Intratracheal instillation of steroids to prevent BPD

Intratracheal instillation of steroids to prevent BPD

Choosing to provide postnatal systemic steroids to preterm infants for treatment of evolving BPD has given many to pause before choosing to administer them. Ever since K Barrington published his systematic review The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. and found a 186% increase in risk of CP among those who received these treatments, efforts have been made to minimize risk when these are given.  Such efforts have included shortening the exposure from the length 42 day courses and also decreasing the cumulative dose of dexamethasone.  Fortunately these efforts have led to findings that these two approaches have not been associated with adverse neurodevelopmental outcomes.  Having said that, I doubt there is a Neonatologist that still doesn’t at least think about long term outcome when deciding to give dexamethasone.  The systemic application certainly will have effects on the lung but the circulating steroid in the brain is what occupies our thoughts.

What About Applying it Directly to the Lung

If you wanted to prevent BPD the way to do it would be to minimize the time infants are exposed to positive pressure ventilation.  Rather than giving steroids after a week or two maybe it would be best to give them early.  Recent evidence supports this for systemic steroids and has been written about recently. Hydrocortisone after birth may benefit the smallest preemies the most! This still involves providing steroid systemically.  Over the years, inhaled steroids have been tried as have intratracheal instillation of steroid with and without surfactant as a vehicle for distribution to the lung.  This month colleagues of mine anchored by Dr. G. t’Jong (a founding member of the “Tall Men of Pediatrics #TMOP) published a systematic review and meta-analysis of all such RCTs in their paper Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and metaanalysis.  The results of the study suggest that there may well be a role for this approach.

All of the included studies used a prophylactic approach of giving between the first 4 hours and the 14th day of postnatal age doses of pulmonary steroids with the goal of preventing death or BPD. The GA of enrolled infants ranged from 26 to 34 weeks, and the birth weight ranged from 801 to 1591 g. Out of 870 possible articles only 12 made the cut and compromised the data for the analysis.

Routes of steroid were by inhalation, liquid instillation though the endotracheal tube or by mixing in surfactant and administering through the ETT.

What Did They Find?

Using 36 weeks corrected age as a time point for BPD or death, the forrest plot demonstrated the following.  A reduction in risk of BPD or death of 15% with a range of 24% to only a 4% reduction.

Looking at the method of administration though is where I find things get particularly interesting.

What this demonstrates is that how you give the steroids matters.  If you use the inhalational or intratracheal instillation (without a vehicle to distribute the steroids) there is no benefit in reduction of BPD or death.  If however you use a vehicle (in both Yeh studies it was surfactant) you find a significant reduction in this outcome.  In fact if you just look at the studies by Yeh the reduction is 36% (CI 34 – 47%).  In terms of reduction of risk these are big numbers.  So big one needs to question if the numbers are real in the long run.

Why might this work though?

In the larger study by Yeh, budesonide was mixed with surfactant and delivered to intubated infants every 8 hours until FiO2 was less than 30%, they were extubated or a maximum of 6 doses were reached.  We know that surfactant spreads throughout the lung very nicely so it stands to reason that the budesonide could have been delivered evenly throughout the lung.  Compare this with inhalational steroid that most likely winds up on the plastic tubing or proximal airway.  The anti-inflammatory nature of steroids should decrease damage in the distal airways offsetting the effects of positive pressure ventilation.

Future Directions

I am excited by these findings (if you couldn’t tell).  What we don’t know though is whether the belief that the steroid stays in the lung is true. Are we just making ourselves feel better by believing that the steroid won’t be absorbed and move systemically.  This needs to be tested and I believe results of such testing will be along in the near future.

Secondly, we need a bigger study or at least another to add to the body of research being done.  Such a study will also need long term follow-up to determine if this strategy does at least have equal neurodevelopmental outcomes to the children who don’t receive steroid.  The meta-analysis above does show in a handful of studies that long term outcome was no different but given the history of steroids here I suspect we will need exceptionally strong evidence to see this practice go mainstream.

What I do believe is whether you choose to use steroids prophylactically using hydrocortisone or using intratracheal surfactant delivered budesonide, we will see one or both of these strategies eventually utilized in NICUs before long.

 

Keeping up with the Kardashians: Should you eat your placenta after delivery?

Keeping up with the Kardashians: Should you eat your placenta after delivery?

The medical term for this is placentophagy and it is a real thing. If you follow the lay press you may have seen that originally this was promoted by Kourtney Kardashian who did this herself and then by Kim who planned on doing the same after delivery. See Did Kourtney Kardashian Eat Her Placenta?

This is not completely without basis as many readers will be thinking already that they have heard about the health benefits of doing the same. Reports of improved mood and reductions in the baby blues following ingestion of placenta as well as improvements in breast milk production have led to this growing practice. The evidence for this up until recently though was quite old and fraught with poorly design of such studies. The bigger driver however has been word of mouth as many women having heard about the promises of better mood at the very least have thought “why not? Can’t hurt.”

What I will do in this post is run through a little background and a few recent studies that have shed some light on how likely this is to actually work.

Where did the idea come from?

Animals eat their placentas after delivery. It turns out that unprocessed placenta is quite high in the hormone prolactin which is instrumental for breastfeeding. Given the large amount of this hormone as well as the number of other hormones present in such tissue it was thought that the same benefits would be found in humans. Eating unprocessed human tissue whether it is put in a capsule or not is unwise as unwanted bacteria can be consumed. In fact, a case of GBS sepsis has been linked to such a practice in which the source of the GBS was thought to be due to contaminated unprocessed maternal placenta that had been ingested. Buser GL, Mat´o S, Zhang AY, Metcalf BJ, Beall B, Thomas AR. Notes from the field: Late-onset infant group B streptococcus infection associated
with maternal consumption of capsules containing dehydrated placenta.

What happens when you process placenta by steaming and drying?

This would be the most common way of getting it into capsules. This process which renders it safe to consume may have significant effects on reducing hormonal levels.This was found in a recent study that measured oxytocin and human placental lactogen (both involved positively in lactation) and found reductions in both of 99.5% and 89.2%, respectively compared versus raw placenta. I would assume that other hormones would be similarly affected so how much prolactin might actually wind up in these capsules after all?

Clinical Randomized Double Blind Controlled Trial

Twenty seven women from Las Vegas were recruited into a pilot trial (12 beef placebo vs 15 steamed and dried placenta) with the authors examining three different outcomes across three studies. The first study Effects of placentophagy on maternal salivary hormones: A pilot trial, part 1 looked at a large number of salivary hormones at four time points. Plasma samples were taken as well to determine the volume of distribution of the same. First samples were at week 36 of gestation then within 4 days (96 h) of birth followed by days 5–7 (120–168 h) postpartum and finally Days 21–27 (504–648 h) postpartum. All consumption of capsules was done in the home as was collection of samples. As per the authors in terms of consumption it was as follows “two 550 mg capsules three times daily for the first 4 days; two 550 mg capsules twice daily on days 5 through 12, and then to decrease the dose to two 550 mg capsules once daily for the remainder of the study (days 13 through approximately day 20 of supplementation).

Outcomes

No difference was found between salivary concentrations of hormones at any time point other than that with time they declined following birth. Curiously the volume of distribution of the hormones in serum was slightly higher in the placenta capsule groups but not enough to influence the salivary concentrations. It was felt moreover that the amount of incremental hormone level found in the serum was unlikely to lead to any clinical response.

The second study was on mood Placentophagy’s effects on mood, bonding, and fatigue: A pilot trial, part 2. Overall there were no differences for the groups but they did find “some evidence of a decrease in depressive symptoms within the placenta group but not the placebo group, and reduced fatigue in placenta group participants at the end of the study compared to the placebo group.”

The last paper published from the same cohort is Ingestion of Steamed and Dehydrated Placenta Capsules Does Not Affect Postpartum Plasma Prolactin Levels or Neonatal Weight Gain: Results from a Randomized, Double-Bind, Placebo-Controlled Pilot Study. This study specifically addressed the issue of prolactin levels and found no difference between the groups. Neonatal weight gain was used as a proxy for breastmilk production as it was thought that if there was an effect on breastmilk you would see better weight gain. About 80% in both groups exclusively breastfed so the influence of formula one can’t take out of the equation. In the end weight gain was no different between groups although a trend to better weight gain was seen in the placebo group.

To eat or not to eat that is the question?

What is clear to me is that the answer to this question remains unclear! What is clear is that I don’t think it is wise to consume raw placenta due to the risks of bacterial contamination. Secondly, the levels of hormones left in the placental preparation and the most common preparation of steaming and drying leave hormone levels that are unlikely to influence much at all from a biochemical standpoint. It also seems that breastmilk production and neonatal weight gain aren’t influenced much by consumption of these pills.
The issue though in all of this is that while the previous research was of low quality, the current research while of better quality is at a low volume. These were pilot trials and not powered to find a difference likely. The finding in the subgroup of some effect on mood at the end of the study does leave some hope to those that believe in the power of the placenta to help. Would a larger study find benefit to this practice? My suspicion from a biochemical standpoint is not but that one may feel a benefit from a placebo response.
Should you go out and have your placenta prepared for consumption? If you have Kardashian like wealth then go for it if you think it will help. If you don’t then I would suggest waiting for something more definitive before spending your money on placentophagy.

Is Prophylactic Hydrocortisone The Magic Bullet For BPD?

Is Prophylactic Hydrocortisone The Magic Bullet For BPD?

I feel like this has been a story in the making for some time. Next to caffeine, the story of prophylactic hydrocortisone must be one of my more popular topics and has been covered more than once before as in A Shocking Change in Position. Postnatal steroids for ALL microprems or Early Hydrocortisone: Short term gain without long term pain. and the last post Hydrocortisone after birth may benefit the smallest preemies the most!  After reporting on this topic about once a year, a recent paper may wrap it all up in a bow for the holidays and present to us the conclusion after all this work on the topic.  I was extremely interested in this topic not just because I believe this therapy may have a future in the standard approach to neonatal care for VLBWs but because I have served on the CPS Fetus and Newborn committee with two of the authors of the paper.  Dr. Lacaze and Dr. Watterberg have an exceptional understanding of this topic and so when they band together with other experts in the field I take notice.  In fact here I am with Dr. Lacaze in case you doubted our history together (we also worked in Edmonton together but that is another story).

An Individual Patient Data Meta-Analysis

If you have read my previous posts then you know the story of why hydrocortisone given over the first 10-12 days of life might help those born before 30 weeks or < 1250g.  In essence the concept is that it has been shown previously that many infants with relative adrenal insufficiency may go on to develop BPD.  If you treat all such infants at risk you could theoretically reduce BPD.  Typically after a few studies examining a similar topic come out, one can combine them in a meta-analysis using aggregate data (averages of effect sizes for the individual studies) and see what the larger sample shows.  Another way to do it though is to go back to the original data and examine the infants at a more granular level allowing a greater identification and control of variables that might influence outcomes.  This is what the authors led my Michele Shaffer did here in the paper Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis.  There were a total of 5 studies on this topic but one study of 40 patients no longer had individual data so was excluded from analysis leaving 4 to look at.  The details of the four studies are shown below.  You can see that the inclusion criteria differed slightly but in general these were all infants up to 27 – 29 completed weeks and 500 – 1250g maximum who were treated with regiments as shown in the table.

 

 

 

 

 

 

What were the results?

Treatment with early low-dose hydrocortisone was associated with greater odds of survival without BPD at 36 weeks PMA after adjustment for sex, gestational age, and antenatal steroid use (aOR, 1.45; 95% CI, 1.11-1.90; I 2 = 0%). Also found were lower individual odds of BPD (aOR, 0.73; 95% CI, 0.54-0.98; I 2 = 0%), but not with a significant decrease in death before 36 weeks PMA (aOR, 0.76; 95% CI, 0.54-1.07; I 2 = 0%). Importantly although death by 36 weeks was not different, a decrease in death before discharge (aOR, 0.70; 95% CI, 0.51-0.97; I 2 = 0%) was found.  Also noted and important was a reduction in medical treatment for PDA OR 0.72 (0.56-0.93)

All of these outcomes sound important but in a subgroup analysis other interesting findings emerged.

When dividing the patients into those less then 26 weeks and those at or greater than that gestational age, the benefits appear to be limited to those in the latter group.  Levels of significance are high once you reach that GA suggesting that issues affecting those at younger gestational ages are less amenable to treatment.  On the other hand one could say that the benefits seen at 26 – 29 weeks GA are relatively strong using a glass is half full approach.  An important outcome worth noting is that while spontaneous intestinal perforation is noted to be a risk with prophylactic hydrocortisone, when you remove indomethacin from the equation the risk disappears.  For those units using prophylactic hydrocortisone one would likely need to choose between the two but if you are like our unit where we don’t have that option this may be one strategy to consider.

In terms of risk to giving such therapy the big one noted in the paper was an increase in risk for late onset sepsis.  Interestingly, this was limited though to the group under 26 weeks GA.  In essence then the messaging would appear to be that under 26 weeks there may be less benefit to such treatment and therefore the increased risk of late onset sepsis without such benefits on BPD would suggest not using it in this GA group.

Where do we land then?

It would be easy to cast this aside I suppose as the group you are most worried about (22-25 weeks) doesn’t seem to really benefit but has a risk of late onset sepsis.  That leaves us though with the group from 26-29 weeks.  They do seem to benefit and may do so to a significant degree.  They do develop BPD and to be honest we don’t have much outside of trying our best to use gentle ventilation to ameliorate their course in hospital.  It is worth noting that the one group that does seem to show the greatest benefit are those exposed to chorioamnionitis.  It is this group in particular that may be the best target for this intervention and I gather this has been discussed at a recent EPIQ meeting.

If one says no to trying this approach then the question that needs to be asked is whether doing nothing for this group is better than supporting them with hydrocortisone?  If your centre’s rates of BPD are top notch then maybe you don’t want to add something in.  If not though maybe it is time to rock the boat and try something different.  Makes me think of the following saying and might be something to think about.

 

What secrets are hiding in your patient monitor?

What secrets are hiding in your patient monitor?

This post is very exciting to me.  All of us in the field of Neonatology are used to staring at patient monitors.  With each version of whatever product we are using there seems to be a new feature that is added to soothe our appetites for more data.  The real estate on the screen is becoming more and more precious as various devices such as ventilators, NIRS and other machines become capable of displaying their information in a centralized place.  The issue though is that there is only so much space available to display all of this information but underneath the hood so to speak is so much more!

Come Along For The Ride

One of our Neonatologists Dr. Yasser Elsayed has been very aware of these features embedded in the patient monitor.  Through teaching on rounds, some of our staff have become aware of these features but delivering this content to the masses has been an issue.  That is where this post and it’s linked content come into play.  I have created a new Youtube playlist where all of this great content can be found.  Each video is very watchable with most being 5-7 minutes long with the longest being 14:16.  Each video starts with a demonstration on the patient monitor of the lesson being taught and how to access the data using the patient monitor (in this case a Phillips but I have no doubt many other monitors have the same tech – just ask your rep how to get it) followed by a brief voice-over powerpoint to deliver the essential concepts.

However you wish to digest the information is up to you but as they are short we hope that you will be able to find the content you need quickly and apply the knowledge to patient care.  How can you use the information?  The next time a patient is giving you cause to worry try looking into some of the deeper trends that the monitor is hiding from plain sight. Is there a trend towards becoming hypotensive for the patient that can be revealed in their blood pressure histogram?  Maybe the issue lies with the way the patient is being ventilated and examining trends in the pleth waveforms may reveal where the underlying problem lies.

 

The Topics (click the links to go to Youtube)

Complete List of Videos

Part 1 – Using Histograms

Part 2 – How to interpret blood pressure histograms

Part 3 – Using vital signs as trends

Part 4 – Impact of ventilation on pleth waveforms

Part 5 – How to interpret arterial pressure waveforms

Part 6 – Near Infrared Spectroscopy

Can topical breast milk cure teenage and adult acne?

Can topical breast milk cure teenage and adult acne?

A recent post on the intranasal application of breast milk Can intranasal application of breastmilk cure severe IVH? garnered a lot of attention and importantly comments.  Many of the comments were related to other uses for breast milk (almost all of which I had no idea about).  A quick search by google uncovered MANY articles from the lay press on such uses from treating ear infections to diaper dermatitis.  One such article 6 Surprising Natural Uses For Breast Milk certainly makes this liquid gold sound like just that!  This got me thinking as I read through the claims as to how much of this is backed by science and how much is based on experience of mothers who have tried using breast milk for a variety of unconventional treatments.  I was intrigued by the claim about acne as with several family members nearing that wonderful period of the teenage years I wondered might there have been a treatment right under my nose all this time?  Before going on I will tell you what this post is not.  This is not going to be about telling everyone that this is a terrible idea. What this is about is breaking down the science that is behind the articles that have surfaced on the internet about its use.  I thought it was interesting and I hope you do too!

The Year Was 2009

The story begins here (or at least this is the point that I found some evidence). A group of nanoengineering researchers published a paper entitled The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes.  The authors examined the antibacterial effect of three fatty acids one of which was lauric acid (which is found in coconut oil but also in breast milk) against Propionibacterium acnes (P. acnes) the bacterium responsible for acne in those teen years.  The results in terms of dose response to lauric acid was quite significant.

This is where the link in the story begins. Lauric acid kills P. Acne and it is found in high concentrations in breast milk so might topical application of breast milk treat acne?  From what I can see this concept didn’t take off right away but a few years later it would.

Next we move on to 2013

This same group published In vivo treatment of Propionibacterium acnes infection with liposomal lauric acids. in 2013.  This time around they used a mouse model and demonstrated activity against P. Acnes using a liposomal gel delivery system to get the Lauric acid onto the skin of the mouse.  Interestingly, the gel did not cause any irritation of the mouse skin but using the traditional benzoyl peroxide and salicylic acid caused severe irritation.  From this it appears that the news story broke about using breast milk to treat acne as I note several lay press news stories about the same after 2013.  Let’s be clear though about what the state of knowledge is at this point.  Lauric acid kills P. Acne without irritating skin in a mouse model.  As with many early discoveries people can get very excited and apply the same to humans after extrapolation.

What Happened Since Then?

Well, in late 2018 this study was released Design, preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies. This is another animal study but this time in the rat which demonstrated application of the gel led to “∼2 fold reduction in comedones count and cytokines (TNF-α and IL-1β) on co-application with curcumin and lauric acid liposomal gel compared to placebo treated group.”  Essentially, comedones were reduced and markers of inflammation.  So not only do we see an antimicrobial effect, once the bacteria are erradicated, there is a clinical reduction in acne lesions!

Where do we go from here?

This story is still evolving.  Based on the animal research thus far here is what I believe.

1. Lauric acid a fatty acid found in breast milk can kill P. Acne.

2. Lauric acid provided in a gel form and topically applied to rodents with acne can achieve clinical benefits.

3. Whereas current standard treatments of benzoyl peroxide and salicylic acid cause inflammation of the skin with a red complexion, lauric acid does not seem to have that effect.

These are pretty incredible findings and I have no doubt, pharmaceutical companies will be bringing forth treatments with lauric acid face creams (they already exist) with a target for acne soon enough.  The question though is whether families should go the “natural route” and apply expressed breast milk to their teenagers face.  Aside from the issue of whether or not your teenager would allow that if they knew what it was the other question is what might grow on the skin where breast milk is left.  I am not aware of any further studies looking at other bacteria (since P. Acnes certainly isn’t welcome around breast milk) but that is one potential concern.

In the end though I think the research is still a little premature.  We don’t have human trials at this point although I suspect they are coming.  Can I say this is a terrible idea if you are currently using breast milk in such a fashion?  I suppose I can’t as there is some data presented above that would give some credibility to the strategy.  I am curious for those who read this post what your experience has been if you have used breast milk for acne or for other skin conditions.

Does it really work?!?