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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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Does size really matter when weaning from an incubator?

Look around an NICU and you will see many infants living in incubators. All will eventually graduate to a bassinet or crib but the question always is when should that happen? The decision is usually left to nursing but I find myself often asking if a baby can be taken out. My motivation is fairly simple. Parents can more easily see and interact with their baby when they are out of the incubator. Removing the sense of “don’t touch” that exists for babies in the incubators might have the psychological benefit of encouraging more breastfeeding and kangaroo care. Both good things. Making the leap For ELBW and VLBW infants humidity is required then of course they need this climate controlled environment. Typically once this is no longer needed units will generally try infants out of the incubator when the temperature in the “house” is reduced to 28 degrees. Still though, it is not uncommon to hear that an infant is “too small”. Where is the threshold though that defines being too small? Past research studies have looked at two points of 1600 vs 1800g for the smallest of infants. One of these studies was a Cochrane review by New K, Flenady V, Davies MW. Transfer of preterm infants for incubator to open cot at lower versus higher body weight. Cochrane Database Syst Rev 2011;(9). This concluded that early transition was safe for former ELBWs at the 1600g weight cut off. What about the majority of our babies? While the ELBW group takes up a considerable amount of energy and resources the later preterm infants from 29 to 33 6/7 weeks are a much larger group of babies. How safe is this transition for this group at these weights? Shankaran et al from the NICHD published an RCT on this topic recently; Weaning of Moderately Preterm Infants from the Incubator to the Crib: A Randomized Clinical Trial. The study enrolled Infants in this gestational age range with a birth weight <1600g were randomly assigned to a weaning weight of 1600 or 1800 g. Within 60 to 100 g of weaning weight, the incubator temperature was decreased by 1.0°C to 1.5°C every 24 hours until 28.0°C. Weaning to the crib occurred when axillary temperatures were maintained 36.5°C to 37.4°C for 8 to 12 hours. Clothing and bedcoverings were standardized. The primary outcome was LOS from birth to discharge. What did they find? A total of 366 babies were enrolled (187 at 1600g and 179 at 1800g. Baseline characteristics of the two groups revealed no statistical differences. Mean LOPS was a median of 43 days in the lower and 41 days in the higher weight group (P = .12). After transition to a crib weight gain was better in the lower weight group, 13.7 g/kg/day vs 12.8 g/kg/ day (P = .005). Tracking of adverse events such as the incidence of severe hypothermia did not differ between groups. The only real significant difference was a better likelihood of weaning from the incubator in the higher group at 98% success vs 92% on the first attempt. Putting. That in perspective though, a 92% success rate by my standards is high enough to make an attempt worthwhile!   Concluding thoughts The authors have essentially shown that whether you wean at the higher or lower weight threshold your chances of success are pretty much the same. Curiously, weight gain after weaning was improved which seems counter intuitive. I would have thought that these infants would have to work extra hard metabolically to maintain their temperature and have a lower weight gain but that was not the case. Interestingly, this finding has been shown in another study as well; New K, Flint A, Bogossian F, East C, Davies MW. Transferring preterm infants from incubators to open cots at 1600 g: a multicentre randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2012;97:F88-92. Metabolic rate has been shown to increase in these infants but skin fold thickness has been shown to increase as well in infants moved to a crib. How these two things go together is a little beyond me as I would have thought that as metabolic rate increases storage of tissue would slow. Not apparently the case but perhaps just another example of the bodies ability to overcome challenges when put in difficult situations. A case maybe of “what doesn’t kill you makes you stronger?” The authors do point out that the intervention was unmasked but the standardization of weaning procedure and garments used in the cribs should have overcome that. There were 36% of parents who did not consent to the study so their inclusion could have swayed the results perhaps but the sample size here was large despite that. That the final results agree with findings in ELBW infants suggests that the results are plausible. What I think this study does though is tell us overall that weaning at a smaller weight is at least alright to try once one is at minimal settings in an incubator. Will this change your units practice? It is something that at least merits discussion.  
 

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>
 

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!
 

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.
 

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?
 

The days of the Apgar score may be numbered

One of the first things a student of any discipline caring for newborns is how to calculate the apgar score at birth.  Over 60 years ago Virginia Apgar created this score as a means of giving care providers a consistent snapshot of what an infant was like in the first minute then fifth and if needed 10, 15 and so on if resuscitation was ongoing.  For sure it has served a useful purpose as an apgar score of 0 and 0 gives one cause for real worry.  What about a baby with an apgar of 3 and 7 or 4 and 8?  There are certainly infants who have done very well who initially had low apgar scores and conversely those who had higher apgar scores who have had very significant deleterious outcomes including death.  I don’t mean to suggest that the apgar scores don’t provide any useful predictive value as they are used as part of the criteria to determine if a baby merits whole body cooling or not.  The question is though after 60+ years, has another score been created to provide similar information but enhance the predictive value derived from a score? The Neonatal Resuscitation and Adaptation Score (NRAS) Back in 2015 Jurdi et al published  Evaluation of a Comprehensive Delivery Room Neonatal Resuscitation and Adaptation Score (NRAS) Compared to the Apgar Score.  This new score added into a ten point score resuscitative actions taken at the 1 and 5 minute time points to create a more functional score that included interventions.  The other thing this new score addressed was more recent data that indicated a blue baby at birth is normal (which is why we have eliminated asking the question “is the baby pink?” in NRP.  Knowing that, the colour of the baby in the apgar score may not really be that relevant.  Take for example a baby with an apgar score of 3 at one minute who could have a HR over 100 and be limp, blue and with shallow breathing.  Such a baby might get a few positive pressure breaths and then within 10 seconds be breathing quite well and crying.  Conversely, they might be getting ongoing PPV for several minutes and need oxygen.  Were they also getting chest compressions?  If I only told you the apgar score you wouldn’t have much to go on.  Now look at the NRAS and compare the information gathered using two cardiovascular (C1&2), one neurological test (N1) and two respiratory assessments (R1&2).   The authors in this study performed a pilot study on only on 17 patients really as a proof of concept that the score could be taught and implemented.  Providers reported both scores and found “superior interrater reliability (P < .001) and respiratory component reliability (P < .001) for all gestational ages compared to the Apgar score.”   A Bigger Study Was Needed The same group in 2018 this time led by Witcher published Neonatal Resuscitation and Adaptation Score vs Apgar: newborn assessment and predictive ability.  The primary outcome was the ability of a low score to predict mortality with a study design that was a non-inferiority trial.  All attended deliveries were meant to have both scores done but due to limited numbers of trained personnel who could appropriately administer both scores just under 90% of the total deliveries were assigned scores for comparison.  The authors sought to recruit 450 infants to show that a low NRAS score (0–3) would not be inferior to a similar Apgar at predicting death.  Interestingly an interim analysis found the NRAS to be superior to Apgar when 75.5% of the 450 were enrolled, so the study was stopped.  What led the apgar score to perform poorly in predicting mortality (there were only 12 deaths though in the cohort) was the fact that 49 patients with a 1 minute apgar score of 0-3 survived compared to only 7 infants with a low NRAS score. The other interesting finding was the ability of the NRAS to predict the need for respiratory support at 48 hours with a one minute apgar score of 0-3 being found in 39% of those on support compared to 100% of those with a low NRAS.  Also at 5 minutes a score of 4-6 for the apgar was found in 48% of those with respiratory support at 48 hours vs 87% of those with a similar range NRAS.  These findings were statistically significant while a host of other conditions such as sepsis, hypoglycemia, hypothermia and others were no different in terms of predictive ability of the scores. An Even Bigger Study is Needed To be sure, this study is still small and missed just over 90% of all deliveries so it is possible there is some bias that is not being detected here.  I do think there is something here though which a bigger study that has an army of people equipped to provide the scoring will add to this ongoing story.  Every practitioner who resuscitates an infant is asked at some point in those first minutes to hour “will my baby be ok?”.  The truth is that the apgar score has never lived up to the hope that it would help us provide an accurate clairvoyant picture of what lies ahead for an infant.   Where this score gives me hope is that a score which would at the very least help me predict whether an infant would likely still be needing respiratory support in 48 hours provides the basic answer to the most common question we get in the unit once admitted; “when can I take my baby home”.  Using this score I could respond with some greater confidence in saying “I think your infant will be on support for at least 48 hours”.  The bigger question though which thankfully we don’t have to address too often for the sickest babies at birth is “will my baby survive?”.  If a larger study demonstrates this score to provide a greater degree of accuracy then the “Tipping Point” might just be that to switching over to the NRAS and leaving the apgar score behind.  That will never happen overnight but medicine is always evolving and with time you the reader may find yourself becoming very familiar with this score!

AllThingsNeonatal

AllThingsNeonatal

 

This Vitamin Could Save A Babies Life

It has been a few months now that I have been serving as Chair of the Fetus and Newborn Committee for the Canadian Pediatric Society. Certain statements that we release resonate strongly with me and the one just released this week is certainly one of them. Guidelines for vitamin K prophylaxis in newborns is an important statement about a condition that thankfully so few people ever experience.  To read the statement on the CPS website click here. Similar story to vaccinations Prior to the American Academy of Pediatrics in 1961 proclaiming that all newborns should receive IM Vitamin K at birth the incidence of Vitamin K deficient bleeding was 0.25 – 1.7%. Think about that for a moment. A new parent could expect that 1/100 babies roughly might have intestinal bleeding or worse an intracranial hemorrhage due to an insufficient amount of vitamin K levels in the newborn. The types of bleeding could be categorized into three different time epochs. Early onset (occurring in the first 24 hours post-birth), classic (occurring at days 2 to 7) and late onset (at 2 to 12 weeks and up to 6 months of age). With a rate that high detractors of providing Vitamin K at birth would say “why should we give it; I haven’t heard of any baby getting such bleeding?” Looking at it another way though, why don’t you see congenital rubella or kids with measles much these days? It’s due to vaccination. Thankfully as a Neonatologist, I don’t see Vitamin K deficient bleeding since most parents provide Vitamin K to their babies at birth.  If you went back to the era prior to 1961 when widespread supplementation of Vitamin K began in the US, I imagine it would not have been too uncommon to hear about a baby who had bleeding issues after birth.  Just because we don’t hear about German Measles much anymore doesn’t mean the virus causing it doesn’t still exist! How Effective is Vitamin K? How effective is Vitamin K administration at birth in preventing hemorrhagic disease of the newborn (HDNB)? Studies estimate an incidence of 0.25 per 100000 live births or 1 in 400000 babies vs the 1/100 risk without any vitamin K. That is one effective intervention! At this point I would ask those families that are still concerned about giving Vitamin K to their infants if this is a risk they can accept? If they refuse Vitamin K and there is a significant bleed how will they react? The Change in this CPS Statement From the Past In the last statement on Vitamin K, the authors suggested that the oral route was a reasonable option. Instead of giving 1 mg of Vitamin K IM one would dose it as 2 mg orally and then repeat at 2-4 weeks and then 6-8 weeks. In looking at the effectiveness though it is worth noting that while we can assure that families will get the first dose, as with any medication that needs repeat dosing there is the risk of forgetfulness leading to missed dosing down the road. In fact when the authors looked at the risk of late HDNB they found the following “The relative risk for VKDB, when comparing PO versus IM vitamin K administration in these two studies, was 28.75 (95% CI 1.64 to 503.45) and 5.97 (95% CI 0.54 to 65.82), respectively [19][20].” The outcome of course remains rare but the risk based on two studies was almost 30 times higher than if IM dosing was given. On this basis IM is recommended. Having said all this I recognize that despite all this information, some families will choose for a number of reasons to still opt for the oral dose. As the statement suggests we need to encourage such use when a family refuses IM vitamin K. The 30 fold risk compared to IM administration is magnitudes lower than the approximate 1/100 risk of giving nothing at all! In the end I believe that one case of intracranial hemorrhage from inadequate vitamin K is too much. This one vitamin indeed could save a life.
 

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.
 

Can video laryngoscopes reduce risk of harm from intubation?

The modern NICU is one that is full of patients on CPAP these days. As I have mentioned before, the opportunity to intubate is therefore becoming more and more rare is non-invasive pressure support becomes the mainstay of therapy. Even for those with established skills in placing an endotracheal tube, the number of times one gets to do this per year is certainly becoming fewer and fewer. Coming to the rescue is the promise of easier intubations by being able to visualize an airway on a screen using a video laryngoscope. The advantage to the user is that anyone who is watching can give you some great tips and armed with this knowledge you may be better able to determine how to adjust your approach. For those of you who have followed the blog for some time, you will recall this is not the first time video laryngoscopy has come up. I have spoken about this before in Can Video Laryngoscopy Improve Trainee Success in Intubation.  In that piece, the case was made that training residents how to intubate using a video laryngoscope (VL) improves their success rate. An additional question that one might ask though has to do with the quality of the intubation.  What if you can place a tube using a video laryngoscope but the patient suffers in some way from having that piece of equipment in the mouth?  Lucky for us some researchers from the Children's Hospital of Philadelphia have completed a study that can help answer this additional question. Video Laryngoscopy may work but does it cause more harm than good? Using a video laryngoscope requires purchasing one first and they aren't necessarily cheap.  If they were to provide a better patient experience though the added cost might well be worth it.  Pouppirt NR et al published Association Between Video Laryngoscopy and Adverse Tracheal Intubation-Associated Events in the Neonatal Care Unit.  This study was a retrospective comparison of two groups; one having an intubation performed with a VL (n=161 or 20% of the group) and the other with a standard laryngoscope (644 or 80% of the group).  The study relied on the use of the National Emergency Airway Registry for Neonates (NEAR4NEOs), which records all intubations from a number of centres using an online database and allows for analysis of many different aspects of intubations in neonates.  In this case the data utilized though was from their centre only to minimize variation in premedication and practitioner experience. Tracheal intubation adverse events (TIAEs) were subdivided into severe (cardiac arrest, esophageal intubation with delayed recognition, emesis with witnessed aspiration, hypotension requiring intervention (fluid and/or vasopressors), laryngospasm, malignant hyperthermia, pneumothorax/pneumomediastinum, or direct airway injury) vs non-severe (mainstem bronchial intubation, esophageal intubation with immediate recognition, emesis without aspiration, hypertension requiring therapy, epistaxis, lip trauma, gum or oral trauma, dysrhythmia, and pain and/or agitation requiring additional medication and causing a delay in intubation. Looking at the patient characteristics and outcomes, some interesting findings emerge. Patients who had the use of the VL were older and weighed more.  They were more likely to have the VL used for airway obstruction than respiratory failure and importantly were also more likely to receive sedation/analgesia and paralysis.  These researchers have also recently shown that the use of paralysis is associated with less TIAEs so one needs to bear this in mind when looking at the rates of TIAEs.  There were a statistically significant difference in TIAEs of any type of 6% in the VL group to 19% in the traditional laryngoscopy arm but severe TIAEs showed not difference. Given that several of the baseline characteristics might play a role in explaining why VL seemed superior in terms of minimizing risk of TIAEs by two thirds, the authors performed a multivariable analysis in which they took all factors that were different into account and then looked to see if there was still an effect of the VL despite these seemingly important differences.  Interestingly, us of VL showed an Odds ratio of 0.43 (0.21,0.87 95% CI) in spite of these differences. What does it mean? Video laryngoscopy appears to make a difference to reducing the risk on TIAEs as an independent factor.  The most common TIAE was esophageal intubation at 10% and reducing that is a good thing as it leads to fewer intubation attempts.  This was also sen as the first attempt success was 63% in the VL group vs 44% in the other. Now we need to acknowledge that this was not a randomized controlled trial so it could indeed be that there are other factors that the authors have not identified that led to improvements in TIAEs as well.  What makes this study so robust though is the rigour with which the centre documents all of their intubations using such a detailed registry.  By using one centre much of the variability in practice between units is eliminated so perhaps these results can be trusted.  Would your centre achieve these same results? Maybe not but it would certainly be interesting to test drive one of these for a period of time see how it performs.
 

Was adding placement of EKG leads to NRP a good idea after all?

It is hard to believe but it has been almost 3 years since I wrote a piece entitled A 200 year old invention that remains king of all tech in newborn resuscitation. In the post I shared a recent story of a situation in which the EKG leads told a different story that what our ears and fingers would want us to believe. The concept of the piece was that in the setting of pulseless electrical activity (where there is electrical conductance in the myocardium but lack of contraction leaves no blood flow to the body) one could pick up a signal from the EKG leads when there is in fact no pulse or perfusion to vital organs. This single experience led me to postulate that this situation may be more common than we think and the application of EKG leads routinely could lead to errors in decision making during resuscitation of the newborn. It is easy to see how that could occur when you think about the racing pulses of our own in such situations and once chest compressions start one might watch the monitor and forget when they see a heart rate of 70 BPM to check for a corresponding pulse or listen with the stethoscope. I could see for example someone stopping chest compressions and continuing to provide BVM ventilation despite no palpable pulse when they see the QRS complex clearly on the monitor. I didn’t really have much evidence to support this concern but perhaps there is a little more to present now. A Crafty Animal Study Provides The Evidence I haven’t presented many animal studies but this one is fairly simple and serves to illustrate the concern in a research model. For those of you who haven’t done animal research, my apologies in advance as you read what happened to this group of piglets. Although it may sound awful, the study has demonstrated that the concern I and others have has is real. For this study 54 newborn piglets (equivalent to 36-38 weeks GA in humans) were anesthetized and had a flow sensor surgically placed around the carotid artery.  ECG leads were placed as well and then after achieving stabilization, hypoxia was induced with an FiO2 of 0.1 and then asphyxia by disconnecting the ventilator and clamping the ETT.  By having a flow probe around the carotid artery the researchers were able to determine the point of no cardiac output and simultaneously monitor for electrical activity via the EKG leads.  Auscultation for heart sounds was performed as well. The results essentially confirm why I have been concerned with an over reliance on EKG leads.   Of the 57 piglets, 14 had asystole and no carotid flow but in 23 there was still a heart rate present on the EKG with no detectable carotid flow. This yields a sensitivity of only 37%.  Moreover, the overall accuracy of the ECG was only 56%. Meanwhile the stethoscope which I have referred to previously as the “king” in these situations had 100% sensitivity so remains deserving of that title. What do we do with such information? I think the results give us reason to pause and remember that faster isn’t always better.  Previous research has shown that signal acquisition with EKG leads is faster than with oximetry.  While a low heart rate detected quickly is helpful to know what the state of the infant is and begin the NRP pathway, we simply can’t rely on the EKG to tell us the whole story.  We work in interdisciplinary teams and need to support one another in resuscitations and provide the team with the necessary information to perform well.  The next time you are in such a situation remember that the EKG is only one part of the story and that auscultation for heart sounds and palpation of the umbilical cord for pulsation are necessary steps to demonstrate conclusively that you don’t just have a rhythm but a perfusing one. I would like to thank the Edmonton group for continuing to put out such important work in the field of resuscitation!
 

Is paralysis for intubation really needed?

A few weeks back I wrote about the topic of intubations and whether premedication is really needed (Still performing awake intubations in newborns? Maybe this will change your mind.) I was clear in my belief that it is and offered reasons why. There is another group of practitioners though that generally agree that premedication is beneficial but have a different question. Many believe that analgesia or sedation is needed but question the need for paralysis. The usual argument is that if the intubation doesn’t go well and the patient can’t spontaneously ventilate could we be worse off if the patient loses their muscle tone. Neonatal Intubation Registry At the CPS meeting last month in Quebec City. I had the pleasure of listening to a talk by Dr. Elizabeth Foglia on the findings from a Neonatal intubation registry that many centres have been contributing to. The National Emergency Airway Registry for Neonates (NEAR4NEOs), records all intubations from a number of centres using an online database and allows for analysis of many different aspects of intubations in neonates. This year, J. Krick et al published Premedication with paralysis improves intubation success and decreases adverse events in very low birth weight infants: a prospective cohort study. This study compared results from the registry of two centres, the University of Washington Medical Center (UWMC) and Seattle Children’s Hospital where the former rarely uses paralysis and the latter in almost all instances of non-emergent intubation. In all, 237 encounters were analyzed in the NICU for babies < 1500g with the majority of encounters (181) being from UWMC. The median PMA at intubation was 28 completed weeks (IQR: 27, 30), chronological age was 9 days (IQR: 2, 26) and weight was 953 g (IQR: 742,1200). The babies were compared based on the following groups. Premedication with a paralytic 21%, without a paralytic 46% and no premedication 31%. This was an observational study that examined the rates of adverse events and subdivided into severe (cardiac arrest, esophageal intubation with delayed recognition, emesis with witnessed aspiration, hypotension requiring intervention (fluid and/or vasopressors), laryngospasm, malignant hyperthermia, pneumothorax/pneumomediastinum, or direct airway injury) vs non-severe (mainstem bronchial intuba- tion, esophageal intubation with immediate recognition, emesis without aspiration, hypertension requiring therapy, epistaxis, lip trauma, gum or oral trauma, dysrhythmia, and pain and/or agitation requiring additional medication and causing a delay in intubation.). How did the groups compare? It turns out paralysis seems to be a big deal (at least in this group of infants). Use of paralysis resulted in less attempts to intubate (median 1 attempt; IQR: 1, 2.25 vs. 2; IQR: 1, 3, p < 0.05)). In fact success was no different between the groups with no paralysis or no premedication at all! When it comes to  tracheal intubation adverse events the impact of using paralysis becomes more evident.   Paralysis does make a difference in reducing the incidence of such events and moreover when only looking at the rate of severe adverse events as defined above the finding was that none occurred when paralysis was used vs 9 when no paralysis was employed and 5 when no premedication was used at all.  The rate of bradycardic events was less in the paralytic group but rates of oxygen desaturation between the three arms were no different. How do we interpret the results? Based on the results from the registry it looks like paralysis is a good thing here when electively intubating infants.   If we try to determine the reason for it I suspect it may have much to do with the higher likelihood of success on the first attempt at placing an ETT. The longer it takes to place the ETT or the more number of attempts requiring intermittent PPV in a patient who truly needs a tube the greater the likelihood that you will see adverse events including bradycardia.  It may simply be that a calm and still patient is an easier intubation and getting the tube in faster yields a more stable patient. I am biased though and I think it is worth pointing out another possible reason for the differing results.  One hospital in this study routinely used premedication and the other did not.  Almost 3/4 of the patients came from one hospital which raises the possibility that skill set could be playing a role.  If the skill of providers at the two hospitals differed, the results could reflect the variable skill in the practitioners versus the difference in the medications used themselves.  What I don’t know though is whether the two share the same training program or not.  Are the trainees the same at both sites (google maps says the two sites are 11 minutes away by car)?  The difference still might be in local respiratory therapists or Neonatologists intubating as well.  Regardless, the study provides evidence that paralysis makes a difference.  To convince those out there though who remain skeptical I think we are going to need the registry to take part in a prospective trial using many centres.  A format in which several centres that don’t use paralysis are compared to several who do routinely would help to sort out the concern in skill when looking only at two centres.  This wouldn’t be randomized of course but I think it would be very difficult at this point to get a centre that strongly believes in using paralysis to randomize so a prospective study using groups chosen by the individual centre might be the next best thing.  If anyone using the registry is reading this let me know what you think?
 

Hospital or Home Based Therapy For Neonatal Abstinence?

This post is very timely as the CPS Fetus and Newborn committee has just released a new practice point: Managing infants born to mothers who have used opioids during pregnancy Have a look at discharge considerations as that section in the statement speaks to this topic as well! As bed pressures mount seemingly everywhere and “patient flow” becomes the catch-word of the day, wouldn’t it be nice to manage NAS patients in their homes?  In many centres, such patients if hospitalized can take up to 3 weeks on average to discharge home off medications.  Although done sporadically in our own centre, the question remains is one approach better than the another?  Nothing is ever simple though and no doubt there are many factors to consider depending on where you live and what resources are available to you.  Do you have outpatient follow-up at your disposal with practitioners well versed in the symptoms of NAS and moreover know what to do about them?  Is there comfort in the first place with sending babies home on an opioid or phenobarbital with potential side effects of sedation and poor feeding?  Nonetheless, the temptation to shift therapy from an inpatient to outpatient approach is very tempting. The Tennessee Experience Maalouf Fl et al have published an interesting account of the experience with outpatient therapy in their paper Outpatient Pharmacotherapy for Neonatal Abstinence Syndrome.  The authors were able to take advantage of the Tennessee Medicaid program using administrative
and vital records data from 2009 to 2011 to capture a cohort of 736 patients who were treated for NAS.  Forty five percent or 242 patients were treated as outpatients vs 290 cared for in hospital for the duration of treatment.  It is worth mentioning at this point that when the authors say they were cared for as outpatients it really is a hybrid model as the duration of hospitalization for the inpatients was a median of 23 days (IQR 14-35) versus 11 days (IQR 7-18) for inpatients (P < .001).  This practice isn’t much different than my own in which I start therapy in hospital and then discharge home with a period of home therapy. The strength of the study is the volume of patients and the ability to follow-up with these babies for the first 6 months of life to determine what happened to them after discharge.  In terms of duration of treatment, the differences are significant but perhaps not surprising. The median length of treatment for outpatients was 60 days (IQR 38-92) compared with 19 days (IQR 10-31) for inpatients (P < .001).  What was interesting as well is that 82% of babies were discharged home on phenobarbital and 9.1% on methadone and 7.4% with both.  A very small minority was discharged home on something else such as morphine or clonidine.  That there was a tripling of medication wean is not surprising as once the patients are out of the watchful eye of the medical team in hospital it is likely that practitioners would use a very slow wean out of hospital to minimize the risk of withdrawal. An Unintended Consequence This study found a statistically significant increase in risk for presenting to the emergency department for those patients treated as outpatients. What this graph demonstrates is that there was no increase risk in the first month but there was for the first 6 months.  Despite the increased risk of presentation to the ED the rate of hospitalization was not different.  Drilling down the data further, the reason for coming to the ED was not for withdrawal which was 10% in the outpatient and 11% in the inpatient group.  The other major reason was The most common diagnoses were upper respiratory infections; 80% outpatient vs 71% inpatient.  So while there was a significant difference (which was not by much) my take on it is that it was most likely by chance as I can’t think of how infections in the first 6 months could be linked to choice of medication wean. What about phenobarbital? Phenobarbital has been used for many years in Neonatology for control of seizures, sedation (taking advantage of a side effect) and management of NAS.  The problem with a median use of phenobarbital for 2 months is its potential to affect development. An animal study by Diaz in 1999 in which rat pups were given two weeks of phenobarbital starting on day 5 of life and then euthanized demonstrated the following weight reductions when high dose phenobarbital was utilized.  In human data, children with febrile seizures treated with phenobarbital in the paper Late cognitive effects of early treatment with phenobarbital. had decreased intelligence than those not exposed to phenobarbital. The issue here for me is not necessarily whether babies can be treated successfully as outpatients for NAS.  The concern is at what cost if the choice of drug is phenobarbital.  The reason phenobarbital was chosen is likely due to compliance.  We know that the more frequently a drug is dose the less likely compliance will be achieved.  Phenobarbital being dosed either q12h or q24h is an ideal drug from a compliance point of view but the ramifications of this treatment deserve reconsideration. I look forward to seeing further studies on this topic and hope that we see the results of an opioid outpatient treatment program.  I know these exist and would welcome any information you as the readers of this blog can offer.  Treating patients in the home makes great sense to me but we need to do it with the right drugs!
 

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!
 

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!    
 

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!
 

Part 2: Does prophylactic dextrose gel really work?

In the first part of this series of posts called Can prophylactic dextrose gel prevent babies from becoming hypoglycemic? the results appeared to be a little lackluster.  The study that this blog post was based on was not perfect and the lack of a randomized design left the study open to criticism and an unbalancing of risks for hypoglycemia.  Given these faults it is no doubt that you likely didn’t run anywhere to suggest we should start using this right away as a protocol in your unit. Another Study Though May Raise Some Eyebrows New Zealand researchers who have been at the forefront of publications on the use of dextrose gel recently published another article on the topic Prophylactic Oral Dextrose Gel for Newborn Babies at Risk of Neonatal Hypoglycaemia: A Randomised Controlled Dose-Finding Trial (the Pre-hPOD Study).  As the short study name suggests “Pre-hPOD” this was a preliminary study to determine which dosing of dextrose gel would provide the greatest benefit to prevent neonatal hypoglycemia.  The study is a little complex in design in that there were eight groups (4 dextrose gel vs 4 placebo) with the following breakdown. Dosing was given either once at 1 h of age (0.5 ml/kg or 1 ml/kg) or three more times (0.5 ml/kg) before feeds in the first 12 h, but not more frequently than every 3 h. Each dose of gel was followed by a breastfeed. The groups given prophylaxis fell into the following risk categories; IDM (any type of diabetes), late preterm (35 or 36 wk gestation), SGA (BW < 10th centile or < 2.5 kg), LBW (birthweight > 90th centile or > 4.5 kg), maternal use of β-blockers. Blood glucose was measured at 2 h of age and then AC feeds every 2 to 4 h for at least the first 12 h.  This was continued until an infant had 3 consecutive blood glucose concentrations of 2.6 mmmol/L.  With a primary outcome of hypoglycemia in the first 48 hours their power calculation dictated that a total sample size of 415 babies (66 in each treatment arm, 33 in each placebo arm) was needed which thankfully they achieved which means we can believe the results if they found no difference! What did they find? One might think that multiple doses and/or higher doses of glucose gel would be better than one dose but curiously they found that the tried and true single dose of 0.5 mL/kg X 1 offered the best result.  “Babies randomised to any dose of dextrose gel were less likely to develop hypoglycaemia than those randomised to placebo (RR 0.79, 95% CI 0.64–0.98, p = 0.03; number needed to 10.” Looking at the different cumulative doses, the only dosing with a 95% confidence interval that does not cross 1 was the single dosing.  Higher and longer dosing showed no statistical difference in the likelihood of becoming hypoglycemic in the first 48 hours.  As was found in the sugar babies study, admission to NICU was no different between groups and in this study as with the sugar baby study if one looked at hypoglycemia as a cause for admission there was a slight benefit.  Curiously, while the previous study suggested a benefit to the rate of breastfeeding after discharge this was not noted here. How might we interpret these results? The randomized nature of this study compared to the one reviewed in part I leads me to trust these findings a little more than the previous paper.  What this confirms in my mind is that giving glucose gel prophylaxis to at risk infants likely prevents hypoglycemia in some at risk infants and given that there were no significant adverse events (other than messiness of administration), this may be a strategy that some units wish to try out.  When a low blood glucose did occur it was later in the group randomized to glucose gel at a little over 3 hours instead of 2 hours.  The fact that higher or multiple dosing of glucose gel given prophylactically didn’t work leads me to speculate this may be due to a surge of insulin.  Giving multiple doses or higher doses may trigger a normal response of insulin in a baby not at risk of hypoglycemia but in others who might already have a high baseline production of insulin such as in IDMs this surge might lead to hypoglycemia.  This also reinforces the thought that multiple doses of glucose gel in babies with hypoglycemia should be avoided as one may just drive insulin production and the treatment may become counterproductive. In the end, I think these two papers provide some food for thought.  Does it make sense to provide glucose gel before a problem occurs?  We already try and feed at risk babies before 2 hours so would the glucose gel provide an added kick or just delay the finding of hypoglycemia to a later point. One dose may do the trick though. A reader of my Facebook page sent me a picture of the hPOD trial which is underway which I hope will definitively put this question to rest.  For more on the trial you can watch Dr. Harding speak about the trial here.        
 

Can prophylactic dextrose gel prevent babies from becoming hypoglycemic?

I have written a number of times already on the topic of dextrose gels. Previous posts have largely focused on the positive impacts of reduction in NICU admissions, better breastfeeding rates and comparable outcomes for development into childhood when these gels are used. The papers thus far have looked at the effectiveness of gel in patients who have become hypoglycemic and are in need of treatment. The question then remains as to whether it would be possible to provide dextrose gel to infants who are deemed to be at risk of hypoglycemia to see if we could reduce the number of patients who ultimately do become so and require admission. Answering that question Recently, Coors et al published Prophylactic Dextrose Gel Does Not Prevent Neonatal Hypoglycemia: A Quasi-Experimental Pilot Study. What they mean by Quasi-Experimental is that due to availability of researchers at off hours to obtain consent they were unable to produce a randomized controlled trial. What they were able to do was compare a group that had the following risk factors (late preterm, birth weight <2500 or >4000 g, and infants of mothers with diabetes) that they obtained consent for giving dextrose gel following a feed to a control group that had the same risk factors but no consent for participation. The protocol was that each infant would be offered a breastfeed or formula feed after birth followed by 40% dextrose gel (instaglucose) and then get a POC glucose measurement 30 minutes later. A protocol was then used based on different glucose results to determine whether the next step would be a repeat attempt with feeding and gel or if an IV was needed to resolve the issue. To be sure, there was big hope in this study as imagine if you could prevent a patient from becoming hypoglycemic and requiring IV dextrose followed by admission to a unit.  Sadly though what they found was absolutely no impact of such a strategy.  Compared with the control group there was no difference in capillary glucose after provision of dextrose gel (52.1 ± 17.1 vs 50.5 ± 15.3 mg/dL, P = .69).   One might speculate that this is because there are differing driving forces for hypoglycemia and indeed that was the case here where there were more IDMs and earlier GA in the prophylactic group.  On the other hand there were more LGA infants in the control group which might put them at higher risk.  When these factors were analyzed though to determine whether they played a role in the lack of results they were found not to. Moreover, looking at rates of admission to the NICU for hypoglycemia there were also no benefits shown.  Some benefits were seen in breastfeeding duration and a reduction in formula volumes consistent with previous studies examining the effect of glucose gel on both which is a win I suppose. It may also be that when you take a large group of babies with risks for hypoglycemia but many were never going to become hypoglycemic, those who would have had a normal sugar anyway dilute out any effect.  These infants have a retained ability to produce insulin in response to a rising blood glucose and to limit the upward movement of their glucose levels.  As such what if the following example is at work? Let’s say there are 200 babies who have risk factors for hypoglycemia and half get glucose gel.  Of the 100 about 20% will actually go on to have a low blood sugar after birth.  What if there is a 50% reduction in this group of low blood sugars so that only 10 develop low blood glucose instead of 20.  When you look at the results you would find in the prophylaxis group 10/100 babies have a low blood sugar vs 20/100.  This might not be enough of a sample size to demonstrate a difference as the babies who were destined not to have hypoglycemia dilute out the effect.  A crude example for sure but when the incidence of the problem is low, such effects may be lost. A Tale of Two Papers This post is actually part of a series with this being part 1.  Part 2 will look at a study that came up with a different conclusion.  How can two papers asking the same question come up with different answers?  That is the story of medicine but in the next part we will look at a paper that suggests this strategy does work and look at possible reasons why.
 

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!
 

Capnography or colorimetric detection of CO2 in the delivery suite. What to choose?

For almost a decade now confirmation of intubation is to be done using detection of exhaled CO2. The 7th Edition of NRP has the following to say about confirmation of ETT placement “The primary methods of confirming endotracheal tube placement within the trachea are detecting exhaled CO2 and a rapidly rising heart rate.” They further acknowledge that there are two options for determining the presence of CO2 “There are 2 types of CO2 detectors available. Colorimetric devices change color in the presence of CO2. These are the most commonly used devices in the delivery room. Capnographs are electronic monitors that display the CO2 concentration with each breath.” The NRP program stops short of recommending one versus the other. I don’t have access to the costs of the colorimetric detectors but I would imagine they are MUCH cheaper than the equipment and sensors required to perform capnography using the NM3 monitor as an example. The real question though is if capnography is truly better and might change practice and create a safer resuscitation, is it the way to go? Fast but not fast enough? So we have a direct comparison to look at. Hunt KA st al published Detection of exhaled carbon dioxide following intubation during resuscitation at delivery this month. They started from the standpoint of knowing from the manufacturer of the Pedicap that it takes a partial pressure of CO2 of 4 mm Hg to begin seeing a colour change from purple to yellow but only when the CO2 reaches 15 mm Hg do you see a consistent colour change with that device. The capnograph from the NM3 monitor on the other hand is quantitative so is able to accurately display when those two thresholds are reached. This allowed the group to compare how long it took to see the first colour change compared to any detection of CO2 and then at the 4 and 15 mm Hg levels to see which is the quicker method of detection. It is an interesting question as what would happen if you were in a resuscitation and the person intubates and swears that they are in but there is no colour change for 5, 10 or 15 seconds or longer? At what point do you pull the ETT? Compare that with a quantitative method in which there is CO2 present but it is lower than 4. Would you leave the tube in and use more pressure (either PIP/PEEP or both?)? Before looking at the results, it will not shock you that ANY CO2 should be detected faster than two thresholds but does it make a difference to your resuscitation? The Head to Head Comparison The study was done retrospectively for 64 infants with a confirmed intubation using the NM3 monitor and capnography.  Notably the centre did not use a colorimetric detector as a comparison group but rather relied on the manufacturers data indicating the 4 and 15 mm Hg thresholds for colour changes.  The mean age of patients intubated was 27 weeks with a range of 23 – 34 weeks.  The results I believe show something quite interesting and informative.   Median time secs (range) Earliest CO2 detection 3.7 (0 – 44s) 4 mm Hg 5.3 (0 – 727) 15 mm Hg 8.1 (0 – 727) I wouldn’t worry too much about a difference of 1.6 seconds to start getting a colour change but it is the range that has me a little worried.  The vast majority of the patients demonstrated a level of 4 or 15 mm Hg within 50 seconds although many were found to take 25-50 seconds.  When compared to a highest level of 44 seconds in the first detection of CO2 group it leads one to scratch their head.  How many times have you been in a resuscitation and with no CO2 change you keep the ETT in past 25 seconds?  Looking closer at the patients, there were 12 patients that took more than 30 seconds to reach a threshold of 4 mm Hg.  All but one of the patients had a heart rate in between 60-85.  Additionally there was an inverse relationship found between gestational age and time to detection.  In other words, the smallest of the babies in the study took the longest to establish the threshold of 4 and 15 mm Hg. Putting it into context? What this study tells me is that the most fragile of infants may take the longest time to register a colour change using the colorimetric devices.  It may well be that these infants take longer to open up their pulmonary vasculature and deliver CO2 to the alveoli.  As well these same infants may take longer to open the lung and exhale the CO2.  I suppose I worry that when a resuscitation is not going well and an infant at 25 weeks is bradycardic and being given PPV through an ETT without colour change, are they really not intubated?  In our own centre we use capnometry in these infants (looks for a wave form of CO2) which may be the best option if you are looking to avoid purchasing equipment for quantitative CO2 measurements.  I do worry though that in places where the colorimetric devices are used for all there will be patients who are extubated due to the thought that they in fact have an esophageal intubation when the truth is they just need time to get the CO2 high enough to register a change in colour. Anyways, this is food for thought and a chance to look at your own practice and see if it is in need of a tweak…
 

Should all babies be screened for hypoglycemia?

Hypoglycemia has to be one of the most common conditions that we screen for or treat in the NICU and moreover in newborn care in general. The Canadian Pediatric Society identifies small for gestational age infants (weight <10th percentile), large for gestational age (LGA; weight > 90th percentile) infants, infants of diabetic mothers (IDMs) and preterm infants as being high risk for hypoglycemia. It is advised then to screen such babies in the absence of symptoms for hypoglycemia 2 hours after birth after a feed has been provided (whether by breast or bottle). I am sure though if you ask just about any practitioner out there, they will tell you a story about a baby with “no risk factors” who had hypoglycemia. These one-off cases have the effect though of making us want to test everyone for fear that we will miss one. If that is the case though should we be recommending that all babies get at least one check? The Canadian Pediatric Surveillance Program (CPSP) The CPSP is a branch of the Canadian Pediatric Society that “provides an innovative means to undertake active paediatric surveillance and increase awareness of childhood disorders that are high in disability, morbidity, mortality and economic cost to society, despite their low frequency. I submit my surveys each month as i hope other Canadian Pediatricians do and help to determine the impact of these rare conditions in our Canadian population.  Like with any survey we rely on people taking the time to submit but there is always the risk that what is being sent in under represents the true burden of illness as some cases may not be identified.  Having said that, it is the best we have! Turning our attention to hypoglycemia in low risk newborns From April 2014 to March 2016 the CPSP searched for these types of patients and just published the results of their findings in Hypoglycemia in unmonitored full-term newborns—a surveillance study by Flavin MP et al.  What I like about the study is that they have been able to look at a group of babies that fall outside those identified as being at risk in the CPS statement Screening guidelines for newborns at risk for low blood glucose.  They were looking for severe hypoglycemia by using a threshold of < 2.0 mmol/L (36 mg/dl) and all infants must have received IV dextrose.  In the end after excluding ineligible cases they had 93 babies who met criteria.  Based on the Canadian birth rate this translates to an incidence of 1 in every 8378 births. These babies were all supposed to be low risk but there were in fact clues that while not strictly identified as risks in the CPS statement could have increased the likelihood of a low blood glucose.  Twenty three percent of mothers had maternal hypertension and another 23% were obese while 47% had excessive weight gain during pregnancy.  Furthermore, 8% of mothers were treated with a beta blocker (most likely labetalol I would think) during pregnancy which is a risk factor for hypoglycemia although not specifically cited in the current CPS statement. A concerning finding as well was the likelihood of severe symptoms in this group on presentation. Twenty percent presented with major clinical signs (seizure, apnea or cyanosis). Median glucose levels at presentation were much lower than those without major signs (median = 0.8 mmol/L, interquartile range [IQR] = 0.5 versus 1.6 mmol/L, IQR = 0.7; P < 0.001).  Lastly, providers were asked about neurodevelopmental concerns at discharge approximately 20% were thought to have issues. Are these patients really low risk though? Twenty five percent of the patients submitted had a birth weight less than the 10%ile for GA.  These patients as per the CPS guideline recommendations are actually considered at risk and should have been screened.  The second issue to address has to do with the way we diagnose diabetes in pregnancy.  All women are provided with the oral glucose tolerance test around 28 weeks of pregnancy. No test is perfect but it is the best we have.  Women who have excessive weight gain in pregnancy (almost 50% of the cohort) are at higher risk of developing diabetes or some degree of insulin resistance as are those who are classified as obese.  I have long suspected and think it may be the case here that some babies who do not meet the criteria for screening as their mothers do not have a diagnosis of GDM actually are at risk due to some degree of insulin resistance or perhaps their mothers develop GDM later.  The evidence for this are the occasional LGA babies who are born to mothers without a GDM diagnosis but who clearly have been exposed to high insulin levels as they behave like such affected infants with poor feeding and low sugars in the newborn period.  The authors here comment on those that were SGA but how many in this cohort were LGA? The effect of hypertension can also not be minimized which was present in about a quarter of patients.  These babies while not being officially SGA may have experienced a deceleration in weight gain in the last few weeks but remained above the 10%ile.  These infants would not have the glycogen stores to transition successfully but would not be targeted as being at risk by the current definitions. Should we be screening everyone then? If we acknowledge that about 25% were IUGR in this study (<10%ile) and should have been screened, the expected rate would be 1:1170 births alone.  In Manitoba with our 17000 births a year we would capture about two extra babies a year which translates into a low of pokes for a lot of healthy babies.  Given the further information that 1:5 babies who are identified may have neurodevelopmental concerns it would take about 2-3 years of testing to prevent one concern.  That pick up rate for me is far too low to subject so many babies to testing.  What this study though does highlight is the need to view risk factors a little less strictly.  Babies who are almost meeting the criteria for being LGA or those whose mother’s have taken lebetalol should have a low threshold for screening.  Should hypertension on medications, excessive maternal weight gain or obesity in the mother be considered a risk?  What I didn’t see in the end of this study were patients who truly were AGA, being born to healthy non overweight mothers presenting as high risk. Maybe what is really needed based on this study is to re-evaluate what we consider at risk.  In the meantime, maybe we should be testing a few extra babies who fall into these “lesser” risk categories.  Better yet a study isolating such patients and looking at the frequency of hypoglycemia in these patients is warranted to get a better idea of whether they are indeed risks.
 

Is skin to skin care truly good for the developing brain?

Skin to skin care or kangaroo care is all the rage and I am the first one to offer my support for it.  Questions persist though as to whether from a physiological standpoint, babies are more stable in an isolette in a quiet environment or out in the open on their mother or father’s chests. Bornhorst et al expressed caution in their study Skin-to-skin (kangaroo) care, respiratory control, and thermoregulation.  In a surprising finding, babies with an average gestational age of 29 weeks were monitored for a number of physiological parameters and found to have more frequent apnea and higher heart rates than when in an isolette.  The study was small though and while there were statistical differences in these parameters they may not have had much clinical significance (1.5 to 2.8 per hour for apnea, bradycardia or desaturation events).  Furthermore, does an increase in such events translate into any changes in cerebral oxygenation that might in turn have implications for later development?  Tough to say based on a study of this magnitude but it certainly does raise some eyebrows. What if we could look at cerebral oxygenation? As you might have guessed, that is exactly what has been done by Lorenz L et al in their recent paper Cerebral oxygenation during skin-to-skin care in preterm infants not receiving respiratory support.The goal of this study was to look at 40 preterm infants without any respiratory distress and determine whether cerebral oxygenation (rStO2)was better in their isolette or in skin to skin care (SSC).  They allowed each infant to serve as their own control by have three 90 minute periods each including the first thirty minutes as a washout period.  Each infant started their monitoring in the isolette then went to SSC then back to the isolette.  The primary outcome the power calculation was based on was the difference in rStO2 between SSC and in the isolette.  Secondary measures looked at such outcomes as HR, O2 sat, active and quiet sleep percentages, bradycardic events as lastly periods of cerebral hypoxia or hyperoxia.  Normal cerebral oxygenation was defined as being between 55 to 85%. Surprising results? Perhaps its the start of a trend but again the results were a bit surprising showing a better rStO2 when in the isolette (−1.3 (−2.2 to −0.4)%, p<0.01).  Other results are summarized in the table below: Mean difference in outcomes Variable SSC Isolette Difference in mean p rStO2 73.6 74.8 -1.3 <0.01 SpO2 (median) 97 97 -1.1 0.02 HR 161 156 5 <0.01 % time in quiet sleep 58.6 34.6 24 <0.01 No differences were seen in bradycardic events, apnea, cerebral hypoexmia or hyperoxemia.  The authors found that SSC periods in fact failed the “non-inferiority” testing indicating that from a rStO2 standpoint, babies were more stable when not doing SSC!  Taking a closer look though one could argue that even if this is true does it really matter?  What is the impact on a growing preterm infant if their cerebral oxygenation is 1.3 percentage points on average lower during SSC or if their HR is 5 beats per minute faster?  I can’t help but think that this is an example of statistical significance without clinical significance.  Nonetheless, if there isn’t a superiority of these parameters it does leave one asking “should we keep at it?” Benefits of skin to skin care Important outcomes such as reductions in mortality and improved breastfeeding rates cannot be ignored or the positive effects on family bonding that ensue. Some will argue though that the impacts on mortality certainly may be relevant in developing countries where resources are scarce but would we see the same benefits in developed nations.  The authors did find a difference though in this study that I think benefits developing preterm infants across the board no matter which country you are in.  That benefit is that of Quiet Sleep (QS).  As preterm infants develop they tend to spend more time in QS compared to active sleep  (AS).  From Doussard- Roossevelt J, “Quiet sleep consists of periods of quiescence with regular respiration and heart rate, and synchronous EEG patterns. Active sleep consists of periods of movement with irregular respiration and heart rate, and desynchronous EEG patterns.”  In the above table one sees that the percentage of time in QS was significantly increased compared to AS when in SSC.  This is important as neurodevelopment is thought to advance during periods of QS as preterm infants age. There may be little difference favouring less oxygen extraction during isolette times but maybe that isn’t such a good thing?  Could it be that the small statistical difference in oxygen extraction is because the brain is more active in laying down tracks and making connections?  Totally speculative on my part but all that extra quiet sleep has got to be good for something. To answer the question of this post in the title I think the answer is a resounding yes for the more stable infant.  What we don’t know at the moment except from anecdotal reports of babies doing better in SSC when really sick is whether on average critically ill babies will be better off in SSC.  I suspect the answer is that some will and some won’t.  While we like to keep things simple and have a one size fits all answer for most of our questions in the NICU, this one may not be so simple.  For now I think we keep promoting SSC for even our sick patients but need to be honest with ourselves and when a patient just isn’t ready for the handling admit it and try again when more stable.  For the more stable patient though I think giving more time for neurons to find other neurons and make new connections is a good thing to pursue!
 

If A Little Caffeine Is Good Is A Lot Better?

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!    
 

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.    
 

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.  
 

Diazoxide for treating hypoglycemia. Is earlier use better?

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.      
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