Your address may be the most important thing when it comes to Synagis and RSV.

Your address may be the most important thing when it comes to Synagis and RSV.

As I said in another post on this topic I have been a huge advocate of RSV prophylaxis since my days as a Pediatric resident. When I started my residency we were not using Palivizumab (Synagis) and I recall admitting 10+ patients per day at times with bronchiolitis.  With the use of passive immunization this rate dropped dramatically in Manitoba although rates in other areas of the country may have not seen such significant impacts.  Manitoba may be somewhat different from many areas due to the communities in Nunavut being so impacted when RSV enters these areas and can infect many of the children due to crowded living conditions and inability to really isolate kids from one and other.  The lack of benefit in other areas though, has no doubt led to controversy among practitioners who often wonder if giving 5 IM injections during the RSV season is indeed worth it.  The real question has not necessarily been does it work but to whom should it be given so that you get the most benefit.

A Big Change in The Last Year

In 2015 the CPS published a revised statement entitled Preventing hospitalizations for respiratory syncytial virus infection.  This statement included a significant change to the recommendation for those who should receive the product.

  • In preterm infants without CLD born before 30 + 0 weeks’ GA who are <6 months of age at the start of RSV season, it is reasonable (but not essential) to offer palivizumab. Infants born after 30 + 0 weeks’ GA have RSV admission rates that are consistently ≤7% (Figure 3), yielding a minimum number needed to treat of 18 (90 doses of palivizumab to prevent one RSV admission) if one assumes 80% efficacy and five doses per infant. Therefore, palivizumab should not be prescribed for this group.

Gone are recommendations for treating those from 30 – 32 weeks and moreover 33- 35 weeks if meeting certain conditions.  There is a provision for those in Northern communities to expand these criteria to 36 0/7 weeks if such infants would require medical transport to receive care for bronchiolitis.  What is not really clear though is what is meant by Northern communities in terms of criteria to determine suitability exactly.

Incidentally, the criteria are not so different than the AAP statement from August 2014.  In their version of the statement they state:

“The burden of RSV disease and costs associated with transport from remote locations may result in a broader use of palivizumab for RSV prevention in Alaska Native populations and possibly in selected other American Indian populations.”

The American guideline also states that it is for those infants who are “well” and under 29 weeks that RSV prophylaxis is appropriate but from 29 – 32 weeks use should be restricted to those babies who are on oxygen at 28 days of life.

AAP News Release From This Week

As stated above there are those who have always been sceptical of the true cost benefit of RSV prophylaxis and I would imagine those individuals must have latched on to the following report. Otherwise healthy premature infants 29 weeks gestation and over unlikely to benefit from palivizumab

The authors of this study found that while during the RSV season admission for RSV bronchiolitis was lower from 29 – 32 weeks in those infants who had received Synagis. This would argue that it should be given in this group except for the fact that as the authors state it was a “wash” since hospitalization for non-RSV bronchiolitis in the same population was increased by a similar amount.  In essence if you didn’t get RSV you wound up getting something else that still put you in hospital.  The conclusion here is that the decision to drop the criterion for prophylaxis to under 29 weeks is supported since from 29 – 32 weeks you can’t prevent hospitalization from viruses that take the place of RSV.

A Few Thoughts Though Before We Conclude It Has No Place

As I stated upfront I am not totally free of bias having seen a very large impact up here in Manitoba.  What I worry about though is that we have in medicine a tendency to try and capture the “gist” of a guideline rather than committing it in its entirety to memory.  We can’t help ourselves as the volume of information we are asked to remember is growing daily.  What this may lead to however is changes to our practice that may expose vulnerable infants.  The AAP guideline was designed to recommend changes for the otherwise healthy infant under 29 weeks.  What I think we are really talking about are the truly exceptional babies.  In our institution babies born at less than 29 weeks and certainly those closer to 24 weeks often spend as much as a month on CPAP. At 28 days even if the patient were on room air it might only be due to the fact that they were on distending pressure.  Put them on nasal prongs and they would qualify.

Another important consideration is the remote location point.  figure35-enHere in Canada the majority of the population lives along the border with the US.  Take a look though at our population density and you can see that for our Aboriginal (Indian) and Inuit populations as well as all those living in the north we have a significant need to protect them.  Living conditions in these places involve overcrowding and high smoking levels both ideal breeding grounds for transmission of RSV and an intolerance to handling the inflammation in your bronchioles.  The same is likely true of many parts of Alaska for my US readers.

It would be too easy to simply state “I only need to give Synagis to those babies under 29 weeks now” but that would do a disservice to the populations in our remote communities both here and in the US.

In case you are wondering, I am not employed by the makers of Synagis here or in the US nor do I have any financial or conflicts otherwise.  I am someone I suppose who has seen the difference of before and after and while I will let others debate the merits of giving Synagis from 29 – 32 weeks and above, I wrote this as a reminder that not all populations are the same and therefore we should not paint all susceptible patients with one brush.

Micropreemie Lives Matter

Micropreemie Lives Matter

It seems the expression “(insert a group) lives matter” is present everywhere these days so I thought I would join in after a moving experience I had today.  For those of you who have been with the blog since the beginning you would have seen a number of posts that if you follow them in time, provide a glimpse into the transformation that Winnipeg has seen over the last year or so.

Prior to that point, 24 weeks was a cutoff for resuscitation that had been in place for some time and after a great amount of deliberation and thought was changed to 23 weeks.  This did not come without a great deal of angst and a tremendous amount of education and teamwork that our nurse educators and clinical leads were so instrumental in helping to role out.  The experience was outlined in a couple of posts that you may find interesting if you didn’t catch them the first time.  The first was Winnipeg hospital now resuscitating all infants at 22 weeks! A media led case of broken telephone. and the second being Winnipeg Hospital About to Start Resuscitating Infants at 23 weeks!

Since these two posts we have certainly had our fair share of experience as we have seen far more babies than anticipated but the region has met the challenge head on and although the numbers are small we appear to have not only more survivors than expected but all but one infant had gone home without O2 and all have been demand feeding at discharge.  While we await the 18 month outcomes, the results thus far appear reassuring.

A Special & Memorable Visit

Then today, a visit occurred from the first of such infants who is now just over a year of age.  He was bright eyed, smiling, interactive and by his parent’s account, has normal tone and assessments thus far by physiotherapy.  His presence in the NICU put smiles on faces and at least for myself made me think of the expression “Micropreemie Lives Matter”.  He was a baby that everyone predicted would not survive and then when he did, that he would be grossly developmentally impaired which he does not appear to be in the least.  His presence in the unit no doubt gives everyone who doubted the merits of moving down this path reason to pause.

Before you accuse me of wearing rose coloured glasses, make no mistake I know that he will not represent the outcome for everyone.  In fact at one of our hospitals two of such infants have died while we await the 18 month outcomes for the other survivors.  What his presence does though, is remind us or at least me that good outcomes are possible and in the case of our experience in Winnipeg may be more common that we thought they would be.

Black Swans and Human Nature

When I have spoken to audiences about the path forward when resuscitating such ELGANS I have often commented on the “Black Swan” effect.  blackswanThis was very nicely described by Nassim Taleb and described the human trait to react to unusual events with extreme reactions.  An example is no one wanting to fly in the months after the world trade centre bombing when statistically this may have been the safest period in history to fly.  Similarly, we as a team need to avoid the extreme reaction of saying that we should not be resuscitating such small infants when a bad outcome occurs.  As I have told many people, we know these patients will not all survive, we know a significant number will have adverse development yet not all will and at least in our small sample thus far the babies would appear to be doing better overall than anticipated.  If we know that bad outcomes will occur then why do we hear the questions come when they do such as “why are we doing this?”, “maybe we should rethink our position on 23 week infants”.  It happens because we care and we hate seeing families and their babies go through such painful experiences.  What we cannot do though for the sake of those such as our visitor today is react with a “Black Swan” reaction and steer the ship so to speak in the previous direction we were in.  There are survivors and they may do well and that is why I say “Micropreemie Lives Matter”.

In the paper by Rysavy the overall finding at 23 weeks was that 1 out of 6 would survive without moderate or severe disability.  What do we do as we increase our experience if the trend bears out that our outcomes are better?  How will we counsel families? Will we continue to use the statistics from the paper or quote our own despite us being a medium sized centre?

The Big Questions

As our experience with such infants increases we will also no doubt see a change in our thoughts about infants at 24 weeks.  I have seen this first hand already with a physician commenting today that 24 weeks is not such a big deal now!  This brings me to the big question (which I will credit a nurse I work with for planting in my head in the last two weeks) which is for another time to answer as this post gets a little lengthy but is something to ponder.  As our outcomes for 23 weeks improve and so do our results at 24 weeks (which is bound to happen with the more frequent team work in such situations) will our approach to infants at 24 weeks change.  In our institution we generally follow the CPS guidelines for the management of infants at extremely low GA and offer the choice of resuscitation at 24 weeks.  As outcomes improve at this GA will we continue to do so or will we reach a threshold where much like the case at 25 weeks we inform families that we will resuscitate their infant without providing the option of compassionate care?

It is too early to answer these questions conclusively but they are very deserving of some thought.  Lastly, I would like to thank the parent who came by today for inspiring me and to all those who will follow afterwards.

 

Do we need so many shots to prevent RSV bronchiolitis?

Do we need so many shots to prevent RSV bronchiolitis?

I have been a huge advocate of RSV prophylaxis since my days as a Pediatric resident. When I started my residency we were not using Palivizumab (Synagis) and I recall admitting 10+ patients per day at times with bronchiolitis.  With the use of passive immunization this rate dropped dramatically in Manitoba although rates in other areas of the country may have not seen such significant impacts.  Manitoba may be somewhat different from many areas due to the communities in Nunavut being so impacted when RSV enters these areas and can infect many of the children due to crowded living conditions and inability to really isolate kids from one and other.  The lack of benefit in other areas though, has no doubt led to controversy among practitioners who often wonder if giving 5 IM injections during the RSV season is indeed worth it.  The real question has not necessarily been does it work but to whom should it be given so that you get the most benefit.

A Big Change in The Last Year

In 2015 the CPS published a revised statement entitled Preventing hospitalizations for respiratory syncytial virus infection.  This statement has caused a great deal of controversy at least among those I have spoken with due to its significant departure from the previous recommendations. As per the statement:

  • In preterm infants without CLD born before 30 + 0 weeks’ GA who are <6 months of age at the start of RSV season, it is reasonable (but not essential) to offer palivizumab. Infants born after 30 + 0 weeks’ GA have RSV admission rates that are consistently ≤7% (Figure 3), yielding a minimum number needed to treat of 18 (90 doses of palivizumab to prevent one RSV admission) if one assumes 80% efficacy and five doses per infant. Therefore, palivizumab should not be prescribed for this group.

Gone are recommendations for treating those from 30 – 32 weeks and moreover 33- 35 weeks if meeting certain conditions.  There is a provision for those in Northern communities to expand these criteria to 36 0/7 weeks if such infants would require medical transport to receive care for bronchiolitis.  What is not really clear though is what is meant by Northern communities in terms of criteria to determine suitability exactly. Incidentally, the criteria are not so different than the AAP statement from August 2014.

Do We Need So Many Shots?

Just at the end of 2016 though Lavoie P et al in Vancouver, BC published a letter outlining their experience with a modified schedule of either 3 or 4 doses of palivizumab during the RSV season.  Included in the letter are their criteria for determining the number of doses and importantly pharmacokinetic data demonstrating the effectiveness of such schedules in achieving protective titres.  pharmacokineticsThe 3 dose schedule was used for those infants born between 29 0/7 and 35 weeks gestational age who had a risk factor score of 42 or more. Interestingly at the end of the RSV season, depriving such infants of 1 or 2 doses did not appear to impair the ability of the infant to maintain protective levels.

From a clinical standpoint the outcome data during this period examining 514 (3 dose) and 666 (4 dose) patients similarly suggests that they were indeed protected from disease.  In the 3 dose cohort only 1 patient was hospitalized with RSV during the dosing period and 1 infant afterwards.  In the 4 dose group, 10 were hospitalized with RSV  during the dosing schedule and a set of twins afterwards.  Aside from these known RSV infections, an additional 7 and 18 patients were hospitalized with bronchiolitis without viral identification during the dosing schedule with no cases of bronchiolitis afterwards.  Taken altogether and assuming that all cases were indeed RSV bronchiolitis the authors conclude that the overall rates are no different than those seen with a 5 dose schedule.

Is Something Rotten In The State of Denmark?

There is something peculiar here though.  There is no doubt that palivizumab must have gone through rigorous pharmacokinetic testing in order to determine the correct number of doses needed. For a 3-4 dose regimen to provide the same coverage in terms of antibody titres seems strange to me. I would love to believe the data but there is a skeptic in me. Secondly with respect to counting hospital admissions is this exhaustive in terms of including all hospitalization a in BC or at only some sites? Clarity is needed before considering such changes to practice.  Strangely it has been several months since this experience was published and there has been no discussion of it at least locally.*  Something as dramatic as this should have sparked some discussion and the absence of such leaves me questioning what am I missing?
From the standpoint of reducing interventions and pain in the neonate I am intrigued by these findings.  Parents as well would no doubt be happier with 3-4 IM injections over 5.  The additional benefit is no doubt financial as this product while effective does carry a significant cost per dose.  As you can see I have my doubts about the reproducibility of the results but it does at least offer some centres that have not been as enthusiastic about palivizumab something to consider. For some, the BC approach just might be the right thing.

  • I indicate that there has been little discussion locally of the article discussed.  There has indeed been discussion both here and in other Canadian provinces.  What I meant by that comment is that among my colleagues in Neonatology and Infectious Diseases and housestaff I have had only one discussion.
Antenatal Steroids After 34 weeks.  Believe the hype?

Antenatal Steroids After 34 weeks. Believe the hype?

What a hard topic to resist commenting on.  This was all over twitter and the general media this week after the New England Journal published the following paper; Antenatal Betamethasone for Women at Risk for Late Preterm Delivery.  The fact that it is the NEJM publishing such a paper in and of itself suggests this is a top notch study…or does it?

In case the idea of giving antenatal steroids after 34 weeks sounds familiar it may be so as I wrote about the use of such an approach prior to elective c-section in a previous post; Not just for preemies anymore? Antenatal steroids for elective c-sections at term.

Is there a benefit to giving antenatal steroids from 34 0/7 – 36 5/7 weeks?

That is the central question the authors here sought to answer. Would women who had a high risk of delivering during this time period have less risk of a composite primary outcome of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery.

On the surface this seems like a very worthwhile set of outcomes to look at and the authors found in the end some pretty remarkable findings in a total of 2827 women randomized to placebo or betamethasone.

composite outcome.png

Looking at the results one sees that the primary outcome showed a significant difference with 2.8% less infants experiencing these conditions. However, when one looks at the details the only contributor to this difference was the need for CPAP or HFNC for >= 2 hours.  A need for over 30% FiO2 for > 4 hours was also not different.  No differences were noted in mechanical ventilation, ECMO, deaths whether stillbirths or neonatal deaths.  Curiously, significant differences for secondary outcomes were seen with incidence of severe respiratory distress, and need for CPAP for over 12 hours.

These results are not truly that surprising at least for the primary outcome as if you asked most people working in the field of Neonatology how likely death, need for ECMO or even mechanical ventilation are from 34 – 36 weeks they would tell you not very likely.  The other thing to consider is that the only real significant difference was noted for infants needing CPAP or HFNC for at least 2 hours.  While this would interrupt maternal infant bonding, it wouldn’t necessarily mean an admission but rather in some cases observation and then transfer to the mother’s room.

Is it worth it?

To answer this question you need to know the best and worst case scenarios I suppose. Based on the reduction of 2.8%, you would need to treat 35 women with betamethasone to avoid the primary outcome but of course there is a range based on the confidence intervals around this estimate.  The true estimate lies somewhere between 18 – 259 to avoid the outcome.  Having said that, the estimate to avoid severe distress is 25 patients with a range of 16 – 56 which is pretty good value.  In a perfect world I would probably suggest to women that there seems to be a benefit especially if one notes that in this study only 60% of the women received 2 dose of betamethasone so if rates of administration were higher one might expect and even better outcome.  Ah but the world is not perfect….

There is only so much betamethasone to go around.

I find it ironic but the same day that this article came across my newsfeed so did a warning that we were about to run out of betamethasone vials in a certain concentration and would need to resort to another manufacturer but that supply may also run out soon as well.  The instructions were to conserve this supply in the hospital for pregnant women.

In Canada as reported by the Canadian Neonatal Network in 2010,  38.1% of babies admitted to NICUs were below 34 weeks.  Given that all babies would be admitted to NICUs at this gestational age and below that likely represents the percentage of births in those ages. An additional 31.8% or almost an equal number of babies will be born between 34 0/7 to 37 0/7 weeks meaning that if we were to start treating women who were deemed to be at risk of preterm delivery in that age range we would have a lot of potential women to choose from as these are the exact women in this strata who actually delivered early in Canada.

If I am forced to choose whether to give betamethasone to the mothers under 34 weeks or above when the resource we need is in scarce supply I don’t think there is much choice at all.  Yes, this article comes from a reputable journal and yes there are some differences some of which are highly significant to consider but at least at this time my suggestion is to save the supply we have the babies who will benefit the most.

 

All Things Neonatal Anniversary Edition

All Things Neonatal Anniversary Edition

It is hard to believe but All Things Neonatal is a year old.  When I started this little concept I had no idea what was to come but am delighted with where it has gone.  While the Blog site itself has about 200 followers, the Facebook page is home to nearly 4200 followers with twitter accounting for over 500 more.  What began as a forum for me to get some thoughts off my chest about neonatal topics or articles of interest has morphed into a place to create change.  As I look back over the last year I thought I would update the readers of this page and other social media platforms what the outcome has been for some of the ideas that I have brought forward.  We have implemented some of these suggestions into our own unit practices, so without further ado here are the updates for some (but not all!) of the changes we have introduced.

Expanding the Circle of Influence With Neonatal Telehealth March 4, 2015

Articles pertaining to use of Telehealth in all aspects of medicine are becoming commonplace.  w-450xq-95-Image01_34781466Locally we have seen expansion of rural sites that can connect with us and a strong desire by existing sites to connect via telehealth for a variety of reasons.  While the thrust of the program was to deliver advice to rural practitioners and support our level I and II units we have found such support leading to possibilities we had not dreamed of. Initial discussions via telehealth and in person have occurred examining whether such treatments as CPAP stabilization and NG feedings could be done in these sites.  Being able to provide such care will no doubt lead to more stable infants being transported to our site and moreover the possibility of moving the care for infants needing only gavage feeding back to their home communities.  Who knows what the future will hold for us as we also look forward to the hiring of a telehealth coordinator for NICU!

A Strategy to Minimize Blood Sampling in ventilated premature and term infants April 13, 2015 

This has been one of my favourite topics to write about.  The ability to sample CO2 from an area near the carina has been demonstrated to be accurate and to save pokes in the long run.  NM3_Heroshot_RGBSince writing this piece we have tried it on several babies by using a double lumen tube and found the results to be as accurate as described in the Israeli papers.  In practice though, secretions have proved difficult to handle for longer periods of use as they can travel up the sampling lines and damage the filters in the analyzers.  A costly issue to deal with that we are currently trying to solve.  Being able to continuously sample CO2 and adjust ventilation without drawing frequent blood gases is somewhat of a dream for me and we will continue to see how we can go about making this an established practice but there is work to be done!

Is it time to ban Cow’s Milk Protein from the diet of our high risk NICU population? June 12, 2015

I think most people in Winnipeg would say the answer is yes.  On this front two major positive changes have occurred in the last year in this regard.  Dont-drink-cows-milkThe first is that through a generous donation and the blessing of our health region we have been able to expand the use of donor breast milk from < 1250g for a two week period to < 1500g for a one month period.   This wonderful change came about after much effort and was celebrated in December as we not only expanded the eligibility criteria but partnered with the NorthernStar Mother’s Milk Bank to provide donor milk to Manitobans (Manitobans Now Able To Support Premature Infants Through Donor Milk Program!).  The other change which the above post also spoke of was the potential to eliminate bovine milk altogether with the use of Prolacta (Human based human milk fortifier).  While we don’t have the approval to use the product as traditionally indicated, we have used it as a “rescue” for those patients who demonstrate a clear intolerance of bovine fortifier.  Such patients would traditionally receive inadequate nutrition with no other option available but now several have received such rescue and we look forward to analyzing the results of such a strategy shortly!

Winnipeg Hospital About to Start Resuscitating Infants at 23 weeks! September 25, 2015

Without question the most talked about change was the change in threshold for recommending resuscitation from 24 to 23 weeks.  2014-11-25-johnandJoyThe change took almost a year to roll out and could not have been done without a massive educational rollout that so many people (a special thank you to our nurse educators!) took part in.  Looking back on the year we have now seen several infants at 23 weeks who survived with a small minority dying in the newborn period.  It is too early to look at long term outcomes but I think many of us have been surprised with just how well many of these children have done.  Moreover I believe we may be seeing a “creep effect” at work as the outcomes of infants under 29 weeks have also improved as we developed new guidelines to provide the best care possible to these vulnerable infants.  Antenatal steroid use is up, IVH down and at least from January to September of last year no infants died at HSC under 29 weeks!  I look forward to seeing our results in the future and cannot tell you how impressed I am with how our entire team came together to make this all happen!

What’s Next?

I wanted to share some of the initiatives that came forward or were chronicled on these pages over the last year to show you that this forum is not just a place for my mind to aimlessly wander.  It is a place that can create change; some good, some great and no doubt some that won’t take.  It has also been a place where ideas are laid out that have come from afar.  From readers anywhere in the world who ask a question on one of the social media sites that get me thinking!  I have enjoyed the past year and expect I will continue to enjoy what may spring forth from these pages for some time to come.  Thank you for your contributions and I hope you get a little something out of this as well!