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About this blog

I am a Neonatologist trained in Winnipeg, Manitoba and Edmonton, Alberta.  My current position is Section Head of Neonatology in Manitoba and over my career my interests have meandered from time to time.  I have been a past Program Director of Neonatology and Medical Director for a level II Intensive Care Unit prior to relocating to Winnipeg become a Section Head.

Welcome to my blog which I hope will provide a forum for discussion on topics that are of interest to Neonatologists, trainees, all health care professionals and in some cases parents of those we care for.  My intent is to post opinions and analysis on both items from the media and literature that pertain to neonates.  While I have many interests, my particular motivation is to find ways to reduce discomfort for the patients that we care for.  Whether it is through the use of non-invasive testing or finding a way to improve the patient experience this is where I find myself most energized.

I chose the picture for this site as since the inception of this site there is hardly a country that has not had an individual or many people view posts.  Moreover I have received comments from many people from so many different countries that have inspired me to think not just about the impact of these posts in North America but more globally as well.

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Entries in this blog

 

Delayed cord clamping may get replaced. Time for physiological-based cord clamping?

Much has been written on the topic of cord clamping.  There is delayed cord clamping of course but institutions differ on the recommended duration.  Thirty seconds, one minute or two or even sometimes three have been advocated for but in the end do we really know what is right?  Then there is also the possibility of cord milking which has gained variable traction over the years.  A recent review was published here. Take the Guessing Out of the Picture? Up until the time of birth there is very little pulmonary blood flow.  Typically, about 10% of the cardiac output passes through the lungs and the remained either moves up the ascending aorta or bypasses the lungs via the ductus arteriosus.  After birth as the lung expands, pulmonary vascular resistance rapidly decreases allowing cardiac output to take on the familiar pattern which we all live with.  Blood returning from the systemic venous circulation no longer bypasses the lung but instead flows through pulmonary capillaries picking up oxygen along the way.  One can imagine then that if a baby is born and the cord is clamped right away, blood returning from the systemic circulation continues to bypass the lung which could lead to hypoxemia and reflexive bradycardia.  This has been described previously by Blank et al in their paper Haemodynamic effects of umbilical cord milking in premature sheep during the neonatal transition. A group of researchers from the Netherlands published a very interesting paper Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: a feasibility study this month.  The study centres around a resuscitation table called the Concord that is brought to the mother for resuscitation after birth.  The intervention here was applied to infants 26 to 35 weeks gestational age.  The cord was clamped after each of the following was achieved for an infant indicating successful transition with opening of the lung and establishment of an FRC. 1. Establishment of adequate breathing (average tidal volume ≥4 mL/kg) on CPAP.  They used a mask capable of measuring expired tidal volumes. 2. HR above 100 bpm 3. SpO2 above 25th percentile using FiO2 <0.4 In this way, the cord was only clamped once the baby appeared to have physiologically made the transition from dependence on umbilical cord blood flow to ventilation perfusion matching in the lung.  Although 82 mothers consented only 37 preterm infants were included in the end.  Exclusion criteria were signs of placental abruption or placenta praevia, signs of severe fetal distress determined by the clinician and the necessity for an emergency caesarean section ordered to be executed within 15 min.  This really was a proof of concept study but the results are definitely worth looking at. How Did These Babies Do? There are many interesting findings from this study. The mean time of cord clamping was 4 minutes and 23 seconds (IQR 3:00 – 5:11).  Heart rate was 113 (81–143) and 144 (129–155) bpm at 1 min and 5 min
after birth.  Only one patient developed bradycardia to <60 BPM but this was during a mask readjustement.  The main issue noted as far as adverse events was hypothermia with a mean temperature of 36.0 degrees at NICU admission.  Almost 50% of infants had a temperature below 36 degrees.  Although the authors clearly indicate that they took measures to prevent heat loss it would appear that this could be improved upon! What stands out most to me is the lengthy duration of cord clamping.  This study which used a physiologic basis to determine when to clamp a cord has demonstrated that even at 1 minute of waiting that is likely only 1/4 of the time needed to wait for lung expansion to occur to any significant degree.  I can’t help but wonder how many of the patients we see between 26-35 weeks who have a low heart rate after delivery might have a higher heart rate if they were given far more time than we currently provide for cord clamping. I can also see why cord milking may be less effective.  Yes, you will increase circulating blood volume which may help with hemodynamic stability but perhaps the key here is lung expansion.  You can transfuse all the blood you want but if it has nowhere to go just how effective is it? As we do more work in this area I have to believe that as a Neonatal community we need to prepare ourselves for the coming of the longer delay for cord clamping.  Do we need to really have the “Concord” in every delivery or perhaps it is time to truly look at durations of 3-4 minutes before the team clamps the cord. Stay tuned!

AllThingsNeonatal

AllThingsNeonatal

 

Don’t let the cord gas fool you

It has to be one of the most common questions you will hear uttered in the NICU.  What were the cord gases?  You have a sick infant in front of you and because we are human and like everything to fit into a nicely packaged box we feel a sense of relief when we are told the cord gases are indeed poor.  The congruence fits with our expectation and that makes us feel as if we understand how this baby in front of us looks the way they do. Take the following case though and think about how you feel after reading it.  A term infant is born after fetal distress (late deceleration to as low as 50 BPM) is noted on the fetal monitor.  The infant is born flat with no heart rate and after five minutes one is detected.  By this point the infant has received chest compressions and epinephrine twice via the endotracheal tube.  The cord gases are run as the baby is heading off to the NICU for admission and low and behold you get the following results back; pH 7.21, pCO2 61, HCO3 23, lactate 3.5.   You find yourself looking at the infant and scratching your head wondering how the baby in front of you that has left you moist with perspiration looks as bad as they do when the tried and true cord gas seems to be betraying you.  To make matters worse at one hour of age you get the following result back; pH 6.99, pCO2 55, HCO3 5, lactate 15.  Which do you believe?  Is there something wrong with the blood gas analyzer? How Common Is This Situation You seem to have an asphyxiated infant but the cord gas isn’t following what you expect as shouldn’t it be low due to the fetal distress that was clearly present?  It turns out, a normal or mildly abnormal cord gas may be found in asphyxiated infants just as commonly as what you might expect.  In 2012 Yeh P et al looked at this issue in their paper The relationship between umbilical cord arterial pH and serious adverse neonatal outcome: analysis of 51,519 consecutive validated samples. The authors sampled a very large number of babies over a near 20 year period to come up with a sample of 51519 babies and sought to pair the results with what they knew of the outcome for each baby. This is where things get interesting.  When looking at the outcome of encephalopathy with seizures and/or death you will note that only 21.71% of the babies with this outcome had a gas under 7.00.  If you include those under 7.10 as still being significantly distressed then this percentage rises to 34.21%.  In other words almost 66% of babies who have HIE with seizures and/or death have a arterial cord pH above 7.1!  The authors did not look at encephalopathy without seizures but these are the worst infants and almost 2/3 have a cord gas that you wouldn’t much as glance at and say “looks fine” How do we reconcile this? The answer lies in the fetal circulation.  When an fetus is severely stressed, anaerobic metabolism takes over and produces lactic acid and the metabolic acidosis that we come to expect.  For the metabolites to get to the umbilcal artery they must leave the fetal tissues and enter the circulation.  If the flow of blood through these tissues is quite poor in the setting of compromised myocardial contractility the acids sit in the tissues.  The blood that is therefore sitting in the cord at the time of sampling actually represents blood that was sent to the placenta “when times were good”.  When the baby is delivered and we do our job of resuscitating the circulation that is restored then drives the lactic acid into the blood stream and consumes the buffering HCO3 leading to the more typical gases we are accustomed to seeing and reestablishing the congruence our brains so desire.  This in fact forms the basis for most HIE protocols which includes a requirement of a cord gas OR arterial blood gas in the first hour of life with a pH < 7.00. Acidosis May Be Good For the Fetus To bend your mind just a little further, animal evidence suggests that those fetuses who develop acidosis may benefit from the same and be at an advantage over those infants who don’t get acidemia.  Laptook AR et al published Effects of lactic acid infusions and pH on cerebral blood flow and metabolism.  In this study of piglets, infusion of lactic acid improved cerebral blood flow.  I would suggest improvement in cerebral blood flow of the stressed fetus would be a good thing.  Additionally we know that lactate may be used by the fetus as additional metabolic fuel for the brain which under stress would be another benefit.  Finally the acidemic fetus is able to offload O2 to the tissues via the Bohr effect.  In case you have forgotten this phenomenon, it is the tendency for oxygen to more readily sever its tie to hemoglobin and move into the tissues. I hope you have found this as interesting as I have in writing it.  The next time you see a good cord gas in a depressed infant, pause for a few seconds and ask yourself is this really a good or a bad thing?

AllThingsNeonatal

AllThingsNeonatal

 

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!    

AllThingsNeonatal

AllThingsNeonatal

 

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 5 mg/kg/d 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!    

AllThingsNeonatal

AllThingsNeonatal

 

Using the printed word to treat apnea of prematurity

As the saying goes, sometimes less is more.  In recent years there has been a move towards this in NICUs as the benefits of family centred care have been shown time and time again.  Hi tech and new pharmaceutical products continue to develop but getting back to the basics of skin to skin care for many hours and presence of families as an integral team member have become promoted for their benefits.  The fetus is a captive audience and hears the mother's heart beat and voice after the development of hearing sometime between 24-26 weeks gestational age.  This is a normal part of development so it would stand to reason that there could be a benefit to hearing this voice especially after hearing has developed and the fetus has grown accustomed to it.  Hospital including my own have developed reading programs for our patients and some companies have developed speakers in isolettes designed to limit the maximum decibel to 45 but allowing parents to make recordings of their voices.  Music may be played through these speakers as well but today we will focus on the benefit of voice. Could reading to your baby reduce apnea of prematurity? This is the question that Scala M et al sought to answer in their paper Effect of reading to preterm infants on measures of cardiorespiratory stability in the neonatal intensive care unit.  This was a small prospective study of the impact of parental reading on cardiorespiratory stability in preterm NICU infants. Eighteen patients were enrolled who were born between 23-31 weeks gestation.  The study was carried out when the babies were between 8-56 days old at a mean postnatal age of 30 weeks. Each patient served as their own control by comparing episodes of oxygen desaturation to <85% during pre-reading periods (3 hours and 1 hour before) to during reading and then 1 hour post reading.  Parents were asked to read or create a recording lasting a minimum of 15 min but up to 60 min of recorded reading.  The parents were offered a standard set of books that had a certain rhythm to the text or could choose their own.  Recorded reading was played for infants up to twice per day by the bedside nurse. While it was small in number of patients the authors point out that the total exposure was large with 1934 min of parental bedside reading analyzed (range 30–270 min per infant, mean 123, median 94 min).  Patients could be on respiratory support ranging from ventilators to nasal cannulae. Was it effective? It certainly was. I should mention though that the authors excluded one patient in the end when it was found that they failed their hearing screen.  Arguably, since the infant could not have benefited from the intervention effect this makes sense to me.  As shown from table 3 there was a statistical reduction in desaturation events during the reading period which was sustained in terms of a downward trend for one hour after the intervention was completed.  In case you are asking was the difference related to oxygen use the answer is no.  There was no difference in the amount of oxygen provided to patients.  While the events were not eliminated they were certainly reduced.  The other point worth mentioning is that there appears to be a difference between live (through open portholes) vs prerecorded reading (through a speaker in the isolette). Now for a little controversy Does source of the reading matter?  The authors found that maternal had a greater effect than paternal voice.  As a father who has read countless books to his children I found this a little off-putting.  As a more objective critic though I suppose I can buy the biologic plausibility here.  I suspect there is an independent effect of voice having a positive impact on development.  If we buy the argument though that the voice that the fetus has most been accustomed to is the mothers, then the findings of an augmented effect of the maternal voice over fathers makes some sense.  I will have to put my ego aside for a moment and acknowledge that the effect here could be real. There will no doubt need to be larger studies done to drill down a number of questions such as what is the ideal type of reading, duration, rhythmic or non etc but this is a great start.  I also think this falls into the category of "could this really be a bad thing?".  Even if in the end no benefit is shown to this type of intervention, the potential for family bonding with their preterm infant alone I think is cause for embracing this intervention. Lastly, with the move to single patient rooms there is one study that demonstrated the isolation encountered from infrequent contact with their newborn can have a long lasting effect on development.  The article by Pineda RG et al Alterations in brain structure and neurodevelopmental outcome in preterm infants hospitalized in different neonatal intensive care unit environments. had a mean parental visitation of 19 +/- 19 hours a week or a little over 2 hours a day but with a very large standard deviation meaning many infants had almost no visitation.  The message here is that while quiet is good for infant development, too much can be a bad thing.  Maybe live reading or even recordings are a way around that.

AllThingsNeonatal

AllThingsNeonatal

 

Partnering With Parents: One Size Does Not Fit All

Originally posted at: https://winnipegneonatal.wordpress.com/ Facebook Page: https://www.facebook.com/allthingsneonatal/ The journey from conception to the labour floor and then for some to the NICU is not a straight one.  There are times of joy, interspersed with sadness, denial, anger and eventually acceptance, as initial news of being pregnant leads to complications in pregnancy and then eventual admission of an infant to the NICU. Much has been said in recent years about the building of partnerships with parents and in fact there is a new catchphrase attached to the concept "shared decision making" (SDM).  There is no question that in the perfect world this is exactly the relationship that we should be striving for with all of our patients.  The world however is not perfect and although this may not be the most popular opinion I have given, I question how applicable this really is in many situations. A Reality Check Take for instance the parents who present to the labour floor of their local hospital in advanced labour at 24 weeks.  Proponents of this SDM model would suggest that a meeting take place and pertinent information be given to a family and together with the assistance of literature applicable to their situation (possibly a pamphlet) the health care providers and families come to a mutually agreeable decision as to what the best course of action is for them and their unborn infant.  This all sounds wonderful but examining the real life situation a little more closely is it actually reasonable to assume we can obtain this?  I have not been, nor will I ever be pregnant and certainly have never experienced contractions and felt the veil clouding my vision as the first dose of analgesia enters my veins to deal with the discomfort a woman experiences during labour.  Not to mention there are people admitting this couple, taking histories, establishing IV access, scanning bellies and a whole host of other pokes and prods along the way. My Role Better Defined Then I come in.  Among all this chaos I deliver the information, pass along a pamphlet and do the best job I can to inform said couple of the upcoming decision.  The trouble of course is how do we come to this mutual decision in the 15 - 30 minutes I spend with them during this crisis?  The answer sadly is we do our best but don't for a minute think that SDM has occurred.  I don't believe this is possible unless the family has prior experience with a preterm birth or perhaps is a HCP working with newborns or children with disabilities themselves.  In fact Boss RD et al in their own research on the subject identified that in hindsight religion, spirituality and hope are what motivated parents rather than what was said at the time.  In essence their minds are already made up.  It doesn't mean we shouldn't strive for the SDM but at least in my opinion, unless their contractions settle, a calmness ensues, they have time to digest the information being given and then meet again under less stressful circumstances, the SDM is a nice idea but for many not a reality. Shifting To The NICU I recall a significant moment in my training when I saw how the SDM model can actually cause more grief than help.  Dr. Keith Barrington a fellow blogger (if you haven't discovered him, his work is fascinating over at Neonatal Research) published one of the most impactful pieces of research of the decade during my fellowship.  The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. Following this analysis there was a near moratorium on the use of post natal steroids.  The issue this created was that to now receive them you had to be close to the end of the limits of care.  At this point you either died (thereby concluding they are of no help) or you survived with disability that was due in part no doubt to how sick you had become (thereby concluding they are dangerous). The moment I am referring to was a conversation with a family in which the attending managing the unit presented the risks and benefits of postnatal steroids to the family when the FiO2 was at 40% one day.  The language used was non directive and the parents asked for another day to decide. The next day and each of the following two days they were unable to choose between giving the steroids and the perceived risk of brain damage versus not and watching the FiO2 climb by about 10% per day.  By the time the FiO2 several days later was at 80-90% they were distraught, teary and feeling helpless.  What they needed was direction; someone to give them some advice or more simply an educated opinion. We can strive to share in the decision making but I continue to believe there is a time and place to help our families by taking a stance or side.  We can equip them with as much information as we want but is there really any replacement for actually taking care of these infants, experiencing the ups and downs and hearing how they have done in follow-up? We simply can't expect the average parent to understand the true long term consequences of their decisions.  I am not saying we go back to a paternalistic time in medicine but I am saying that one size does not fit all. We owe it to our families to pursue SDM when we can but we have an equal obligation to recognize when this ideal state is simply not possible.  At this point we have to use the experiences and knowledge we have to provide them with the best advice we can.  We have gone through medical training, and gone down these paths so many times.  We can avoid biased opinion and rely on the facts as they are in our institutions but to not take a stand when it is needed at least for me is doing a disservice to those we are so eager to help.

AllThingsNeonatal

AllThingsNeonatal

 

Advice for Parents Regarding Hemangiomas: Time to change our approach in Pediatrics?

The story is typical.  A family notices a small red spot in the weeks following delivery which enlarges over the next month.  They present to their family doctor or Pediatrician who identifies the most common skin lesion in childhood; a hemangioma affecting about 3-10% of all children depending on the population observed.  As a resident I was given the following advice regarding hemangiomas; "As long as the hemangioma is not of cosmetic concern, sight threatening, multiple in number or causing anemia or thrombocytopenia watchful waiting is recommended."  Furthermore I recall the following general advice that while they tend to enlarge over the first year of life, 40% are gone by 4 years, 60% by 6 years and 90% by 9 years.  After my training I started a practice passing along the same advice to the infants I now cared for. Then something happened similar to the serendipitous discovery of penicillin.  In 2008, Leaute-Labreze et al published a case report in which they described a child being treated for a facial hemangioma with corticosteroids.  Unfortunately the hemangioma did not respond to treatment but rather led to a cardiomyopathy requiring treatment with propranolol. Curiously the hemangioma demonstrated significant regression on propranolol.  The results of this case report prompted further treatments with propranolol in an unblinded fashion.  Since this time propranolol and more recently topical Timolol (sample size 41) have been studied both in observational and small randomized controlled trials.  Propranolol while effective has potential side effects such as hypotension, bradycardia and bronchospasm which has limited it's widespread application except for those patients with either large, sight threatening or multiple hemangiomas. Topical timolol in the RCT above was demonstrated to be safe and when given locally, free of such side effects making it a seemingly ideal treatment for smaller hemangiomas that may have some cosmetic concerns later in life as they regress. That being said, the time of onset for regression was noted to be after 12-16 weeks of therapy and the target they aimed for was a reduction of >5% which is certainly modest.  While only a small improvement it was seen 60% of the time in the treatment group and 11% in the placebo arm. From personal experience I have used topical Timolol with patients in the NICU with varying success but in some cases the results were quite impressive.  Looking at the RCT by Chan, timolol was only applied to those hemangiomas that were small and deemed unsuitable for treatment with propranolol. This leaves us with the question; what does one use if anything for larger hemangiomas which traditionally don't fit into the category of needing treatment vs patient observation.  Secondly, is it wise to systematically treat all larger hemangiomas with propranolol as outpatients, given the potential severity of the side effects, some of which may be life threatening. This past week in the New England Journal of Medicine we have come full circle as Leaute-Labreze et all have published a large prospective RCT http://bit.ly/1ACqn2Cto determine the optimal dose and duration of propranolol for treatment of hemangiomas requiring systemic treatment. The number of patients enrolled in this study was 456 which makes it the largest study to date in this field.  This study sought to determine whether 1 mg/kg/day vs 3 mg/kg/day divided twice a day for 3 or 6 months would provide the best resolution without unacceptable side effects.  Eligible patients were between 1-5 months of age with a proliferating hemangioma and were treated for either 3 or 6 months depending on which arm of the study they were on. The results of this trial were striking and found that the best balance of benefit and risk was with 3 mg/kg/day for 6 months and is shown below graphically compared to placebo. This difference translates into a number need to treat to cause regression = 1.7 or rounded up 2.  For every two patients that you treat with propranolol you will cause one hemangioma to regress.  Try finding a therapeutic benefit like that in another trial! But what about safety?  Side effects were rare compared to placebo but not negligible. The most common side effect was diarrhea and with respect to life threatening adverse effects the only one really noted was bradycardia but in a patient with enterocolitis.  My take on this treatment is that it appears to have great impact with little downside! How do we apply these results though to "real life" situations.  We now have as I see it a "one-two punch".  Hemangiomas that are deemed to require no systemic treatment can be treated with a safe topical drop that has been used for years for glaucoma patients.  Patients with larger more significant hemangiomas may be treated with a highly efficacious treatment that may have very few side effects. The downside of systemic therapy at least in Winnipeg is that treatment with propranolol generally requires a hospital admission at the start of treatment to monitor for side effects that would be considered life threatening.  With an incidence of 5% of children it would be impractical to admit 600 children a year for such treatment based on an estimated 12000 births in the region a year. I do believe the time is upon us for change though.  As I see it, gone are the days where we tell parents that we will see what develops when their child has a small hemangioma.  If you have a willing parent who is concerned about the hemangioma and it is < 1.5 cm in size I believe topical Timolol should be offered to the family for a period of 6 months treatment.  Anything larger than that would merit treatment with propranolol.  Nine years is potentially a very long time to wait for a lesion to regress and potentially leave a scar or telangiectasia behind.  If we can do something about it now with such a high rate of success and minimal risk to the patient, why wait? My advice to you if you either have a child with a hemangioma or know someone else with one is to have them ask their doctor whether Timolol or Propranolol would be right for them.  Given these findings I know my practice will change.

AllThingsNeonatal

AllThingsNeonatal

 

Gentle ventilation must start from birth

The lungs of a preterm infant are so fragile that over time pressure limited time cycled ventilation has given way to volume guaranteed (VG) or at least measured breaths.  It really hasn’t been that long that this has been in vogue.  As a fellow I moved from one program that only used VG modes to another program where VG may as well have been a four letter word.  With time and some good research it has become evident that minimizing excessive tidal volumes by controlling the volume provided with each breath is the way to go in the NICU and was the subject of a Cochrane review entitled Volume-targeted versus pressure-limited ventilation in neonates. In case you missed it, the highlights are that neonates ventilated with volume instead of pressure limits had reduced rates of: death or BPD pneumothoraces hypocarbia severe cranial ultrasound pathologies duration of ventilation These are all outcomes that matter greatly but the question is would starting this approach earlier make an even bigger difference? Volume Ventilation In The Delivery Room I was taught a long time ago that overdistending the lungs of an ELBW in the first few breaths can make the difference between a baby who extubates quickly and one who goes onto have terribly scarred lungs and a reliance on ventilation for a protracted period of time.  How do we ventilate the newborn though?  Some use a self inflating bag, others an anaesthesia bag and still others a t-piece resuscitator.  In each case one either attempts to deliver a PIP using the sensitivity of their hand or sets a pressure as with a t-piece resuscitator and hopes that the delivered volume gets into the lungs.   The question though is how much are we giving when we do that? High or Low – Does it make a difference to rates of IVH? One of my favourite groups in Edmonton recently published the following paper; Impact of delivered tidal volume on the occurrence of intraventricular haemorrhage in preterm infants during positive pressure ventilation in the delivery room. This prospective study used a t-piece resuscitator with a flow sensor attached that was able to calculate the volume of each breath delivered over 120 seconds to babies born at < 29 weeks who required support for that duration.  In each case the pressure was set at 24 for  PIP and +6 for PEEP.  The question on the authors’ minds was that all other things being equal (baseline characteristics of the two groups were the same) would 41 infants given a mean volume < 6 ml/kg have less IVH compared to the larger group of 124 with a mean Vt of > 6 ml/kg.  Before getting into the results, the median numbers for each group were 5.3 and 8.7 mL/kg respectively for the low and high groups.  The higher group having a median quite different than the mean suggests the distribution of values was skewed to the left meaning a greater number of babies were ventilated with lower values but that some ones with higher values dragged the median up. Results IVH < 6 mL/kg > 6 ml/kg p 1 5% 48%   2 2% 13%   3 0 5%   4 5% 35%   Grade 3 or 4 6% 27% 0.01 All grades 12% 51% 0.008 Let’s be fair though and acknowledge that much can happen from the time a patient leaves the delivery room until the time of their head ultrasounds.  The authors did a reasonable job though of accounting for these things by looking at such variables as NIRS cerebral oxygenation readings, blood pressures, rates of prophylactic indomethacin use all of which might be expected to influence rates of IVH and none were different.  The message regardless from this study is that excessive tidal volume delivered after delivery is likely harmful.  The problem now is what to do about it? The Quandry Unless I am mistaken there isn’t a volume regulated bag-mask device that we can turn to to control delivered tidal volume.  Given that all the babies were treated the same with the same pressures I have to believe that the babies with stiffer lungs responded less in terms of lung expansion so in essence the worse the baby, the better they did in the long run at least from the IVH standpoint.  The babies with the more compliant lungs may have suffered from being “too good”.  Getting a good seal and providing good breaths with a BVM takes a lot of skill and practice.  This is why the t-piece resuscitator grew in popularity so quickly.  If you can turn a couple dials and place it over the mouth and nose of a baby you can ventilate a newborn.  The challenge though is that there is no feedback.  How much volume are you giving when you start with the same settings for everyone?  What may seem easy is actually quite complicated in terms of knowing what we are truly delivering to the patient.  I would put to you that someone far smarter than I needs to develop a commercially available BVM device with real time feedback on delivered volume rather than pressure.  Being able to adjust our pressure settings whether they be manual or set on a device is needed and fast! Perhaps someone reading this might whisper in the ear of an engineer somewhere and figure out how to do this in a device that is low enough cost for everyday use.    

AllThingsNeonatal

AllThingsNeonatal

 

Intubating to give surfactant is so 2017!

A catchy title for sure and also an exaggeration as I don’t see us abandoning the endotracheal tube just yet.  There has been a lot of talk about less invasive means of giving surfactant and the last few years have seen several papers relating to giving surfactant via a catheter placed in the trachea (MIST or LISA techniques as examples).  There may be a new kid on the block so to speak and that is aerosolized surfactant.  This has been talked about for some time as well but the challenge had been figuring out how to aerosolize the fluid in such a way that a significant amount of the surfactant would actually enter the trachea.  This was really a dream of many Neonatologists and based on a recently published paper the time may be now for this technique to take off. A Randomized Trial of Aerosolized Surfacant Minocchieri et al as part of the CureNeb study team published Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. This trial set out to obtain a sample size of 70 patients between 29 0/7 to 33 6/7 weeks to demonstrate a difference in need for intubation from 30% down to 5% in patients treated with CPAP (30% was based on the historical average).  The authors recognizing that the babies in this GA bracket might behave differently, further stratified the randomization into two groups being 29 0/7 – 31 6/7 weeks and 32 0/7 to 33 6/7 weeks.  Those babies who were on CPAP and met the following criteria for intubation were either intubated in the control group and given surfactant (curosurf) using the same protocol as those nebulized or had surfactant delivered via nebulisation (200 mg/kg: poractant alfa) using a customised vibrating membrane nebuliser (eFlow neonatal). Surfactant nebulisation(100 mg/kg) was repeated after 12 hours if oxygen was still required.  The primary dichotomous outcome was the need for intubation within 72 hours of life, and the primary continuous outcome was the mean duration of mechanical ventilation at 72 hours of age. Criteria for intubation 1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at
anytime.
2. More than four apnea/hour OR two apnea requiring BVM
3. Two cap gases with pH <7.2 and PaCO2 >65 mm Hg (or) >60 mm Hg if arterial blood gas sample).
4. Intubation deemed necessary by the attending physician. Did It Work? Eureka! It seemed to work as 11 of 32 infants were intubated in the surfactant nebulisation group within 72 hours of birth vs.22 out of 32 infants receiving CPAP alone (RR (95% CI)=0.526 (0.292 to 0.950)). The reduction though was accounted for by the bigger babies in the 32 0/7 to 33 6/7 weeks group as only 1 of 11 was intubated when given nebulized surfactant compared to 10 of 13 managed with CPAP.  The duration of ventilation in the first 72 hours was not different between the groups: the median (range) 0 (0–62) hour for the nebulization group and 9 (0–64) hours for the control group (p=0.220).  It is important in seeing these results that the clinicians deciding whether infants should be intubated for surfactant administration were blind to the arm the infants were in.  All administration of curosurf via nebulization or sham procedures were done behind a screen. The total number of infants randomized were 66 so they did fall shy of the necessary recruitment but since they did find a difference the results seem valid.  Importantly, there were no differences in complications although I can’t be totally confident there really is no risk as this study was grossly underpowered to look at rarer outcomes. Breaking down the results This study has me excited as what it shows is that “it kind of works“.  Why would larger babies be the ones to benefit the most?  My guess is that some but not a lot of surfactant administered via nebulization reaches the alveoli.  Infants with lesser degrees of surfactant deficiency (32 0/7 to 33 6/7) weeks might get just enough to manage without an endotracheal tube.  Those infants (in particular less than 32 0/7 weeks) who have more significant surfactant deficiency don’t get enough and therefore are intubated.  Supporting this notion is the overall delay in time to intubation in those who were intubated despite nebulization (11.6 hours in the nebulization group vs 4.9 hours in the control arm).  They likely received some deposition in the distal alveoli but not enough to completely stave off an endotracheal tube. One concerning point from the study though had to do with the group of infants who were intubated despite nebulization of surfactant.  When you look at total duration of ventilation (hours) it was 14.6 (9.0–24.8) in the control arm vs 25.4 (14.6–42.2) p= 0.029*.  In other words infants who were intubated in the end spent about twice as long intubated as those who were intubated straight away.  Not a huge concern if you are born at 32 weeks or more but those additional thousands of positive pressure breaths are more worrisome as a risk for CLD down the road. As it stands, if you had an infant who was 33 weeks and grunting with an FiO2 of 35% might you try this if you could get your hands on the nebulizer?  It appears to work so the only question is whether you are confident enough that the risk of such things as pneumothorax or IVH isn’t higher if intubation is delayed.  It will be interesting to see if this gets adopted at this point. The future no doubt will see a refinement of the nebulizer and an attempt to see how well this technique works in infants below 29 weeks.  It is in this group though that prolonging time intubated would be more worrisome.  I don’t want to dismiss this outright as I see this as a pilot study that will lead the way for future work that will refine this technique.  If we get this right this would be really transformative to Neonatology and just might be the next big leap.

AllThingsNeonatal

AllThingsNeonatal

 

Still performing awake intubations in newborns? Maybe this will change your mind.

If I look back on my career there have been many things I have been passionate about but the one that sticks out as the most longstanding is premedicating newborns prior to non-emergent intubation.  The bolded words in the last sentence are meant to reinforce that in the setting of a newborn who is deteriorating rapidly it would be inappropriate to wait for medications to be drawn up if the infant is already experiencing severe oxygen desaturation and/or bradycardia.  The CPS Fetus and Newborn committee of which I am a member has a statement on the use of premedication which seems as relevant today as when it was first developed.  In this statement the suggested cocktail of atropine, fentanyl and succinylcholine is recommended and having used it in our centre I can confirm that it is effective.  In spite of this recommendation by our national organization there remain those who are skeptical of the need for this altogether and then there are others who continue to search for a better cocktail.  Since I am at the annual conference for the CPS in Quebec city  I thought it would be appropriate to provide a few comments on this topic. Three concerns with rapid sequence induction (RSI) for premedication before intubation 1. "I don't need it.  I don't have any trouble intubating a newborn" - This is perhaps the most common reason I hear naysayers raise.  There is no question that an 60-90 kg practitioner can overpower a < 5kg infant and in particular an ELBW infant weighing < 1 kg.  This misses the point though.  Premedicating has been shown to increase success on the first attempt and shorten times to intubation. Dempsey 2006, Roberts 2006, Carbajal 2007, Lemyre 2009 2.  "I usually get in on the first attempt and am very slick so risk of injury is less." Not really true overall.  No doubt there are those individuals who are highly successful but overall the risk of adverse events is reduced with premedication. (Marshall 1984, Lemyre 2009). I would also proudly add another Canadian study from Edmonton by Dr. Byrne and Dr. Barrington who performed 249 consecutive intubations with predication and noted minimal side effects but high success rates at first pass. 3. "Intubation is not a painful procedure".  This one is somewhat tough to obtain a true answer for as the neonate of course cannot speak to this.  There is evidence available again from Canadian colleagues in 1984 and 1989 that would suggest that infants at the very least experience discomfort or show physiologic signs of stress when intubated using an "awake" approach.  In 1984 Kelly and Finer in Edmonton published Nasotracheal intubation in the neonate: physiologic responses and effects of atropine and pancuronium. This randomized study of atropine with or without pancuronium vs control demonstrated intracranial hypertension only in those infants in the control arm with premedication ameliorating this finding.  Similarly, in 1989 Barrington, Finer and the late Phil Etches also in Edmonton published Succinylcholine and atropine for premedication of the newborn infant before nasotracheal intubation: a randomized, controlled trial. This small study of 20 infants demonstrated the same finding of elimination of intracranial hypertension with premedication.  At the very least I would suggest that having a laryngoscope blade put in your oral cavity while awake must be uncomfortable.  If you still doubt that statement ask yourself whether you would want sedation if you needed to be intubated?  Still feel the same way about babies not needing any? 4.  What if I sedate and paralyze and there is a critical airway?  Well this one may be something to consider.  If one knows there is a large mass such as a cystic hygroma it may be best to leave the sedation or at least the paralysis out.  The concern though that there might be an internal mass or obstruction that we just don't know about seems a little unfounded as a justification for avoiding medications though. Do we have the right cocktail? The short answer is "I don't know".  What I do know is that the use of atropine, an opioid and a muscle relaxant seems to provide good conditions for intubating newborns.  We are in the era of refinement though and as a recent paper suggests, there could be alternatives to consider;Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency IntubationA Randomized Clinical Trial.  I personally like the idea of a two drug combination for intubating vs.. three as it leaves one less drug to worry about a medication error with.  There are many papers out there looking at different drug combinations.  This one though didn't find a difference between the two combinations in terms of prolonged desaturations between the two groups which was the primary outcome. Interestingly though the process of intubating was longer with atropine and propofol.  Given some peoples reluctance to use RSI at all, any drug combination which adds time to the the procedure is unlikely to go over well.  Stay tuned though as I am sure there will be many other combinations over the next few years to try out!    

AllThingsNeonatal

AllThingsNeonatal

 

Every drop counts

As a Neonatologist, there is no question that I am supportive of breast milk for preterm infants.  When I first meet a family I ask the question “are you planning on breastfeeding” and know that other members of our team do the same.  Before I get into the rest of this post, I realize that while breast milk may be optimal for these infants there are mother’s who can’t or won’t for a variety of reasons produce enough breast milk for their infants.  Fortunately in Manitoba and many other places in the world breast milk banks have been developed to provide donor milk for supporting these families.  Avoidance of formula in the early days to weeks of a ELBWs life carries benefits such as a reduction in NEC which is something we all want to see. Mother’s own milk though is known to have additional benefits compared to donor milk which requires processing and in so doing removes some important qualities.  Mother’s own milk contains more immunologic properties than donor including increased amounts of lactoferrin and contains bioactive cells.  Growth on donor human milk is also reduced compared to mothers’ own milk and lastly since donor milk is obtained from mothers producing term milk there will be properties that differ from that of mothers producing fresh breast milk in the preterm period.  I have no doubt there are many more detailed differences but for basic differences are these and form the basis for what is to come. The Dose Response Effect of Mother’s Own Milk Breast milk is a powerful thing.  Previous studies on the impact of mother’s own milk (MOM) have shown that with every increment of 10 mL/kg/d of average intake, the risk of such outcomes as BPD and adverse developmental outcomes are decreased. In the case of BPD the effect is considerable with a 9.5% reduction in the odds of BPD for every 10% increase in MOM dose.  With respect to developmental outcome ach 10 mL/kg/day increase in MOM was associated with a 0.35 increase in cognitive index score. One of the best names for a study has to be the LOVE MOM study which enrolled 430 VLBW infants from 2008-2012.    The results of this study Impact of early human milk on sepsis and health-care costs in very low birth weight infants.indicated that with incremental increases of 10 mL/kg of MOM reductions in sepsis of 19% were achieved and in addition overall costs were reduced. The same group just published another paper on this cohort looking at a different angle. NICU human milk dose and health care use after NICU discharge in very low birth weight infants.  This study is as described and again looked at the impact of every 10 mL/kg increase in MOM at two time points; the first 14 and the first 28 days of life.  Although the data for the LOVE MOM trial was collected prospectively it is important to recognize how the data for this study was procured. At the first visit after NICU discharge the caregiver was asked about hospitalizations, ED visits and specialized therapies and specialist appointments. These were all tracked at 4 and 8 months of corrected age were added to yield health care utilization in the first year, and the number of visits or provider types at 4, 8, and 20 months of corrected age provided health care utilization through 2 years. What were the results? “Each 10 mL/kg/day increase in HM in the first 14 days of life was associated with 0.26 fewer hospitalizations (p =
0.04) at 1 year and 0.21 fewer pediatric subspecialist types (p = 0.04) and 0.20 fewer specialized therapy types (p = 0.04) at 2 years.” The results at 28 days were not statistically significant.  The authors reported both unadjusted and adjusted results controlling for many factors such as gestational age, completion of appointments and maternal education to name a few which may have influenced the results.  The message therefore is that the more of MOM a VLBW is provided in the first 14 days of life, the better off they are in the first two years of life with respect to health care utilization.   That even makes some sense to me.  The highest acuity typically for such infants is the first couple of weeks when they are dealing with RDS, PDA, higher oxygen requirements etc.  Could the protective effects of MOM have the greatest bang for your buck during this time.  By the time you reach 28 days is the effect less pronounced as you have selected out a different group of infants at that time point? What is the weakness here though?  The biggest risk I see in a study like this is recall bias. Many VLBW infants who leave the NICU have multiple issues requiring many different care providers and services.  Some families might keep rigorous records of all appointments in a book while others might document some and not others.  The big risk here in this study is that it is possible that some parents overstated the utilization rates and others under-reported.  Not intentionally but if you have had 20 appointments in the first eight months could the number really by 18 or 22? Another possibility is that infants receiving higher doses of MOM were healthier at the outset.  Maternal stress may decrease milk production so might mothers who had healthier infants have been able to produce more milk?  Are healthier infants in the first 14 days of life less likely to require more health care needs in the long term? How do we use this information? In spite of the caveats that I mentioned above there are multiple papers now showing the same thing.  With each increment of 10 mL/kg of MOM benefits will be seen.  It is not a binary effect meaning breastfed vs not.  Rather much like the medications we use to treat a myriad of conditions there appears to be a dose response.  It is not enough to ask the question “Are you intending to breastfeed?”.  Rather it is incumbent on all of us to ask the follow-up question when a mother says yes; “How can we help you increase your production?” if that is what the family wants>

AllThingsNeonatal

AllThingsNeonatal

 

Giving surfactant through an LMA. Time to ditch the endotracheal tube?

In the spirit of full disclosure I have to admit I have never placed a laryngeal mask airway (LMA) in a newborn of any gestational age.  I have played with them in simulated environments and on many occasion mentioned that they are a great alternative to an ETT especially in those situations where intubation may not be possible due to the skill of the provider or the difficulty of the airway in the setting of micrognathia for example. In recent years though we have heard of examples of surfactant delivery via these same devices although typically these were only case reports. More recently a small randomized study of 26 infants by Attridge et al demonstrated in the group randomized to surfactant administration through an LMA that oxygen requirements were reduced after dosing.  This small pilot provides sufficient evidence to show that it is possible to provide surfactant and that at least some gets into the airway of the newborn.  This proof of concept though while interesting, did not answer the question of whether such delivery of surfactant would be the same or better than through an ETT.  As readers of my blog posts know, my usual stance on things is that the less invasive the better and as I look through the literature, I am drawn to concepts such as this to see if they can be added to our toolbox of non or less invasive strategies in the newborn. A Minimally Invasive Technique For The Masses? This past month, a small study by Pinheiro et al sought to answer this question by using 61 newborns between 29 0/7 - 36 6/7 weeks and greater than 1000g and randomizing them to either surfactant via the INSURE technique or LMA.  I cannot stress enough so will get it out of the way at the start that this strategy is not for those <1000g as the LMA is not designed to fit them properly and the results (to be shown) should not be generalized to this population. Furthermore then study included only those infants who needed surfactant between 4 - 48 hours of age, were on CPAP of at least 5 cm H2O and were receiving FiO2 between 30 - 60%.  All infants given surfactant via the insure technique were premedicated with atropine and morphine while those having an LMA received atropine only.  The primary outcome of the study was need for subsequent intubation or naloxone within 1 hour of surfactant administration.  The study was stopped early after an interim analysis (done as the fellow involved was finishing their fellowship - on a side note I find this an odd reason to stop) demonstrated better outcomes in the group randomized to the LMA. Before we get into the results let's address the possible shortcomings of the study as they might already be bouncing around your heads.  This study could not be blinded and therefore there could be a significant bias to the results.  The authors did have predetermined criteria for reintubation and although not presented, indicate that those participating stuck to these criteria so we may have to acknowledge they did the best they could here.  Secondly the study did not reach their numbers for enrolment based on their power calculation.  This may be ok though as they found a difference which is significant.  If they had found no difference I don't think I would be even writing this entry!  Lastly this study used a dose of surfactant at 3 mL/kg.  How well would this work with the formulation that we use BLES that requires 5 mL/kg? What were the results? Intervention Failure LMA Group ETT group p Any failure 9 (30%) 23(77%) <0.001 Early failure 1 (3%) 20 (67%) <0.001 Late failure 8 (27%) 3 (10%) 0.181 What do these results tell us?  The majority of failures occurred within an hour of delivery of surfactant in the ETT group?  How does this make any sense?  Gastric aspirates for those in the LMA group but not the INSURE group suggest some surfactant missed the lung in the former so one would think the intubation group should have received more surfactant overall however it would appear to be the premedication.  The rate of needing surfactant afterwards is no different and in fact there is a trend to needing reintubation more often in the LMA group but the study was likely underpowered to detect this difference.  Only two patients were given naloxone to reverse the respiratory depressive effects of morphine in those given the INSURE technique so I can't help but speculate that if this practice was more frequent many of the reintubations might have been avoided.  This group was quite aggressive in sticking to the concept of INSURE as they aimed to extubate following surfactant after 5 - 15 minutes.  I am a strong advocate of providing RSI to those being electively intubated but if the goal is to extubate quickly then I believe one must be ready to administer naloxone soon after extubation if signs of respiratory depression are present and this did not happen effectively in this study.  Some may argue those getting the INSURE technique should not be given any premedication at all but that is a debate that will go on for years I am sure but they may have a valid point given this data. Importantly complications following either procedure were minimal and no different in either group. Where do we go from here? Despite some of the points above I think this study could prove to be important for several reasons.  I think it demonstrates that in larger preterm infants it is possible to avoid any mechanical ventilation and still administer surfactant.  Many studies using the minimally invasive surfactant treatment (MIST) approach have been done but these still require the skill of laryngoscopy which takes a fair bit of skill to master.  The LMA on the other hand is quite easy to place and is a skill that can be taught widely.  Secondly, we know that even a brief period of over distension from PPV can be harmful to the lung therefore a strategy which avoids intubation and direct pressure to the lung may offer some longer term benefit although again this was not the study to demonstrate that. Lastly, I see this as a strategy to look at in more rural locations where access to highly skilled level III care may not be readily available.  We routinely field calls from rural sites with preterm infants born with RDS and the health care provider either is unable to intubate or is reluctant to try in favour of using high flow oxygen via mask.  Many do not have CPAP either to support such infants so by the time our Neonatal Transport team arrives the RDS is quite significant.  Why not try surfactant through the LMA?  If it is poorly seated over the airway and the dose goes into the stomach I don't see them being in any worse shape than if they waited for the team to arrive.  If some or all of the dose gets in though there could be real benefit. Might this be right for your centre?  As we think about outreach education and NRP I think this may well become a strong reason to spend a little more time on LMA training.  We may be on to something!  

AllThingsNeonatal

AllThingsNeonatal

 

High Flow Nasal Cannula: Be Careful Out There

As the saying goes the devil is in the details.  For some years now many centres worldwide have been publishing trials pertaining to high flow nasal cannulae (HFNC) particularly as a weaning strategy for extubation.  The appeal is no doubt partly in the simplicity of the system and the perception that it is less invasive than CPAP.  Add to this that many centres have found less nasal breakdown with the implementation of HFNC as standard care and you can see where the popularity for this device has come from. This year a contact of mine Dominic Wilkinson@NeonatalEthics on twitter (if you don’t follow him I would advise having a look!) published the following cochrane review, High flow nasal cannula for respiratory support in preterm infants.  The review as with most cochrane systematic reviews is complete and comes to a variety of important conclusions based on 6 studies including 934 infants comparing use of HFNC to CPAP. 1.  No differences in the primary outcomes of death (typical RR 0.77, 95% CI 0.43 to 1.36; 5 studies, 896 infants) or CLD. 2.  After extubation to HFNC no difference in the rate of treatment failure(typical RR 1.21, 95% CI 0.95 to 1.55; 5 studies, 786 infants) or reintubation(typical RR 0.91, 95% CI 0.68 to 1.20; 6 studies, 934 infants). 3.  Infants randomised to HFNC had reduced nasal trauma (typical RR 0.64, 95% CI 0.51 to 0.79; typical risk difference (RD) -0.14, 95% CI -0.20 to -0.08; 4 studies, 645 infants). 4. Small reduction in the rate of pneumothorax (typical RR 0.35, 95% CI 0.11 to 1.06; typical RD -0.02, 95% CI -0.03 to -0.00; 5 studies 896 infants) in infants treated with HFNC but the RR crosses one so this may be a trend at best. If one was to do a quick search for the evidence and found this review with these findings it would be very tempting to jump on the bandwagon.  Looking at the review a little closer though there is one line that I hope many do not miss and I was happy to see Dominic include it. “Subgroup analysis found no difference in the rate of the primary outcomes between HFNC and CPAP in preterm infants in different gestational age subgroups, though there were only small numbers of extremely preterm and late preterm infants.” In his conclusion he further states: Further evidence is also required for evaluating the safety and efficacy of HFNC in extremely pretermand mildly preterm subgroups, and for comparing different HFNC devices. With so few ELBW infants included and with these infants being at highest risk of mortality and BPD our centre has been reluctant to adopt this mode of respiratory support in the absence of solid evidence that it is equally effective to CPAP in these smallest infants.  A big thank you to our Respiratory Therapy Clinical Specialist for harping on this point over the years as the temptation to adopt has been strong as other centres turn to this strategy. Might Not Be So Safe After All Now do not take what I am about to say as a slight against my twitter friend.  The evidence to date points to exactly what he and his other coauthors concluded but with the release of an important paper in May by Taka DK et al, I believe caution is needed when it comes to our ELBW infants. High Flow Nasal Cannula Use Is Associated with Increased Morbidity and Length of Hospitalization in Extremely Low Birth Weight Infants This paper adds to the body of literature on the topic as it truly focuses on the outcome of infants < 1000g.  While this study is retrospective in nature it does cover a five year period and examines important outcomes of interest to this population. The primary outcome in this case was death or BPD and whether HFNC was used alone or with CPAP, this was more frequent than when CPAP was used alone.  Other important findings were the need for multiple and longer courses of ventilation in those who received at least some HFNC.  In these times of overburdened health care systems with goals of improving patient flow, it is also worth noting that there was a significant prolongation of length of stay with use of HFNC or HFNC and CPAP. One interesting observation was that the group that fared the worst across the board was the combination of CPAP and HFNC rather than HFNC alone.   CPAP (941) HFNC (333) HFNC +/- CPAP (1546) CPAP d (median, IQR) 15(5-28)   7 (1-19) HFNC d (median, IQR) 14(5-25) 13 (6-23) HFNC +/- CPAP 15 (5-28) 14(5-25) 26 (14-39) BPD or death % 50.40% 56.80% 61.50% BPD % 42.20% 52.20% 59.00% Multiple ventiation courses 51.10% 53.10% 64.70% More than 3 vent courses 17.60% 21.00% 29.40% Ventilator d (median, IQR) 18(5-42) 25 (6-52) 30 (10-58) I believe the finding may be explained by the problem inherent with retrospective studies.  This is not a study in which patients were randomized to either CPAP, HFNC or CPAP w/HFNC.  If that were the case one would expect lung pathologies and severity of illness to even ou,t such that differences between groups might be explained by the difference in treatments.  In this study though we are looking though the rearview mirror so to speak.  How could we account for the combination being worse than the HFNC alone?  I suspect it relates to the severity of lung disease.  The babies who were placed on HFNC and did well on it might have had less severe chronic changes.  What might be said about those that had the combination?  Well, one could postulate that there might be some who were extubated to HFNC and collapsed needing escalation to CPAP and then failing that therapy were reintubated.  Another explanation could be those babies who were placed on CPAP after extubation and transitioned before their lungs were ready to HFNC may have failed and lost FRC thereby going back to CPAP and possibly intubation.  Exposure in either circumstance to HFNC would therefore put them at risk of further positive pressure ventilation and subsequent further lung injury.  The babies who could tolerate transition to HFNC without CPAP might be intermediary in their outcomes (as they were found to be) as they lost FRC but were able to tolerate it but consumed more calories leaving less for growth and repair of damaged tissue leading to prolonged need for support. Either way, the use of HFNC was found to lead to worse outcomes and in the ELBW infant should be avoided as routine practice pending the results of a prospective RCT on the subject. Is it a total ban though? As with many treatments that one should not consider standard of care there may be some situations where there may be benefit.  The ELBW infant with nasal breakdown from CPAP that despite excellent nursing and RRT attention continues to demonstrate tissue damage is one patient that could be considered.  The cosmetic implications and potential for surgical correction at a later date would be one reason to consider a trial of HFNC but only in the patient that was close to being able to come off CPAP.  In the end I believe that if a ELBW infant needs non invasive pressure support then it should be with CPAP but as there saying goes there may be a right time and a place for even this modality.

AllThingsNeonatal

AllThingsNeonatal

 

The Eyes Have It. No Not Really

Every now and then I come across an instance when I discover that something that I have known for some time truly is not as well appreciated as I might think. Twice in my career I have come across the following situation which has been generalized to eliminate any specific details about a patient.  In essence this is a fictional story but the conclusions are quite real. Case of the Flat Baby A mother arrives at the hospital with severe abdominal pain and in short order is diagnosed with a likely abruption at 26 weeks gestational age. Fetal monitors are attached and reveal a significant fetal bradycardia with a prolonged period of minutes below 100 and sometimes below 60 beats per minute.  She is rushed to the OR where an emergency c-section is performed. A live born infant is handed to the resuscitation team after cord clamping is stopped at 30 seconds due to significant cyanosis and no respirations.  After placing the infant in a polyethylene wrap and performing the initial steps of ventilation there is no respiratory effort and the baby is given PPV.  After no heart rate is noted chest compressions commence followed by intubation and then epinephrine when a heart rate while detected remains below 60.  The team gives a bolus of saline followed by another round of epinephrine and by 10 minutes a pulse of 80 BPM is detected.  While a pulse is present it remains borderline and the baby shows no sign of any respiratory efforts. The care providers at this point have a decision to make about continuing resuscitative efforts or not.  One of the team members performs a physical exam at this stage and notes that the pupils are unresponsive to light with a 3 mm pupillary diameter.  The team questions whether based on this finding irreversible neurological damage has occurred. Pupillary Reactions in Preterm Infants It turns out that much like many organs in the body which have yet to fully mature the same applies to the eye or more specifically in this case the pupil. Robinson studied 50 preterm infants in 1990 and noted that none of the infants under 30 weeks gestational age demonstrated any reaction to light shone in the eye.  After 30 weeks the infants gradually realized this function until by 35 weeks all infants had attained this pupillary reaction to light. Isenberg in the same year when examining 30 preterm infants under 30 weeks noted that in addition to the lack of pupillary constriction to light, as the gestational age decreased the pupillary diameter enlarged.  The youngest infants in this study at 26 weeks had a mean pupillary diameter of 4.7 mm while by 29 weeks this number decreased to 2.9 mm.  This means that the smaller the infant the larger the pupillary size and given that these are also the highest risk infants one can see how the appearance of a "fixed and dilated pupil" could lead one down the wrong path. Conclusion Deciding when to stop a resuscitation is never an easy decision.  Add to this as I recently wrote, even after 10 minutes of resuscitation outcomes may not be as bad as we have thought; Apgar score of 0 at 10 minutes: Why the new NRP recommendations missed the mark.  What I can say and obviously was the main thrust of this piece is that at least when you are resuscitating an infant  < 30 weeks gestational age, leave the eyes out of the decision.  The eyes in this case "do not have it".

AllThingsNeonatal

AllThingsNeonatal

 

Does High Flow Really Have A Place in the NICU At All?

This may sound familiar as I wrote about this topic in the last year but the previous post was restricted to infants who were under 1000g.  High Flow Nasal Cannula be careful out there had a main message that suggested the combined outcome of BPD or death was more prevalent when HFNC is used alone or with CPAP than when CPAP is used alone.  The question remains though whether this applies to larger infants.  Without looking at the evidence for that combined outcome most people would say there is unlikely to be a difference.  Larger more mature babies have a much lower risk of BPD or death so proponents of HFNC would say it is simpler to use and helps prevent nasal breakdown as well.  The question remains as to whether all outcomes are the same in larger infants and that is the point of this post. A Non-Inferiority Trial First off it is important to understand what this type of trial is.  The first requirement is that the two treatments have both been compared to a placebo and found to be both effective.  Once you establish that you have a choice between two treatment options then you eliminate the placebo and compare them head to head.  What you are looking for in this type of trial is to determine not whether one is better than the other but that there is no difference in a clinical outcome of interest.  If you find no difference then the next step is to look at other outcomes that might be of interest and see if there are any benefits to picking one versus the other.  In the case of CPAP vs HNFC, if a non-inferiority trial showed no difference in an important outcome such as length of stay but nasal breakdown was less with HFNC it might lead a unit to use HFNC for their infants.  Okay, now that we have that cleared up we can move on to an actual study examining this very subject. Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants. This was an interesting study with a great name (The HIPSTER trial) that enrolled infants > 28 weeks and 0 days with none of the infants receiving surfactant but either being randomized to HFNC or CPAP after delivery.  These infants were your typical modern day cohort of babies who may avoid intubation and surfactant by establishing FRC early with positive pressure applied to the nose through one of these devices.  The end point for the study was treatment failure within 72 hours.  If an infant failed in the HFNC they could have a trial of CPAP whereas in the CPAP group they were intubated.  For each infant in the HFNC group flow was set from 6-8 l/min and for CPAP 6-8 cmH2O. Treatment was considered to have failed if an infant receiving maximal support (high-flow therapy at a gas flow of 8 liters per minute or CPAP at a pressure of 8 cm of water) met one or more of the following criteria: FiO2 of 0.4 or higher Arterial or free flowing cap gas with a pH of 7.2 or less plus a pCO2 > 60 mm Hg obtained at least 1 hour after starting treatment Two or more episodes of apnea requiring positive-pressure ventilation within a 24-hour period or six or more episodes requiring any intervention within a 6-hour period. Infants with an urgent need for intubation and mechanical ventilation. So what happened? The trial randomized 583 infants (278 HFNC, 286 CPAP) but was halted by the data and safety monitoring committee after an analysis of the first 515 revealed that the outcome was worse in the HFNC group (25.5% failure rate vs 13.3 for CPAP).  Interestingly treatment failures were more common in babies below and above 32 weeks so it was not just the smallest infants who failed. Another interesting finding was that the most common reason for treatment failure was criteria 1 (FiO2 > 40%) while intubation was higher for all infants but did not reach statistical significance.  Curiously what did reach a significant difference was criteria #4 (18.4% urgent intubations in the CPAP group vs 5.6% in the HFNC group). You might be tempted to therefore ponder which is worse, a little O2 or being intubated but you need to recall the trial design which was set up to provide this kind of result.  If you failed HFNC you were placed on CPAP whereas if you failed CPAP you were intubated.  In the HFNC group, 78 infants were deemed to have failed but 28 of them were in fact “rescued by CPAP”.  It therefore isn’t a fair comparison when it comes to urgent intubation since if you failed CPAP there wasn’t another option. Not a total loss Nasal trauma was indeed much lower in the HFNC group, occurring only 8.3% vs 18.5% of the time with CPAP.  Pneumothorax was also found to be significantly different with none of the patients in the HFNC group having that complication vs 2.1% in the CPAP group.  What this study tells us is that as a primary modality to treat newborns with RDS who have not received surfactant it is preferable to use CPAP in the first 72 hours.  Some of you may say it might not say that at all but consider the impact of having more babies exposed to high FiO2.  We know from other studies that high FiO2 can be quite damaging to preterm infants and this study was certainly not powered to look at all those important outcomes such as ROP, PVL and BPD.  The authors report them and found no difference but without adequate power to show a difference I wouldn’t take much comfort in those findings. I think were things may settle out though is what to do in more mature infants.  There is no question that for those on chronic respiratory support there is some risk of nasal breakdown.  Although I don’t have much experience with HFNC I would think that for the older patient who either already has BPD at 36 weeks or is close to that point but reliant on +4 or +5 CPAP that HFNC might help “give them a break”.  As such I don’t see this as a total loss but rather an option to try when CPAP for whatever reason is not tolerated. As a primary therapy for non-invasive management RDS I will keep my CPAP for all babies thank you.

AllThingsNeonatal

AllThingsNeonatal

 

Can't Intubate To Give Surfactant? No Problem!

A common concern in the NICU these days is the lack of opportunity to intubate. A combination of an increasing pool of learners combined with a move towards a greater reliance on non-invasive means of respiratory support is to blame in large part. With this trend comes a declining opportunity to practice this important skill and with it a challenge to get a tube into the trachea when it really counts. One such situation is a baby with escalating FiO2 requirements who one wishes to provide surfactant to. Work continues to be done in the area of aerosolized surfactant but as of yet this is not quite ready for prime time. What if there was another way to get surfactant to where it was needed without having to instill it directly into the trachea whether through a catheter (using minimally invasive techniques) or through an endotracheal tube? Installation of surfactant into the trachea Lamberska T et al have published an interesting pilot study looking at this exact strategy. Their paper entitled Oropharyngeal surfactant can improve initial stabilisation and reduce rescue intubation in infants born below 25 weeks of gestation takes a look at a strategy of instilling 1.5 mL of curosurf directly into the pharynx for infants 22-24 weeks through a catheter inserted 3-4 cm past the lips as a rapid bolus concurrent with a sustained inflation maneuver (SIM) of 25 cm of H2O for 15 seconds. Two more SIMs were allowed of the heart rate remained < 100 after 15 seconds of SIM. The theory here was that the SIM would trigger an aspiration reflex as the pressure in the pharynx increased leading to distribution of surfactant to the lung. The study compared three epochs from January 2011 - December 2012 when SIM was not generally practiced to July 2014 - December 2015 when SIM was obligatory. The actual study group was the period in between when prophylactic surfactant with SIM was practiced for 19 infants. A strength of the study was that resuscitation practices were fairly standard outside of these changes in practice immediately after delivery and the decision to intubate if the FiO2 was persistently above 30% for infants on CPAP. A weakness is the size of the study with only 19 patients receiving this technique being compared to 20 patients before and 20 after that period. Not very big and secondly no blinding was used so when looking at respiratory outcomes one has to be careful to ensure that no bias may have crept in. If the researchers were strongly hoping for an effect might they ignore some of the "rules around intubation" and allow FiO2 to creep a little higher on CPAP as an example? Hard to say but a risk with this type of study. What did they find? The patients in the three epochs were no different from one and other with one potentially important exception. There were higher rates of antenatal steroid use in the study group (95% vs 75 and 80% in the pre and post study epochs). Given the effect of antenatal steroids on reducing respiratory morbidity, this cannot be ignored and written off. Despite this difference it is hard to ignore the difference in endotracheal intubation in the delivery room with only 16% needing this in the study group vs 75 and 55% in the other two time periods. Interestingly, all of the babies intubated in the delivery area received surfactant at the same percentages as above. The need for surfactant in the NICU however was much higher in the study period with 79% receiving a dose in the study group vs 20 and 35% in the pre and post study groups. Other outcomes such as IVH, severe ROP and BPD were looked at with no differences but the sample again was small. What can we take from this? Even taking into account the effect of antenatal steroids, I would surmise that some surfactant did indeed get into the trachea of the infants in the study group. This likely explains the temporary benefit the babies had in the delivery suite. I suspect that there simply was not a big enough dose to fully treat their RDS leading to eventual failure on CPAP and a requirement for intubation. Is all lost though? Not really I think. Imagine you are in a centre where the Neonatologist is not in house and while he/she is called to the delivery they just don't make it in time. The trainee tries to intubate but can't get the tube in. Rather than trying several times and causing significant amounts of airway trauma (as well as trauma to their own self confidence) they could abandon further attempts and try instilling some surfactant into the pharynx and proving a SIM. If it works at all the baby might improve enough to buy some time for them to be stabilized on CPAP allowing time for another intubater to arrive. While I don't think there is enough here to recommend this as an everyday practice there just might be enough to use this when the going gets tough. No doubt a larger study will reveal whether there really is something here to incorporate into the tool chest that we use to save the lives of our smallest infants.  

AllThingsNeonatal

AllThingsNeonatal

 

Parental stress in the NICU; effect of parental presence on rounds.

To many of you the answer is a resounding yes in that it reduces stress.  Why is that though?  Is it because you have had a personal experience that has been favourable, it is the practice in your unit or it just seems to make sense?  It might come as a surprise to you who have followed this blog for some time that I would even ask the question but a social media friend of mine Stefan Johansson who runs 99NICU sent an article my way on this topic. Having participated in the FiCare study I realised that  I have a bias in this area but was intrigued by the title of the paper.  The study is Parental presence on neonatal intensive care unit clinical bedside rounds: randomised trial and focus group discussion by Abdel-Latif ME et al from New Zealand and was performed due to the lack of any RCTs on the subject specifically in the NICU. Before I go on though I have to disclose a few biases.  I love parents being on rounds so I can speak with them directly and have them ask me any questions they may have after hearing about their infants condition. Our unit encourages the practice. We are rolling out the principals of FiCare after being part of the study which encourages parental presence at the bedside for far more than just rounds.For information on implementing FiCare click here While this study is the only reported RCT on the subject in the NICU, the FiCare results will be published before long. What is the problem with having families on rounds? The detractors would say that sensitive information may be more difficult to discuss out in the open for fear that the family will take offence or be hurt.  Another concern may be that teaching will be affected as the attending may not want to discuss certain aspects of care in order to prevent creating fear in the parents or awkwardness in the event that the management overnight was not what they would have done.  Lastly, when patient volumes and acuity are high, having parents ask questions on rounds may lead to excessive duration of this process and lead to fatigue and frustration by all members of the team. So what does this study add? This particular study enrolled 72 families of which 63 completed the study.  The study required 60 families to have enough power to detect the difference in having parents on rounds or not.The design was interesting in that the randomisation was a cross over design in which the following applied.  One arm was having parents on rounds and the other without.  The unit standard at the time was to not have parents on rounds. ≤30 weeks 1 week in one arm, one week washout period then one week in the other arm >30 weeks 3 days in one arm, three day washout and then three days in the other arm The primary outcome was to see if there would be a significant difference in the Parental Stressor Scale.   Surprisingly there was no difference across any domains of measuring parental stress.  When we look at questions though pertaining to communication in the NICU we see some striking differences. The families see many benefits to the model of being on rounds.  They appear to have received more information, more contact with the team, contributed more to the planning of the course of their babies care and been able to ask more questions.  All of these things would seem to achieve the goals of having parents on rounds. So why aren’t parents less stressed? This to me is the most interesting part of this post.  The short answer is I am not sure but I have a few ideas.  The study could not be blinded.  If the standard of care in the unit was to not have parents on rounds, what kind of conversations happened after rounds?  Were staff supportive of the families or were they using language that had a glass is half empty feel to it?  Much like I am biased towards having parents on rounds and thanking them for their participation were there any negative comments that may have been unintentional thrown the families way. Is a little knowledge a dangerous thing?  Perhaps as families learn more details about the care of their baby it gives them more things to worry about.  Could the increase in knowledge while in some ways being pleasing to the family be offset by the concern that new questions raise. Was the intervention simply too short to detect a difference?  This may have been a very important contributor.  This short period of either a week or two leaves the study open to a significant risk that an event in either week could acutely increase stress levels.  What if the infant had to go back on a ventilator after failing CPAP, needed to be reloaded with caffeine or developed NEC?  With such short intervals one cannot say that while communication was better the parents were not stressed due to something unrelated to communication.  In an RCT these should balance out but in such a small study I see this as a significant risk. So where do we go from here? I applaud the authors for trying to objectively determine the effect of parental presence on rounds in the NICU.  Although I think they did an admirable job I believe the longer time frame of the FiCare study and the cluster randomised strategy using many Canadian centres will prove to be the better model to determine effectiveness.  What the study does highlight though in a very positive way is that communication is enhanced by having parents on rounds and to me that is a goal that is well worth the extra time that it may take to get through rounds.  Looking at it another way, we as the Neonatologists may need to spend less time discussing matters after rounds as we have taken care of it already.  In the end it may be the most efficient model around!

AllThingsNeonatal

AllThingsNeonatal

 

Is there really a place for standard phototherapy in the NICU anymore?

I have been mulling over this piece for some time.  In my own practice I have long questioned the role for standard phototherapy (the equivalent of a single light source) vs intensive phototherapy (delivering >30 microwatts/cm2/nm and usually two light sources) when treating jaundice for all patients. I have bolded that last part to emphasize that I am not just talking about newborns with severe hyperbilirubinemia but rather all infants with treatable jaundice based on local treatment curves such as shown in the CPS and AAP statements.  When newborns are only 30 - 50 micromol/L above the treatment threshold as an example, I will see standard phototherapy ordered or after initiating treatment with intensive phototherapy as the level approaches no treatment required you will see people switch to standard phototherapy again.  Why is that and does it make sense? The rationale for using less intensive phototherapy has been to minimize side effects.  Historically, these were retinal damage (hence the eye covers), electrolyte disturbances, increased insensible water loss and occasionally rashes.  I use the word historically as they for the most part are no longer relevant today provided a narrow spectrum LED light source is utilized which is the technology used in most modern phototherapy light sources now.  Backing up this claim, in 2008 Dr. Maisels, showed that in preterm infants receiving LED based light there were no increases in transepidermal water loss.  By limiting the wavelength of light emitted to 430  - 490 nm and avoiding the infrared wavelengths.  Whether the concern exists with respect to retinal effects is tough to say for sure so continued precautions with eye covers are recommended. Go Big or Go Home If there is little harm to phototherapy then is there a reason to use more?  The effectiveness of phototherapy is generally based on three things.  The first is the proximity of the light source to the patient (< 15 cm is ideal), the second is the intensity of the lamp and the third is the surface area covered.  If you are using a single focused spot and covering only 15- 20% of the body you are missing out on a lot of skin that could be helping to lower an infants bilirubin more rapidly.  As I see it, if there is little harm in giving phototherapy and the rate of bilirubin decline is faster with better phototherapy, why would you use anything less than intensive using two light sources?  Also from a developmental care point of view, less time under the lights means more time for skin to skin and that is always a good thing. Phototherapy and DNA damage What prompted me to write this piece actually was the following paper Jaundice, phototherapy and DNA damage in full-term neonates by Ramy N et al from November of 2015.    In this paper the authors used a validated measure of DNA damage and assessed infants both before and after phototherapy.  Thirty six newborns with jaundice were compared to 30 controls.  The results are shown in the following figure. Figure B demonstrates that prior to initiation of phototherapy the extent of DNA damage in tested cells is no different whether you are jaundiced or not.  In essence bilirubin is not toxic to cells which also makes sense knowing that bilirubin has antioxidant properties and hence one would think it might be protective against DNA damage.  It is figure C and D that provide the most interesting information.  Figure C demonstrates that phototherapy (conventional and intensive groups combined) leads to an increase in DNA damage.  Figure D is important in that it illustrates that comparing conventional and intensive phototherapy groups there is no difference in rates of DNA damage.  This would indicate that more intensive phototherapy is not hazardous to cells. What was noted in the end though is what is most important here.  As expected the duration of phototherapy differed between the two strategies.  Infants in the conventional group were under lights for 62.2 ± 23.02 hrs vs 41.3 ± 22.9 hrs, P = 0.005 in the intensive group.  When the authors analyzed the relationship between DNA damage and length of phototherapy there was a statistically significant relationship between the two. In summary then Intensive phototherapy is more effective than conventional at reducing levels of jaundice Phototherapy is associated with minimal clinical side effects whether intensive or conventional. Infants receiving conventional phototherapy require longer courses of treatment. Longer courses are associated with greater levels of DNA damage. The significance of this DNA damage is unknown based on this study but in principal avoiding such injury may be a wise thing to do. One last benefit - less needle pokes and shorter lengths of stay! If an infant spends an average of one less day under phototherapy lights do not underestimate the added benefit with respect to avoiding needle pokes.  Typically such infants receive one poke a day to "check how the decline is going".  Shortening the course of phototherapy may translate into one or two less pokes or more and that is definitely a good thing! Lastly I will leave you with a tip from my own practice which I have found very useful to eliminate at least one poke.  When phototherapy is effective and the bilirubin is coming down (and is close to the threshold for stopping but not quite there yet) it is common for people on rounds to order another bilirubin for the morning and continue phototherapy until that result.  The result comes back the following morning and the practitioner orders a follow-up bilirubin  for the following day to check for the "rebound". An alternative strategy is to keep the infant on phototherapy overnight and rather than checking on the bilirubin in the morning just stop the phototherapy on rounds.  Eight hours later check the bilirubin and if it is below the threshold for treatment send the infant home.  You avoid an overnight stay and instead of poking twice in two days do it all in one. Whether you take this advice or not is up to you but if all that comes from this post is a decrease in the general fear of intensive phototherapy I may have gotten somewhere and the DNA of many babies out there will thank you!

AllThingsNeonatal

AllThingsNeonatal

 

High frequency nasal ventilation: Ready for prime time?

I will admit it.  I resist change at times just like many others.  This may come as a surprise to some of you who have worked with me and accused me of bringing too much change at times to the units.  The truth though is that when one understands something and is enthusiastic about implementation the change does not seem so difficult.  When it isn't your idea though we may find ourselves a little uneasy about adopting this unfamiliar practice. Such has been my experience with nasal HFOV.  It is a strategy that has been around for over five years but has seen slow adoption among centres in Canada and has trickled into practice in Winnipeg on a few occasions.  In each occasion when I have been asked about either continuing or perhaps starting this therapy I have shrugged my shoulders and confessed my inexperience with the modality.  Sure I have used HFOV through an ETT but through prongs or a mask?!  How would it work?  Could it cause harm?  What would the actual indications be?  How would our in house physicians and NNPs respond to abnormal gases overnight even if I felt comfortable with using it?  These sorts of questions have led to virtual inertia in my acceptance of the strategy. Before I go on it would be good to see an example of how it is set up.  The MedinCNO device is capable of delivering such non-invasive HFOV and can be seen in this short video.           One could use the strategy either prophylactically to extubate an infant or as rescue to prevent reintubation if trials of either CPAP or NIPPV were unsuccessful.  HFOV is known to be very effective at clearing CO2 when used through an ETT so perhaps nasal application could also lower pCO2 and achieve a similar effect.  This was tested using a neonatal lung simulator by Mukeji A et al Nasal high-frequency oscillation for lung carbon dioxide clearance in the newborn.  In this study CO2 was introduced into the manequin and the amount of exhaled CO2 determined while on CPAP, NIPPV and nasal HFOV.  Interestingly during CPAP no exhaled CO2 could be detected while CO2 clearance occurred during NIPPV and nasal HFOV although it was three-fold greater with HFOV.  In theory then CO2 clearance would appear to be better so in the case of ventilatory failure as evidenced by CO2 retention this modality would seem to win out. Clinical Evidence for Use There is one RCT in term infants with TTN to support the practice while the rest are unblinded case series with no controls. Four Canadian NICUs recently described their experience however using a retrospective analysis.  Included were 79 instances of HFOV distributed as follows; 73% utilized as rescue from another mode and in 27% used as the primary mode for extubation.  The outcomes are shown in the table: In 45% of cases the patients needed  intubation after first trialing CPAP or NIPPV while in 33% of cases following extubation the infants needed replacement of the endotracheal tube.  The numbers here are small so it is difficult to truly compare them to other studies with confidence but reintubation rates of 40-44% have been noted recently when using NIPPV or CPAP so the numbers are at least consistent. One aspect though that caught my eye was the duration of use for HFOV across these 79 patients.  The median use was 57 hours with the longest duration being just over 400 hours.  It would seem that the use of this modality for the most part is as a bridge to something else.  The median duration of 2.5 days is much shorter than the weeks that some of our smallest infants remain on CPAP/NIPPV for.  Whether for rescue or prophylaxis this is not a long term option. Another point worth noting though is the question of whether it is the pressure or oscillatory wave that is leading to success.  As the authors note, there were a wide range in applications of MAP, delta P and frequency. MAP ranges from 8 - 24 cm H2O while frequency from 6 - 14 hz and amplitude varied widely depending on the device used but was as high as 100%.  While high MAP has been used invasively though an ETT I can't help but wonder if in some cases the real benefit was the high MAP.  What would happen for example if the centres had simply raised the CPAP to 10, 12 or even higher? In the end it would seem that in principal it is an effective therapy that may be able to remove CO2 more efficiently than the other modes.  What we don't have are RCTs in the smallest babies comparing HFOV to NIPPV or CPAP with adequate power to detect differences.  I suspect these will come soon enough but what do we do in the meantime?   The main reservation I have has to do with safety.  We truly have little if any data on this without proper trials to ease such worry.  When a patient is in front of us though and is failing CPAP or NIPPV what are we to do?  Should we intubate or trial this modality based on the evidence thus far? I might be tempted to trial HFOV in this circumstance but as with any new therapy we need education for all staff.  Everyone caring for our infants need to understand what they are using and how to respond based on clinical findings.  This is the real issue with safety that I see and until such time that we have widespread education across RRT, nursing and medicine I would suggest we use this with trepidation.  This is not a rejection of the modality in the least but rather a call to come together as a team and see how implement this in such a way that will provide direction to caregivers, provide a consistent approach with respect to length of use, indications and when to change direction entirely.  Time to call a meeting of the minds I think.

AllThingsNeonatal

AllThingsNeonatal

 

How long should we treat preterm infants with caffeine?

Much has been written about methylxanthines over the years with the main questions initially being, “should we use them?”, “how big a dose should we use” and of course “theophylline vs caffeine”. At least in our units and in most others I know of caffeine seems to reign supreme and while there remains some discussion about whether dosing for maintenance of 2.5 -5 mg/kg/d of caffeine base or 5 – 10 mg/kg/d is the right way to go I think most favour the lower dose. We also know from the CAP study that not only does caffeine work to treat apnea of prematurity but it also appears to reduce the risk of BPD, PDA and duration of oxygen therapy to name a few benefits. Although initially promising as providing a benefit by improving neurodevelopmental outcomes in those who received it, by 5 and 11 years these benefits seem to disappear with only mild motor differences being seen. Turning to a new question The new query though is how long to treat? Many units will typically stop caffeine somewhere between 33-35 weeks PMA on the grounds that most babies by then should have outgrown their irregular respiration patterns and have enough pulmonary reserve to withstand a little periodic breathing. Certainly there are those who prove that they truly still need their caffeine and on occasion I have sent some babies home with caffeine when they are fully fed and otherwise able to go home but just can’t seem to stabilize their breathing enough to be off a monitor without caffeine. Then there is also more recent data suggesting that due to intermittent hypoxic episodes in the smallest of infants at term equivalent age, a longer duration of therapy might be advisable for these ELBWs. What really hasn’t been looked at well though is what duration of caffeine might be associated with the best neurodevelopmental outcomes. While I would love to see a prospective study to tackle this question for now we will have to do with one that while retrospective does an admirable job of searching for an answer. The Calgary Neonatal Group May Have The Answer Lodha A et al recently published the paper Does duration of caffeine therapy in preterm infants born ≤1250 g at birth influence neurodevelopmental (ND) outcomes at 3 years of
age? This retrospective study looked at infants under 1250g at birth who were treated within one week of age with caffeine and divided them into three categories based on duration of caffeine therapy. The groups were as follows, early cessation of caffeine ≤ 14 days (ECC), intermediate cessation of caffeine 15–30 days (ICC), and late cessation of
caffeine >30 days (LCC).  In total there were 508 eligible infants with 448 (88%)  seen at 3 years CA at follow-up. ECC (n = 139), ICC (n = 122) and LCC (n = 187).  The primary outcome here was ND at 3 years of age while a host of secondary outcomes were also examined such as RDS, PDA, BPD, ROP as typical morbidities.  It made sense to look at these since provision of caffeine had previously been shown to modify such outcomes. Did they find a benefit? Sadly there did not appear to be any benefit regardless of which group infants fell in with respect to duration of caffeine when it came to ND. When looking at secondary outcomes there were a few key differences found which favoured the ICC group.  These infants had the lowest days of supplemental oxygen, hospital stay ROP and total days of ventilation.  This middle group also had a median GA 1 week older at 27 weeks than the other two groups.  The authors however did a logistic regression and ruled out the improvement based on the advanced GA.  The group with the lowest use of caffeine had higher number of days on supplemental oxygen and higher days of ventilation on average than the middle but not the high caffeine group.  It is tempting to blame the result for the longer caffeine group on these being babies that were just sicker and therefore needed caffeine longer.  On the other hand the babies that were treated with caffeine for less than two weeks appear to have likely needed it longer as they needed longer durations of oxygen and were ventilated longer so perhaps were under treated. What is fair to say though is that the short and long groups having longer median days of ventilation were more likey to have morbidities associated with that being worse ROP and need for O2.  In short they likely had more lung damage.  What is really puzzling to me is that with a median GA of 27-28 weeks some of these kids were off caffeine before 30 weeks PMA and in the middle group for the most part before 32 weeks!  If they were in need of O2 and ventilation for at least two weeks maybe they needed more caffeine or perhaps the babies in these groups were just less sick? What is missing? There is another potential answer to why the middle group did the best.  In the methods section the authors acknowledge that for each infant caffeine was loaded at 10 mg/kg/d.  What we don’t know though is what the cumulative dose was for the different groups.  The range of dosing was from 2.5-5 mg/kg/d for maintenance.  Lets say there was an over representation of babies on 2.5 mg/kg/d in the short and long duration groups compared to the middle group.  Could this actually be the reason behind the difference in outcomes?  If for example the dosing on average was lower in these two groups might it be that with less respiratory drive the babies in those groups needed faster ventilator rates with longer durations of support leading to more lung damage and with it the rest of the morbidities that followed? It would be interesting to see such data to determine if the two groups were indeed dosed on average lower by looking at median doses and total cumulative doses including miniloads along the way.  We know that duration may need to be prolonged in some patients but we also know that dose matters and without knowing this piece of information it is tough to come to a conclusion about how long exactly to treat. What this study does though is beg for a prospective study to determine when one should stop caffeine as that answer eludes us!

AllThingsNeonatal

AllThingsNeonatal

 

Screening for congenital heart disease; will early discharge be its ruin?

In 2017 the Canadian Pediatric Society published the practice point Pulse oximetry screening in newborns to enhance detection of critical congenital heart disease.  In this document we recommended universal screening for CCHDs but stressed the following: “Recognizing that delivery and time of discharge practices vary across Canada, the timing of testing should be individualized for each centre and (ideally) occur after 24 hours postbirth to lower FP results. And because the intent is to screen newborns before they develop symptoms, the goal should be to perform screening before they reach 36 hours of age.” This recommendation was put in place to minimize the number of false positive results and prevent Pediatricians and Cardiologists nationwide from being inundated with requests to rule out CCHD as earlier testing may pick up other causes for low oxygen saturation such as TTN.  The issue remains though that many patients are indeed discharged before 24 hours and in the case of midwife deliveries either in centres or in the home what do we do? A Population Study From the Netherlands May Be of Help Here Researchers in the Netherlands had a golden opportunity to answer this question as a significant proportion of births occur there in the home under the care of a midwife. Accuracy of Pulse Oximetry Screening for Critical Congenital Heart Defects after Home Birth and Early Postnatal Discharge by Ilona C. Narayen et al was published this month in J Peds. About 30% of births are cared for by a midwife with about 20% occurring in the home. The authors chose to study this population of infants who were all above 35 weeks gestation and not admitted to an intensive care nor had suspicion of CCHD prior to delivery. The timing of the screening was altered from the typical 24-48 hours to be two time points to be more reflective of midwives practice. All patients were recruited after birth with the use of information pamphlets. The prospective protocol was screening on 2 separate moments: on day 1, at least 1 hour after birth, and on day 2 or 3 of life. The criteria for passing or failing the test are the same as those outlined in the CPS practice point. As part of the study, patients with known CCHDs were also screened separately as a different group to determine the accuracy of the screening test in patients with known CCHD. Results There were nearly 24000 patients born during this period. Only 49 cases of CCHD were identified by screening and of these 36 had been picked up antenatally giving a detection rate of 73%. Out of 10 patients without prenatal diagnosis who also had saturation results available the detection rate was 50%. Three of the misses were coarctation of the aorta (most likely diagnosis to be missed in other studies), pulmonary stenosis (this one surprises me) and TGA (really surprises me). The false-positive rate of pulse oximetry screening (no CCHD) was 0.92%. The specificity was over 99% meaning that if you didn’t have CCHD you were very likely to have a negative test. Not surprisingly, most false- positives occurred on day 1 (190 on day 1 vs 31 infants on day 2 or 3). There were five patients missed who were not detected either by antenatal ultrasound. These 5 negatives ultimately presented with symptoms at later time points and all but one survived (TGA) so out of 24000 births the system for detecting CCHD did reasonably well in enhancing detection as they picked up another 5 babies that had been missed antenatally narrowing the undetected from 10 down to 5. Perhaps the most interesting thing about the study though is what they also found. As the authors state: “Importantly, 61% (134/221) of the infants with false-positive screenings proved to have significant noncardiac illnesses re- quiring intervention and medical follow-up, including infection/ sepsis (n = 31) and PPHN or transient tachypnea of the newborn (n = 88)” There are certainly detractors of this screening approach but remember these infants were all thought to be asymptomatic. By implementing the screening program there was opportunity to potentially address infants care needs before they went on to develop more significant illness. Under appreciated TTN could lead to hypoxia and worsen and PPHN could become significantly worse as well. I think it is time to think of screening in this way as being more general and not just about finding CCHD. It is a means to identify children with CCHD OR RESPIRATORY illnesses earlier in their course and do something about it!

AllThingsNeonatal

AllThingsNeonatal

 

Apgar score of 0 at 10 minutes: Why the new NRP recommendations missed the mark.

Originally posted at: https://winnipegneonatal.wordpress.com/ Facebook Page: https://www.facebook.com/allthingsneonatal/ As I read through the new NRP recommendations and began posting interesting points on my Facebook Page I came across a section which has left me a little uneasy. With respect to a newborn 36 weeks and above who is born asystolic and by ten minutes of age continues to remain so and has an apgar score of zero the recommendation that has been put forward is this: An Apgar score of 0 at 10 minutes is a strong predictor of mortality and morbidity in late-preterm and term infants.  We suggest that, in babies with an Apgar score of 0 after 10 minutes of resuscitation, if the heart rate remains undetectable, it may be reasonable to stop resuscitation; however, the decision to continue or discontinue resuscitative efforts should be individualized. Variables to be considered may include whether the resuscitation was considered to be optimal, availability of advanced neonatal care, such as therapeutic hypothermia, specific circumstances before delivery (eg, known timing of the insult), and wishes expressed by the family (weak recommendation, very-low-quality evidence). There are some significant problems with this part of the statement. They claim that the apgar score at ten minutes is a strong predictor but when you look at the analysis of the evidence presented in the body of the paper it is weak at best.  I am not clear how one declares the prediction is strong in the face of poor evidence but I will acknowledge intuitively that this makes some sense but do challenge them on the use of the word "strong". 2.  They are correct in acknowledging that the introduction of hypothermia in such settings has changed the landscape in as much as I find it quite difficult to prognosticate unless a child is truly moribund after resuscitation.  Given such uncertainty it is concerning to me that this recommendation may be committed to memory incorrectly in some places that do have access to cooling and may be used more rigidly as though shalt stop at 10 minutes. 3.  In the middle of a resuscitation it is quite difficult to process all of the facts pertaining to a particular newborn while orders for chest compressions, emergency UVCs and epinephrine are being given.  Can we really individualize within ten minutes accurately and take the families wishes truly into account?  This just does not seem practical. 4.  The families wishes are taken into account but inserted as a "weak recommendation".  How can the wishes of the family in any family centred model of care be minimized in such a way even if we believe the situation to be dire? 5.  Since the introduction of hypothermia there appears to be a near 50% survival rate in such newborns and as the authors state 27% of survivors who received cooling had no moderate or severe disability.  Here in lies my greatest issue with this guideline and that is the hypocrisy this position takes when you compare populations at 23 and 24 weeks gestational age.  Survival at these GA in the recent NEJM study of almost 5000 preterm infants under 27 weeks were 33 and 57 % respectively at 23 & 24 weeks with rates of survival without moderate or severe disability being 16 and 31% in the two groups.  The fallout from this and other studies at the extremes of gestational age have been that we should be more aggressive as the outcomes are not as bad as one would predict.  How can we argue this for the 23-24 week infants and for term infant with the same likelihood of outcomes we would unilaterally stop in many centres?! So Now What Do We Do? We are supposed to be practising family centred care and much like the argument at the edge of viability the same should apply here.  The wishes of the family should never be minimized.  Arguably it may be very difficult in such an unexpected scenario to appraise a family of the situation and have clarity around the issue but if a heart rate can be restored after a few more minutes do we not owe it to the family and the child to bring the infant back to the NICU and see what transpires especially if cooling is available? The million dollar question of course is where do we draw the line?  No heart rate at 15, 20 minutes?  Based on the evidence thus far it seems to me that a little longer than 10 minutes is reasonable especially in well equipped centres with access to cooling and modern ventilation and treatments for pulmonary hypertension.  How long though must be individualized and should be determined in partnership with the team caring for the patient which must include the family.

AllThingsNeonatal

AllThingsNeonatal

 

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!

AllThingsNeonatal

AllThingsNeonatal

 

Has the Magic Bullet to Prevent Kernicterus Been (Re)Discovered?

As the saying goes "What is old is new again" and that may be applicable here when talking about prevention of kernicterus.  In the 1990s there was a great interest in a class of drugs called mesoporphyrins in the management of hyperbilirubinemia.  The focus of treatment for many years had been elimination of bilirubin through the use of phototherapy but this shifted with the recognition that one could work on the other side of the equation.  That is to prevent the production of bilirubin in the first place. Tin mesoporphyrins (SnMP) have the characteristic of being able to inhibit the enzyme hemo oxygenase quite effectively.  By achieving such blockade the breakdown of heme to carbon monoxide and biliverdin (the precursor of bilirubin) is inhibited.  In so doing, the production of bilirubin is reduced making one less dependent on phototherapy to rid the body of elevated levels.  So simple and as you might imagine a good reason for there to have been significant interest in the product.  One article by Martinez et al entitled Control of severe hyperbilirubinemia in full-term newborns with the inhibitor of bilirubin production Sn-mesoporphyrin. was published in 1999 and demonstrated that infants with severe hyperbilirubinemia between 48-96 hours could have their need for phototherapy eliminated by use of the product compared to 27% of the infants in the control group needing treatment.  Additionally, total bilirubin samples were reduced from a median of 5 to 3 with the use of one IM injection of SnMP.  This small study was hampered though by inability to really look at adverse outcomes despite its effectiveness.  What has been seen however is that SnMP if given to infants who are then treated with white lights can create a rash which is not seen however when special blue light is employed. Two other studies followed exploring the use of SnMP in cases of severe hyperbilirubinemia in term infants and were the subject of a Cochrane review in 2003.  The conclusions of the review essentially became the death nell for the therapy as they were as follows. "...may reduce neonatal bilirubin levels and decrease the need for phototherapy and hospitalization. There is no evidence to support or refute the possibility that treatment with a metalloporphyrin decreases the risk of neonatal kernicterus or of long-term neurodevelopmental impairment due to bilirubin encephalopathy... Routine treatment of neonatal unconjugated hyperbilirubinemia with a metalloporphyrin cannot be recommended at present." The literature after this basically dries up, that is until this month when a paper emerges that is best described as a story of mystery and intrigue! Prophylactic Use of SnMP From 2003 Published in 2016! This paper as you read it almost seems like a conspiracy story.  The paper is by Bhutani et al (as in the nomogram) Clinical trial of tin mesoporphyrin to prevent neonatal hyperbilirubinemia.  The study set out to answer a different question than had been previously studied.  The question here was, if you provided a single IM dose of SnMP to infants who were at or above the 75%ile on the risk nomogram, could you prevent the need for phototherapy or exchange transfusion as the primary outcome.  Secondarily, the authors truly wanted to demonstrate safety of the product and planned on recruiting 800 patients per arm in the study.  The study appeared to be well planned and as with many studies had a safety monitoring committee which was to do interim analyses.  After the first analysis the FDA became involved and recommended studies to look at a prophylactic versus therapeutic approach.  Due to the interim analysis the study had been halted and after the FDA made their suggestion the study was simply never restarted as future studies were planned to look at the effectiveness and safety of the two approaches.  The authors state that they planned on reporting their results in 2006/7 but elected to wait until long term data emerged.  Now finally 9 years later they decided to release the results of the partially completed study.  The story around this study I find as interesting as the results they obtained! So What Happened? Before closing the study they managed to recruit 87 into the intervention arm and 89 into the placebo group and lost none to follow-up.  One dose of SnMP had a significant effect on the trajectory of curves for bilirubin production as can be seen in the first figure.   The graph below demonstrates what percentage of patients had a bilirubin level above 220 umol/L (12.9 mg/dl) after the single injection of SnMP (black bars) compared to placebo (white bars). What can we do with these results? It would be tough to argue anything other than this being an effective treatment to prevent significant hyperbilirubinemia.  Unfortunately, like many studies that were never completed this one remains underpowered to conclusively demonstrate that the use of SnMP is safe in both the short and long term periods.  The absence of such data make it very difficult to recommend SnMP as standard of care.  One has to add to this that while we have evidence to show it reduces the rate of rise of bilirubin, what we don't know is whether in a larger study the incidence of bilirubins > 425 umol/L or the need for exchange transfusion might be reduced.  If this were the case, it would make for a compelling argument to try SnMP. That is the approach for standard of care though.  In the setting of a patient with a known blood group incompatibility who was at high risk for exchange transfusion, if they received IVIG and the bilirubin continued to climb might there be a role here?  I would tend to say yes if we could get our hands on some.  The authors by sharing this data have shown the medication is effective in doing what it is supposed to do.  Given that at least in our centre all of our lights are of the new variety, the risk of rash would be nonexistent.  The risk for kernicterus or at least an exchange transfusion though would not be minimal so if we have this in our toolbox I would after weighing the risks opt to give it. I certainly wonder if there are places out there who have used it and if so what is your experience?

AllThingsNeonatal

AllThingsNeonatal

 

A New Years Wish. Are We Up to It?

I have been at this writing thing for almost a year and as I was approaching the end of 2015 my thoughts turned to asking myself what I have learned.  There have been so many posts, in fact so many between the blog and Facebook posts that I have truly lost count.  Having said that the posts have generally fallen into two dominant categories; those promoting a therapy or diagnostic tool and those suggesting that we should avoid certain practices. If I had to have one wish though it would be that we could improve upon our diagnostic accuracy when it comes to treating suspected infections in the newborn.  As health care providers we have an extremely loud inner voice trying to tell us to minimize risk when it comes to missing a true bacterial infection.  On the other hand so much evidence has come forth in the last few years demonstrating that prolonging antibiotics beyond 48 hours is not just unwise in the absence of true infection but can be dangerous.  Increased rates of necrotizing enterocolitis is just one such example but other concerns due to interfering with the newborn microbiome have arisen in more recent years.  What follows are some general thoughts on septic workups that may help you (and myself in my own practice) as we move ahead into the New Year and may we cause less harm if we consider these. The Role of Paired Blood Cultures Although not published by our centre yet, we adopted this strategy for late onset sepsis a couple years back and have seen a significant reduction in work-ups deemed as true infections since adoption.  While the temptation to do only one blood culture is strong as we have a desire to minimize skin breaks consider how many more there will be if you do one culture and get a CONS organism back.  There will be several IV starts, perhaps a central line, repeat cultures etc.  If you had done two at the start and one was positive and the other negative you could avoid the whole mess as it was a contaminant from the start.  On my list of do no harms I think this may have the greatest benefit. The Chest X-Ray Can Be Your Friend While I am not a fan of routine chest x-rays I do believe that if you are prepared to diagnose an opacification on a chest x-ray as being due to a pneumonia (VAP or in those non-ventilated) that you need to follow this up with a repeat x-ray 24 - 48 hours later.  If the opacity is gone it was atelectasis as a true pneumonia will not clear that easily. Well worth the radiation exposure I say. If You Are Going To Do a Work-up Make It A Complete One We hear often in rounds the morning after a septic work-up that the baby was too sick to have an LP and that we can just check the CSF if the blood is positive.  There are two significant problems to this approach.  The first which is a significant concern is that in a recent study of patients with GBS meningitis, 20% of those who had GBS in the CSF had a negative blood culture.  Think about that one clearly... relying on a positive culture to decide to continue antibiotics may lead to partially treated GBS meningitis when you discontinue the antibiotics prematurely.  Not a good thing.  The second issue is that infants with true meningitis can have relatively low CSF WBC counts and may drift lower with treatment. Garges et al in a review of 95 neonates with true meninigits found that CSF WBC counts >21 cells per mm3 had a sensitivity of 79% and specificity at 81%.   This means that in those with true meningitis 19% of the time the WBC counts would be below 21 leading to the false impression that the CSF was "fine".  If antibiotics were effective it could well be by 48 hours that the negative CSF culture you find would incorrectly lead you to stop antibiotics.  Message:  Do the CSF sampling at the time of the septic work-up whenever possible. If We Aren't Prepared To Do a Supra Pubic Aspirate Should We Not Collect Urine At All? This provocative question was asked by a colleague last week and is based on the results of a study which was the topic of the following post: Bladder Catherterizations for UTI: Causing more harm than good?  The gist of it is that it would appear that in many cases the results of a catheter obtained urine cannot be trusted.  If that is the case then are we ultimately treating infections that don't actually exist when the only positive culture is from a urine.  I believe using point of care ultrasound to obtain specimens from a SPA will be the way to go but in the meantime how do we address the question of whether a UTI is present or not?  May need to rely on markers of inflammation such as a CRP or procalcitonin but that is not 100% sensitive or specific either but may be the best we have at the moment to determine how to interpret such situations. Lastly, Slow Down And Practice Good Hand Hygiene So much of what I said above is important when determining if an infection is present or not. The importance of preventing infection cannot be understated. Audits of hand hygiene practice more often than not demonstrate that physicians are a group with some of the lowest rates of compliance. Why is that? As a physician I think it has nothing to do with ignorance about how to properly perform the procedure but rather a tendency to rush from patient to patient in order to get all the things done that one needs to do well on service or call. If we all just slow down a little we may eventually have less need to run from patient to patient as the rate of infections may drop and with it demand for our time.  If slowing down is something that you too think is a good idea you may want to have a look at the book In Praise of Slowness by Carl Honore (TED Talk by Carl Below)  which may offer some guidance how to do something that is more easily said than done. Here is hoping for a little slower pace in the new year. We could reap some fairly large benefits! https://www.ted.com/talks/carl_honore_praises_slowness?language=en    

AllThingsNeonatal

AllThingsNeonatal

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