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    • By AllThingsNeonatal in All Things Neonatal
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      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.
       
    • By AllThingsNeonatal in All Things Neonatal
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      Hypoglycemia has to be one of the most common conditions that we treat in the newborn admitted to NICU. For many infants the transitional phase of hypoglycemia can be longer than a couple low blood sugars and as nurses commonly express, it doesn’t take long before the heels of these infants begin to resemble hamburger.  For those of you who have used diazoxide in the treatment of hypoglycemia you know that it works and it works quickly to raise the blood sugar.  It works by blocking the production of insulin from the pancreas, so particularly in the setting of an infant with detectable insulin levels while hypoglycemic (should be undetectable with a low blood sugar) it can be quite effective. In my own practice I have found that often within one or two doses of the medication with treatment being 5-15 mg/kg/d it can seem to work miracles.  Years ago I heard rumours of a trial from birth of this medication in infants of diabetic mothers but saw nothing come to fruition.  As someone though who really strives to critically look at every needle poke and strongly consider the need I have always leaned towards the use of this medication if only to reduce what I suspected would be a large number of heel lances.
      A Study Comes Forward
      Balachandran B et al published a paper on this topic this week in Acta Paediatrica entitled Randomised controlled trial of diazoxide for small for gestational age neonates with hyperinsulinaemic hypoglycaemia provided early hypoglycaemic control without adverse effects. To be clear this is a very small study with only 30 patients in total (15 in the diazoxide and 15 in the placebo arms) and as they had nothing to go on for determining a sample size needed there was no power calculation.  The authors chose to look at a very specific group of neonates that were SGA and had hypoinsulinemic hypoglycemia so we need to resist extrapolating to other patient groups such as IDMs in case there is a positive effect here.
      With those warnings though, what they did was devise a stepwise approach to initiating diazoxide at 8 mg/kg/d and escalating the dose to as much as 12 mg/kg/d followed by a standardized wean following blood glucose stability.  The primary outcome in this case was the number of hours required to achieve a stable glucose with a glucose infusion rate of =< 4mg/kg/min.   They examined a number of secondary outcomes as well including duration of IV fluids, episodes of sepsis and time to achieve full feeds as well as mortality.  Given the small sample size though I would resist drawing too many conclusions about these secondary outcomes but they are reported nonetheless. From the paper the Kaplan Meier curve indicates a faster time to stability of blood sugars for 6 hours favouring the diazoxide group.  Importantly there were no differences in  baseline insulin or cortisol levels between the groups which might explain differing times to glycemic control.  Intravenous reductions with feeding increments were also standardized for the study to ensure comparable treatment strategies aside from the provided diazoxide or placebo.
      Claim of Safety
      The authors note there were no differences in mortality or number of sepsis episodes between the groups.  They did find a statistically significant reduction in duration of IV fluid requirements which is likely believable despite my earlier warning as the length of time to achieve control was significantly reduced.  The fact remains though with such few patients I would take claims of safety with a grain of salt.  You might think at this point though that I would be a champion for the therapy but despite my earlier enthusiasm I do have some reservations.  The median time to achieve glycemic control was 40 vs 72.5 hours with a p value of 0.015 which is certainly significant but really we are talking about nearly 2 vs 3 days of management.  Is diazoxide truly safe enough to warrant the 30 hour reduction in time to glycemic control?  Assuming q3h point of care glucose checks this would be about 8-10 less pokes as a best case scenario but more likely 4-6 less as near the end of checking glucoses as the patient becomes more stable the number of pokes usually decreases.  Is diazoxide worth it though?

      Back in 2015 the FDA issued a warning that diazoxide can lead to pulmonary hypertension.  In truth we have seen it in babies where I practice and as such now routinely have an ECHO done before starting the drug to determine if there is any pulmonary hypertension prior to starting the drug and if there is even a hint it is contraindicated.  It isn’t too common a complication as in the FDA bulletin (read here) there have been only 11 cases reported since 1973 but it is a risk nonetheless.
      Thirty patients sadly isn’t enough to rule out this complication and it is worth nothing that the authors did not look for this outcome so we don’t know if any patients suffered this.
      Am I saying that one should never use diazoxide?  Absolutely not but I am suggesting that if you use it then use it with great caution.  Although I am delighted the authors chose to perform this study taking all risks into account and looking at the benefit in terms of time on IV and that needed to gain control of blood sugars I can’t say this should be standard of care.
       
         
    • By Stefan Johansson in Reflections incubated in the 99nicu HQ
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      As you know, our conference the Future of Neonatal care in Vienna is approaching!
      When we went through the registrations yesterday, it struck us that delegates will come from all corners of the world. There are already delegates coming from 21 countries!
      Just to visualize, we marked the countries on the map below.
      It will be great to meet up with all of you coming! And, although we will represent many different context, I also believe it is a very good example of how a great diversity of people are sharing common questions and problems. My personal reflection is that not only infants are similar around the globe, neonatal staff also share a passion of doing great things for the tiny ones.
      And yes, we still have vacant chairs in the lecture hall. Be mostly welcome to register for the meeting, regardless if you already have colleagues from your country attending
       

    • By AllThingsNeonatal in All Things Neonatal
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      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!
         
    • By Stefan Johansson in Reflections incubated in the 99nicu HQ
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      The Society for Evidence-Based Neonatology (EBNEO) had its 4th International Conference in Hyderabad, India, last November. Although being baised, as the chairman of EBNEO, the conference was a huge success, thanks to that the EBNEO was held in association with Indian Association of Pediatrics Neonatology Chapter. Without the IAP/NEOCON committee led by Dr Srinivas Murki, we would not have managed to set this conference up, that counted many hundreds of national delegates from all regions of India.
      A set of lectures by Barbara Schmidt, Ashok Deorari, Sourabh Dutta, Courtney Wusthoff, Roger Soll and many others, are now available on Youtube. 
      You can also view my lecture on Fetal Programming
      Enjoy!
       
  • Upcoming Events

    • 09 March 2018 Until 10 March 2018
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      https://www.mcascientificevents.eu/intensive-care-newborn2018/
      MAIN TOPICS
      Resuscitation
      Oxygen And Ventilation
      Infections
      High-Tech Monitoring
      Nursing Ventilation
    • 22 March 2018
      0  
      The 2018 Stockholm Conference on Ultra-Early Intervention
      Pleasurable feeding for premature infants: 
      - Food for thought!
      Thursday 22 March in Nanna Svartz Aula, ”Old” Karolinska University Hospital in Solna
      The 9th Stockholm Conference on Ultra-Early Intervention will 2018 continue the theme on how to achieve the optimal long-term outcomes by an active involvement of families in the care of the newborn infant. . There will be a section for short presentations.
      The conference with handouts will be available free on the Internet two weeks after the meeting as in previous years. We usually have 2-3,000 visitors from all over the world. Please view 2017 Ultra-Early: http://ultra-early-intervention.creo.tv/2017/ultra-early-convention
      Registration and submission of abstracts by mail to nidcap.karolinska@sll.se
      Deadline is 28 February 2018
      Conference fee is 3000 SEK, including coffee, lunch and conference dinner [corresponding fee for accepted speakers for the short presentations is SEK 1100]. Conference language is English.
       
      Welcome,
      Stina Klemming, Björn Westrup, Ann-Sofi Ingman, Veronica Berggren and Lena Westas
      Organizing committee 
    • 09 April 2018 Until 12 April 2018
      2  
      Welcome to the “Future of Neonatal Care – advancing the management of newborns”,
      in Vienna, 9-12 April 2018!
      This is our own 99nicu Meetup!
      Click here for more info!
    • 23 April 2018 Until 26 April 2018
      0  
      Barnveckan 2018 i Västerås
      Neonatologiprogram med bl.a. inledningstalare samt föreläsare Professor Lex Doyle, Australien samt Edward Shepherd, MD, USA om Ohio-modellen/BPD
       
      se det preliminära programmet på www.barnveckan.se 
      och följ på instagram: barnveckan2018

    • 17 May 2018 Until 18 May 2018
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      2ND NEONATAL NEUROLOGY CONFERENCE
      Neonatal neurology is ever evolving and new knowledge is always emerging. Assessment techniques have become more advanced.  Newer imaging modalities are increasingly used to help map the extent of brain injury and its implications for neurodevelopment.  This meeting lines up exciting talks from experts in the field.
      More info on: https://www.lutonneocon.co.uk/fom-neurology
    • 23 May 2018 Until 26 May 2018
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      https://www.mcascientificevents.eu/iccn2018/
      MAIN TOPICS
      Hypothermia in preterms: what’s new?
      Teamworking in the NICU
      EPO and neuroprotection: an update
      NIDCAP and family-centered care
      Delivery of fetal CHD patients
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