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  • Blog Entries

    • By AllThingsNeonatal in All Things Neonatal
      Caffeine seems to be good for preterm infants.  We know that it reduces the frequency of apnea in the this population and moreover facilitates weaning off the ventilator in a shorter time frame than if one never received it at all.  The earlier you give it also seems to make a difference as shown in the Cochrane review on prophylactic caffeine. When given in such a fashion the chances of successful extubation increase. Less time on the ventilator not surprisingly leads to less chronic lung disease which is also a good thing.
      I have written about caffeine more than once though so why is this post different?  The question now seems to be how much caffeine is enough to get the best outcomes for our infants.  Last month I wrote about the fact that as the half life of caffeine in the growing preterm infant shortens, our strategy in the NICU might be to change the dosing of caffeine as the patient ages.  Some time ago though I wrote about the use of higher doses of caffeine and in the study analyzed warned that there had been a finding of increased cerebellar hemorrhage in the group randomized to receive the higher dosing.  I don’t know about where you work but we are starting to see a trend towards using higher caffeine base dosing above 5 mg/kg/d.  Essentially, we are at times “titrating to effect” with dosing being as high as 8-10 mg/kg/d of caffeine base.
      Does it work to improve meaningful outcomes?
      This month Vliegenthart R et al published a systematic review of all RCTs that compared a high vs low dosing strategy for caffeine in infants under 32 weeks at birth; High versus standard dose caffeine for apnoea: a systematic review. All told there were 6 studies that met the criteria for inclusion.  Low dosing (all in caffeine base) was considered to be 5- 15 mg/kg with a maintenance dose of 2.5 mg/kg to 5 mg/kg.  High dosing was a load of 5 mg/kg to 40 mg/kg with a maintenance of 2.5 mg/kg to 15 mg/kg.  The variability in the dosing (some of which I would not consider high at all) makes the quality of the included studies questionable so a word of warning that the results may not truly be “high” vs “low” but rather “inconsistently high” vs. “inconsistently low”.
      The results though may show some interesting findings that I think provide some reassurance that higher dosing can allow us to sleep at night.

      On the positive front, while there was no benefit to BPD and mortality at 36 weeks PMA they did find if they looked only at those babies who were treated with caffeine greater than 14 days there was a statistically significant difference in both reduction of BPD and decreased risk of BPD and mortality.  This makes quite a bit of sense if you think about it for a moment.  If we know that caffeine improves the chances of successful extubation and we also know it reduces apnea, then who might be on caffeine for less than 2 weeks?  The most stable of babies I would expect!  These babies were all < 32 weeks at birth.  What the review suggests is that those babies who needed caffeine for longer durations benefit the most from the higher dose.  I think I can buy that.
      On the adverse event side, I suppose it shouldn’t surprise many that the risk of tachycardia was statistically increased with an RR of 3.4.  Anyone who has explored higher dosing would certainly buy that as a side effect that we probably didn’t need an RCT to prove to us.  Never mind that, have you ever taken your own pulse after a couple strong coffees in the morning?
      What did it not show?
      It’s what the study didn’t show that is almost equally interesting.  The cerebellar hemorrhages seen in the study I previously wrote about were not seen at all in the other studies.  There could be a lesson in there about taking too much stock in secondary outcomes in small studies…
      Also of note, looking at longer term outcome measures there appears to be no evidence of harm when the patients are all pooled together.  The total number of patients in all of these studies was 620 which for a neonatal systematic review is not bad.  A larger RCT may be needed to conclusively tell us what to do with a high and low dosing strategy that we can all agree on.  What do we do though in the here and now?  More specifically, if you are on call tomorrow and a baby is on 5 mg/kg/d of caffeine already, will you intubate them if they are having copious apneic events or give them a higher dose of caffeine when CPAP or NIPPV that they are already on isn’t cutting it?  That is where the truth about how you feel about the evidence really comes out.  These decisions are never easy but unfortunately you sometimes have to make a decision and the perfect study hasn’t been done yet.  I am not sure where you sit on this but I think this study while certainly flawed gives me some comfort that nothing is truly standing out especially given the fact that some of the “high dose” studies were truly high.  Will see what happens with my next patient!
    • By AllThingsNeonatal in All Things Neonatal
      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
      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.
      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.
    • By Stefan Johansson in Reflections incubated in the 99nicu HQ
      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

      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
      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.
  • Upcoming Events

    • 22 March 2018
      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.
      Stina Klemming, Björn Westrup, Ann-Sofi Ingman, Veronica Berggren and Lena Westas
      Organizing committee 
    • 09 April 2018 Until 12 April 2018
      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
      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
      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

      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
    • 02 June 2018 Until 03 June 2018
      the United States Institute of Kangaroo Care (USIKC) arranges the 14th Annual International Kangaroo Care Certification Course,
      June 2-3 2018, at the Fairview Hospital, 18101 Lorain Avenue, Cleveland OH.
      More info is available at http://www.kangaroocareusa.org/ and in the attached PDF.