 >65 mmHg on arterial or capillary blood gas or >70 on venous blood gas, or (3) pH <7.22 or 1 of the following: (1)  recurrent or severe apnea, (2) hemodynamic instability requiring pressors, (3) repeat surfactant dose, or (4) deemed necessary by medical provider.

Did it work?

It actually did. Of the 103 patients enrolled (50 LMA and 53 control) 38% required intubation in the LMA group vs 64% in the control arm.  The authors did not reach their desired enrollment based on their power calculation but that is ok given that they found a difference.  What is really interesting is that they found a difference in the clinical end point despite many infants clearly not receiving a full dose of surfactant as measured by gastric aspirate. Roughly 25% of the infants were found to have not received any surfactant, 20% had >50% of the dose in the stomach and the other 50+% had < 10% of the dose in the stomach meaning that the majority was in fact deposited in the lungs.  I suppose it shouldn’t come as a surprise that among the secondary outcomes the duration length of mechanical ventilation did not differ between two groups which I presume occurred due to the babies needing intubation being similar.  If you needed it you needed it so to speak. Further evidence though of the effectiveness of the therapy was that the average FiO2 30 minutes after being treated was significantly lower in the group with the LMA treatment 27 vs 35%.  What would have been interesting to see is if you excluded the patients who received little or no surfactant, how did the ones treated with intratracheal deposition of the dose fare?  One nice thing to see though was the lack of harm as evidenced by no increased rate of pneumothorax, prolonged ventilation or higher oxygen.

Should we do this routinely?

There was a 26% reduction in intubations in te LMA group which if we take this as the absolute risk reduction means that for every 4 patients treated with an LMA surfactant approach, one patient will avoid intubation.  That is pretty darn good!  If we also take into account that in the real world, if we thought that little of the surfactant entered the lung we would reapply the mask and try the treatment again.  Even if we didn’t do it right away we might do it hours later.

In a tertiary care centre, this approach may not be needed as a primary method.  If you fail to intubate though for surfactant this might well be a safe approach to try while waiting for a more definitive airway.  Importantly this won’t help you below 28 weeks or 1250g as the LMA is too small but with smaller LMAs might this be possible.  Stay tuned as I suspect this is not the last we will hear of this strategy!