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About this blog

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

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

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

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Entries in this blog

 

How long should we treat preterm infants with caffeine?

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

AllThingsNeonatal

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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.      
 

Perhaps it is time to change the way we use caffeine in the NICU.

This has been a question that has befuddled Neonatologists for years.  Get ten of us in a room and you will get a variety of responses ranging from (talking about caffeine base) 2.5 mg/kg/day to 10 mg/kg/day.  We will espouse all of our reasons and question the issue of safety at higher doses but in the end do we really know?  As I was speaking to a colleague in Calgary yesterday we talked about how convinced we are of our current management strategies but how we both recognize that half of what we think we know today we will be questioning in 10 years.  So how convinced should we really be about caffeine? Even the Cochrane Review Suggests There Is Something Amiss Back in 2010 the Cochrane Collaboration examining 6 trials on caffeine for treating apnea of prematurity concluded “Methylxanthine is effective in reducing the number of apnoeic attacks and the use of mechanical ventilation in the two to seven days after starting treatment.” Notice the bolded section.  Two to seven days.  Interesting that we don’t see the effect last in perpetuity.  Why might that be?  Do babies become resistant with time or is there a change in the way these infants metabolize the drug such that levels in the bloodstream drop after that time point.  It is almost certainly the latter and in the last 7 years have we really seen any response to this finding?  I would say no for the most part although I don’t work in your unit so hard to say for sure. At least where I practice we pick a dose somewhere between 2.5-5 mg/kg/day and give a load of 10 mg/kg when we start the drug.  From time to time we give a miniload of 5 mg/kg and may or may not increase the dose of maintenance based on the number of apneic events the babies are having.  What if we could be proactive instead of reactive though.  Do the babies need to have multiple events before we act or could we prevent the events from happening at all? Proactive Treatment With Caffeine We have known that caffeine clearance increases with postnatal age.  The half-life of the drug shortens from about a week at the earliest gestational ages to 2-2.5 days by term equivalent age.  For those infants who are older such as 32 weeks and above we expect them to be off caffeine (if they need it) within 2-3 weeks so I am not really talking about them but what about the babies born earlier than that or certainly MUCH earlier at 23 and 24 weeks who will be on caffeine possibly till term.  Should one size (dose) fit all?  No it really shouldn’t and some crafty researchers led by Koch G have published a paper that demonstrates why entitled Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates. In this paper the authors armed with knowledge of the half life of caffeine at different gestational ages were able to calculate the clearance of the drug at different postnatal ages to demonstrate in a model of a 28 week male infant weighing 1150g. The authors further took into account predicted weight changes and were able to calculate what the expected caffeine levels would be in the fictional infant at various time points.  The target caffeine levels for this patient were a trough level of 15 -20 mg/L which are the currently acceptable ranges in the literature.  The testing was first done using a standard load of 10 mg/kg (base) followed by 5 mg/kg/d and demonstrated levels which yielded the following graph over time.    What this demonstrates is that if the dose is unchanged over the first 7 weeks, this hypothetical infant will only achieve effective concentrations for the first week.  Interesting isn’t it that the Cochrane review found clinical effect over the first 2-7 days? What if you were to double the dose to really “hit” the infant with a good dose of caffeine from the start and maintain at that level based on their weight gain as shown next. Well, you will get what you are hoping for and keep the trough level above 15 mg/L but you will hit 30 mg/L that some have said is too high and can lead to adverse effects (ever seen SVT with these high doses? I have).  Like Goldilocks and the Three Bears could there be a dosing strategy that might be just right?  The authors put in another model based on the knowledge of caffeine clearance over time and suggested a strategy in which after the first week the adjusted maintenance doses would be 3 mg/kg/day and 3.5 mg/kg/day in the third to fourth weeks and lastly 4 mg/kg/d in the 5th to 8th week.  Using that dosing schedule the model produced this curve. As you can see, the infant would have a therapeutic target without reaching levels above 30 mg/L and potential for side effects. As many of you read this however you may ask the obvious question. Each of us have seen infants who require higher doses than this to rid themselves of significant apnea and escape reintubation.  Given that this is a mathematical model it assumes that this fictional infant will respond beautifully to a trough level of 15 to 20 mg/L but some will not. Even in the curve shown it is clear that there is some room to go higher in the dosing as the curve is just touching 20 mg/L. A Suggestion For The Future What grabbed my attention here is the possibility that we could take a proactive rather than reactive approach to these infants.  Once a small baby is controlled on their dose of caffeine whether it is 2.5, 3, 5 or even 6 mg/kg/d of caffeine should we wait for more events to occur and then react by increasing caffeine?  What if we are too late to respond and the patient is intubated.  What effect does this have on the developing lung, what about the brain that is subjected to bradycardic events with resultant drops in cardiac output and cerebral perfusion.  Perhaps the solution is to work with our pharmacists and plan to increase dosing at several time points in the infants journey through the NICU even if they aren’t showing symptoms yet.  No doubt this is a change in approach at least for the unit I work in but one that should start with a conversation!    
 

Hydrocortisone after birth may benefit the smallest preemies the most!

This must be one of my favourite topics as I have been following the story of early hydrocortisone to reduce BPD for quite some time. It becomes even more enticing when I have met the authors of the studies previously  and can see how passionate they are about the possibilities. The PREMILOC study was covered on my site twice now, with the first post being A Shocking Change in Position. Postnatal steroids for ALL microprems? and the second reviewing the 22 month outcome afterwards /2017/05/07/early-hydrocortisone-short-term-gain-without-long-term-pain/. The intervention here was that within 24 hours of birth babies born between 24-27 weeks gestational age were randomized to receive placebo or hydrocortisone 1 mg/kg/d divided q12h for one week followed by 0.5 mg/kg/d for three days. The primary outcome was rate of survival without BPD at 36 weeks PMA. The finding was a positive one with a 9% reduction in this outcome with the use of this strategy. Following these results were the two year follow-up which reported no evidence of harm but the planned analysis by gestational age groupings of 24-25 and 26-27 weeks was not reported at that time but it has just been released this month. Is there a benefit? Of the original cohort the authors are to be commended here as they were able to follow-up 93% of all infants studied at a mean age of 22 months. The methods of assessing their neurological status have been discussed previously but essentially comprised standardized questionnaires for parents, assessment tools and physical examinations. Let’s start off with what they didn’t find. There was no difference between those who received placebo vs hydrocortisone in the 26-27 week group but where it perhaps matters most there was. The infants born at 24-25 weeks are certainly some of our highest risk infants in the NICU. It is in this group that the use of hydrocortisone translated into a statistically significant reduction in the rate of neurodevelopmental impairment. The Global Neurological Assessement scores demonstrated a significant improvement in the hydrocortisone group with a p value of 0.02. Specifically moderate to severe disability was noted in 18% compared to 2% in the group receiving hydrocortisone.They did not find a difference in the neurological exam but that may reflect the lack of physical abnormalities with cognitive deficit remaining.  It could also be explained perhaps by the physical examination not being sensitive enough to capture subtle differences.   Why might this be? Adding an anti-inflammatory agent into the early phase of a preemies life might spare the brain from white matter damage. Inflammation is well known to inflict injury upon the developing brain and other organs (think BPD, ROP) so dampening these factors in the first ten days of life could bring about such results via a mechanism such as that. When you look at the original findings of the study though, a couple other factors also pop up that likely contribute to these findings as well. Infants in the hydrocortisone group had a statistical reduction in the rate of BPD and PDA ligations. Both of these outcomes have been independently linked to adverse neurodevelopmental outcome so it stands to reason that reducing each of these outcomes in the most vulnerable infants could have a benefit. In fact when you add everything up, is there much reason not to try this approach? Ten days of hydrocortisone has now been shown to reduce BPD, decrease PDA ligations and importantly in the most vulnerable of our infants improve their developmental outcome. I think with this information at our fingertips it becomes increasingly difficult to ignore this approach. Do I think this will become adopted widely? I suspect there will be those who take the Cochrane approach to this and will ask for more well designed RCTs to be done in order to replicate these results or at least confirm a direction of effect which can then be studied as part of a systematic review. There will be those early adopters though who may well take this on. It will be interesting to see as these centres in turn report their before and after comparisons in the literature what the real world impact of this approach might be. Stay tuned as I am sure this is not the last we will hear on this topic!
 

Can’t intubate to give surfactant? Maybe try this!

Intubation is not an easy skill to maintain with the declining opportunities that exist as we move more and more to supporting neonates with CPAP.  In the tertiary centres this is true and even more so in rural centres or non academic sites where the number of deliveries are lower and the number of infants born before 37 weeks gestational age even smaller.  If you are a practitioner working in such a centre you may relate to the following scenario.  A woman comes in unexpectedly at 33 weeks gestational age and is in active labour.  She is assessed and found to be 8 cm and is too far along to transport.  The provider calls for support but there will be an estimated two hours for a team to arrive to retrieve the infant who is about to be born.  The baby is born 30 minutes later and develops significant respiratory distress.  There is a t-piece resuscitator available but despite application the baby needs 40% oxygen and continues to work hard to breathe.  A call is made to the transport team who asks if you can intubate and give surfactant.  Your reply is that you haven’t intubated in quite some time and aren’t sure if you can do it.  It is in this scenario that the following strategy might be helpful. Surfactant Administration Through and Laryngeal Mask Airway (LMA) Use of an LMA has been taught for years in NRP now as a good choice to support ventilation when one can’t intubate.  The device is easy enough to insert and given that it has a central lumen through which gases are exchanged it provides a means by which surfactant could be instilled through a catheter placed down the lumen of the device.  Roberts KD et al published an interesting unmasked but randomized study on this topic Laryngeal Mask Airway for Surfactant Administration in Neonates: A Randomized, Controlled Trial. Due to size limitations (ELBWs are too small to use this in using LMA devices) the eligible infants included those from 28 0/7 to 35 6/7 weeks and ≥1250 g.  The infants needed to all be on CPAP +6 first and then fell into one of two treatment groups based on the following inclusion criteria: age ≤36 hours,
(FiO2) 0.30-0.40 for ≥30 minutes (target SpO2 88% and 92%), and chest radiograph and clinical presentation consistent with RDS.
Exclusion criteria included prior mechanical ventilation or surfactant administration, major congenital anomalies, abnormality of the airway, respiratory distress because of an etiology other than RDS, or an Apgar score <5 at 5 minutes of age. Procedure & Primary Outcome After the LMA was placed a y-connector was attached to the proximal end.  On one side a CO2 detector was placed and then a bag valve mask in order to provide manual breaths and confirm placement over the airway.  The other port was used to advance a catheter and administer curosurf in 2 mL aliquots.  Prior to and then at the conclusion of the procedure the stomach contents were aspirated and the amount of surfactant determined to provide an estimate of how much surfactant was delivered to the lungs.  The primary outcome was treatment failure necessitating intubation and mechanical ventilation in the first 7 days of life.  Treatment failure was defined upfront and required 2 of the following: (1) FiO2 >0.40 for >30
minutes (to maintain SpO2 between 88% and 92%), (2) PCO2 >65 mmHg on arterial or capillary blood gas or >70 on venous blood gas, or (3) pH <7.22 or 1 of the following: (1)  recurrent or severe apnea, (2) hemodynamic instability requiring pressors, (3) repeat surfactant dose, or (4) deemed necessary by medical provider. Did it work? It actually did. Of the 103 patients enrolled (50 LMA and 53 control) 38% required intubation in the LMA group vs 64% in the control arm.  The authors did not reach their desired enrollment based on their power calculation but that is ok given that they found a difference.  What is really interesting is that they found a difference in the clinical end point despite many infants clearly not receiving a full dose of surfactant as measured by gastric aspirate. Roughly 25% of the infants were found to have not received any surfactant, 20% had >50% of the dose in the stomach and the other 50+% had < 10% of the dose in the stomach meaning that the majority was in fact deposited in the lungs.  I suppose it shouldn’t come as a surprise that among the secondary outcomes the duration length of mechanical ventilation did not differ between two groups which I presume occurred due to the babies needing intubation being similar.  If you needed it you needed it so to speak. Further evidence though of the effectiveness of the therapy was that the average FiO2 30 minutes after being treated was significantly lower in the group with the LMA treatment 27 vs 35%.  What would have been interesting to see is if you excluded the patients who received little or no surfactant, how did the ones treated with intratracheal deposition of the dose fare?  One nice thing to see though was the lack of harm as evidenced by no increased rate of pneumothorax, prolonged ventilation or higher oxygen. Should we do this routinely? There was a 26% reduction in intubations in te LMA group which if we take this as the absolute risk reduction means that for every 4 patients treated with an LMA surfactant approach, one patient will avoid intubation.  That is pretty darn good!  If we also take into account that in the real world, if we thought that little of the surfactant entered the lung we would reapply the mask and try the treatment again.  Even if we didn’t do it right away we might do it hours later. In a tertiary care centre, this approach may not be needed as a primary method.  If you fail to intubate though for surfactant this might well be a safe approach to try while waiting for a more definitive airway.  Importantly this won’t help you below 28 weeks or 1250g as the LMA is too small but with smaller LMAs might this be possible.  Stay tuned as I suspect this is not the last we will hear of this strategy!    

AllThingsNeonatal

AllThingsNeonatal

 

An Old Drug Finds A New Home In The Treatment of BPD.

What is old is new again as the saying goes.  I continue to hope that at some point in my lifetime a “cure” will be found for BPD and is likely to centre around preventing the disease from occurring.  Will it be the artificial placenta that will allow this feat to be accomplished or something else?  Until that day we unfortunately are stuck with having to treat the condition once it is developing and hope that we can minimize the damage.  When one thinks of treating BPD we typically think of postnatal steroids.  Although the risk of adverse neurodevelopmental outcome is reduced with more modern approaches to use, such as with the DART protocol,most practitioners would prefer to avoid using them at all if possible.  We know from previous research that a significant contributor to the development of BPD is inflammation.  As science advanced, the specific culprits for this inflammatory cascade were identified and leukotrienes in particular were identified in tracheal lavage fluid from infants with severe lung disease.  The question then arises as to whether or not one could ameliorate the risk of severe lung disease by halting at least a component of the inflammatory cascade leading to lung damage. Leukotriene Antagonists In our unit, we have tried using the drug monteleukast, an inhibitor of leukotrienes in several patients.  With a small sample it is difficult to determine exactly whether this has had the desired effect but in general has been utilized when “all hope is lost”.  The patient has severe disease already and is stuck on high frequency ventilation and may have already had a trial of postnatal steroids.  It really is surprising that with the identification of leukotriene involvement over twenty years ago it took a team in 2014 to publish the only clinical paper on this topic.  A German team published Leukotriene receptor blockade as a life-saving treatment in severe bronchopulmonary dysplasia.in 2014 and to date as far as I can see remains the only paper using this strategy. Given that we are all looking for ways to reduce BPD and this is the only such paper out there I thought you might want to see what they found.  Would this be worth trying in your own unit?  Well, read on and see what you think! Who was included? This study had an unusual design that will no doubt make statistical purists cringe but here is what they did.  The target population for the intervention were patients with “life threatening BPD”.  That is, in the opinion of the attending Neonatologist the patient had a greater than 50% likelihood of dying and also had to meet the following criteria; born at < 32 weeks GA, <1500g and had to be ventilated at 28 days.  The authors sought a blinded RCT design but the Research Ethics Board refused due to the risk of the drug being low and the patients having such a high likelihood of death.  The argument in essence was if the patients were likely to die and this drug might benefit them it was unethical to deny them the drug.  The authors attempted to enroll all eligible patients but wound up with 11 treated and 11 controls.  The controls were patients either with a contraindication to the drug or were parents who consented to be included in the study as controls but didn’t want the drug.  Therapy was started for all between 28 – 45 days of age and continued for a wide range of durations (111+/-53 days in the study group).  Lastly, the authors derived a score of illness severity that was used empirically: PSC = FiO2 X support + medications – support was equal to 2.5 for a ventilator. 1.5 for CPAP and 1 for nasal cannulae or an oxygen hood – medications were equal to 0.2 for steroids, 0.1 for diruetics or inhaled steroids, 0.05 for methylxanthines or intermittent diruetics. Did it make a difference? The study was very small and each patient who received the medication was matched with one that did not receive treatment.  Matching was based on GA, BW and the PSC with matching done less than 48 hours after enrollment in an attempt to match the severity of illness most importantly.   First off survival in the groups were notably different.  A marked improvement in outcome was noted in the two groups.  Of the deaths in the control group, the causes were all pulmonary and cardiac failure, although three patients died with a diagnosis of systemic inflammatory response syndrome.  That is quite interesting given that monteleukast is an anti-inflammatory medication and none of the patients in the treatment arm experienced this diagnosis. The second point of interest is the trend in the illness severity score over time.  The time points in the figure are time 1 (start of study), time 2 (4 weeks of treatment), time 3 (end of treatment).  These patients improved much more over time than the ones who did not receive treatment. The Grain of Salt As exciting as the results are, we need to acknowledge a couple things.  The study is small and with that the risk of the results appearing to be real but in actual fact there being no effect is not minimal.  As the authors knew who was receiving monteleukast it is possible that they treated the kids differently in the unit.  If you believed that the medication would work or moreover wanted it to work, did you pay more attention on rounds and during a 24 hour period to those infants?  Did the babies get more blood gases and tighter control of ventilation with less damage to the lungs over time?  There are many reasons why these patients could have been different including earlier attempts to extubate.  The fact is though the PSC scores do show that the babies indeed improved more over time so I wouldn’t write it off entirely that they did in fact benefit.  The diagnosis of SIRS is a tough one to make in a newborn and I worry a little that knowing the babies didn’t receive an anti-inflammatory drug they were “given” that diagnosis. Would I use it in spite of these faults? Yes.  We have used it in such cases but I can’t say for sure that it has worked.  If it does, the effect is not immediate and we are left once we start it not knowing how long to treat.  As the authors here say though, the therapeutic risk is low with a possibly large benefit.  I doubt it is harmful so the question we are left asking is whether it is right for you to try in your unit?  As always perhaps a larger study will be done to look at this again with a blinded RCT structure as the believers won’t show up I suspect without one!    

AllThingsNeonatal

AllThingsNeonatal

 

Stubborn PDAs despite prophylactic indomethacin!

As time goes by, I find myself gravitating to reviews of Canadian research more and more.  We have a lot of great research happening in this country of ours and especially when I see an author or two I know personally I find it compelling to review such papers.  Today is one of those days as the lead author for a paper is my colleague Dr. Louis here in Winnipeg.  Let me put his mind at ease in case he reads this by saying that what follows is not a skewering of the paper he just published using Canadian Neonatal Network data (CNN).  Over the last twenty years that I have had the privilege of working in the field of Neonatology we continue to discuss the same things when it comes to the PDA.  Does it really cause problems or is it an association for many outcomes? Does treatment make a difference?  If you treat then what should you use (ibuprofen, indomethacin, paracetamol)? When should you treat and if you treat early should it be in the first few days or right after birth using a prophylactic approach (provided within 12 hours of delivery)?  It is the prophylactic approach which is the subject of this post! Why treat prophylactically? The TIPP trial reported the results in 2001 of the study whose goal was to determine if prophylactic indomethacin use could improve neurosensory impairment at 18 months by reducing rates of severe IVH.  The results of the study are well known and showed that while the rates of severe IVH and PDA ligations were reduced through this approach, there was no actual effect on long term outcome.  The use of this approach fell off after that for many years but recently resurfaced as some units in Canada opted to start the practice again as the two benefits seen above appeared to be worth using the approach.  The thought from a family centred approach, was that eliminating the stress for families of informing them their tiny preterm infant had a serious intracranial bleed and potentially avoiding a surgical ligation with probably vocal cord impairment afterwards were good enough outcomes to warrant this practice.  Having used this approach myself I have to admit one consequence is that indomethacin was so effective at closing the PDA most of the time that over time one begins to assume the PDA is in fact closed and is less likely to go hunting for one when the baby is misbehaving later on in their course.  What if it didn’t close though?  Are there any predictors that can increase our index of suspicion? Answering the question The CNN provides a large database to look retrospectively to answer such a question.  In this article, the authors looked at a period from 2010 to 2015 including all infants < 28 weeks gestational age at birth yielding a very large sample of 7397 infants.  Of these 843 or 12% received prophylactic indomethacin and from there a little over half (465) still had a PDA.  From there, 367 received treatment with eventually 283 needing only medical, 11 having a PDA ligation and 73 having both medical and surgical closure.  From this analysis so far I can tell you that providing prophylactic indomethacin certainly does not guarantee closure! When a myriad of risk factors were put into logistic regression a number of interesting risk factors arose accounting for more of less risk of a PDA that needed surgical ligation despite prophylactic treatment.  Much like all infants in the NICU, the risk for a persistent PDA was highest with declining GA.  The combination of outborn status and short interval of ruptured membranes predicted higher risk.  No doubt this is reflective of less frequent antenatal steroid use and even if provided time for it to work.  Looking at medical or surgical treatment, surfactant therapy increased risk which may be explained by an improvement in oxygenation contributing to increased left to right shunting as PVR drops.  Maternal hypertension and longer duration of rupture of membranes again play a role in reducing risk likely through the mechanism of the former increasing endogenous steroid production and the latter again allowing for steroids to be provided. What can we learn from this paper? I suppose the biggest benefit here is the realization that even with prophylactic indomethacin we are not assured of closure.  In particular if there is a lack of antenatal steroid use or a stressed fetus one should be vigilant for the PDA.  Interestingly, all of the risks seem to point towards antenatal steroid use.  The bottom line then is that this reinforces what is already known and should be the focus of improvement strategies for centres.  Increase the rate of antenatal steroid use and you will reduce the risk of a PDA even in the baby receives prophylactic indomethacin.  I am happy to report that our centre has taken one step towards this goal by reinforcing to our Obstetrical colleagues that when they receive a call from a referring centre and have a woman who might be in labour it is better to err on the side of caution and just give the steroid course.  If they are wrong on arrival then one can always repeat a course later on as we do although repeated courses of steroids are in and of themselves a contentious issue.  What can your centre do to improve your results when it comes to antenatal steroid coverage?

AllThingsNeonatal

AllThingsNeonatal

 

Continuous glucose monitoring in NICU may be around the corner

We sure do poke a lot of babies to test their blood glucose levels.  Some of these babies don’t have so much blood to spare either so checking sugars multiple times a day can drain the body of that precious blood they so need for other functions.  Taking too much can always be addressed with a blood transfusion but that as I see it may be avoidable so shouldn’t we do what we can to cut down on blood work? Those with diabetes will be familiar with a continuous glucose monitor (CGM) which is implanted in the skin and can stay in place up to 7 days.  The device does require calibration twice a day with a capillary sample to verify it is reading well but this saves a couple pokes a day for those who check four times a day.  Such a device could be useful in the NICU where those with hypoglycemia may be checked 6 or more times per day if they are either hypo or hyperglycemic.  Cutting this down to two a day would certainly we something worth striving for and if not for the reduction in blood loss then for the minimization of painful procedures. Does it work in small babies? A natural question for sure.Uettweller et al published Real-time continuous glucose monitoring reduces the duration of hypoglycemia episodes: a randomized trial in very low birth weight neonates. In babies with a BW < 1500g they were able to demonstrate in 43 babies (21 with traditional intermittent glucose checks vs 22 with CGM)  a  reduction in duration of hypoglycemia episodes per patient (CGM 44[10-140] min versus IGM 95[15-520] min, p<0.05). Moreover in this brief study of the first three days of life they also found a reduction in the total number of pokes per patient of 5 pokes (22 vs 16).  The numbers however are small and the duration short in only being three days so it did not provide a perfect answer as to whether this technology would work in babies from 500-750g reliably but certainly for older babies, continuous knowledge of the blood glucose in theory would allow for faster response to low sugars and as a result as evidenced by the results led to a decrease in time with a low blood glucose. Improving on these results Galderisi et al just published Continuous Glucose Monitoring in Very Preterm Infants: A Randomized Controlled Trial.  The study remains small at 50 and the target group ranging from 28-31 weeks (all < 1500g) but the study followed babies for a longer time frame of 7 days. This study employed an algorithm for adjustments in glucose infusion that required staff to first put data into an excel spreadsheet and then the predictive algorithm dictated whether to increase or decrease the rate of dextrose infusion.  In one arm, CGM results were unblinded and the practitioners relied on the rate of change to determine the predicted glucose 15 minutes into the future while in the blinded group the CGM was used but results were not available (retrospectively yes) so changes were made based on the usual practice of obtaining point of care results and modifying glucose infusion rates based on that result.  The primary outcome of interest here was percentage of time in the euglycemic range of 72 – 144 mg/dL (4-8 mmol/L).   Secondary outcomes were time spent hypo or hyperglycemic (mild hypoglycemia (M-HYPO) (47–71 mg/dL); severe hypoglycemia (S-HYPO) (<47 mg/dL); mild hyperglycemia (M-HYPER) (145–180 mg/dL); and severe hyperglycemia (S-HYPER) (>180 mg/dL)).  The study lasted a total of seven days allowing the use of one subcutaneous probe per patient as they can last one week after insertion. How did the approaches compare? As you might have expected, having a predictive model proved superior.  Overall after adjusting for sex, gestational age and weight mean time in target using the unblinded CGM was 83% [95% CI, 79%–87%] and of 71% [95% CI, 67%–76%] in B-CGM [P < .001]). As for secondary outcomes one can see that the time spent in the hypo/hyper areas was much less as a percentage of time than using traditional methods of intermittent sampling.  One interesting outcome was that the total number of samples used over the study was an average of 2.4 tests per day in the unblinded group vs 2.59 per day in the intermittent sampling group which although statistically different does not seem to have much clinical impact. A few questions remain The idea of using an implanted CGM for infants in the NICU is one that excites me.  The lack of a reduction in pokes in a meaningful way is disappointing but I can’t help but wonder if the effect was different whether you were in the first or second half of the week.  What if glycemic control in these 29-31 week infants had stabilized by 2-3 days such that you only needed one or two glucose checks in the last half of the week per day?  The CGM requires calibration twice daily with POC samples so the lack of a difference my be due to those issues.  Future, calibration is rumoured to be possible with one sample so that may change. There is no disputing though that the use of the predictive algorithm made a difference in terms of avoidance of hypo/hyperglycemic episodes.  A larger study would be needed to look at whether this impacts harm that may be associated with such variability such as IVH or ROP but it certainly is promising.  The biggest issue here is that I cannot see people manually inputting glucose readings on the CGM into an excel sheet in everyday practice.  For this to become widely adopted, a simplified approach to prediction would be required or even better a feedback loop whereby data from the CGM would relay to the infusion pump and rates adjusted automatically (with manual override available). The use of CGM is coming though and I can’t help but think in the larger babies born to mothers with diabetes there would be a real heal sparing effect with these.  Might this be the next study?

AllThingsNeonatal

AllThingsNeonatal

 

Resuscitating before 22 weeks. It’s happening.

Given that today is world prematurity day  it seems fitting to talk about prematurity at the absolute extreme of it. It has been some time since as a regional program we came to accept that we would offer resuscitation to preterm infants born as early as 23 weeks gestational age.  This is perhaps a little later in the game that other centers but it took time to digest the idea that the rate of intact survival was high enough to warrant a trial of resuscitation.  This of course is not a unilateral decision but rather a decision arrived at after consultation with the family and interprofessional team.  To be sure it is not an easy one.  Other centers have argued that resuscitation should be offered to those infants as young as 22 weeks gestational age and data now exists due to enough centres doing so to provide families with some guidance as to expected survival rates and importantly the likelihood of disability. This topic has been covered previously in /2015/09/25/winnipeg-hospital-about-to-start-resuscitating-infants-at-23-weeks/. Why cover this topic again?  Well an article on CNN might have something to do with it. Resuscitating Below 22 weeks This week as I was perusing the news I came across a rather shocking article on CNN. Born before 22 weeks, ‘most premature’ baby is now thriving.  The article tells the tale of a baby delivered at 21 weeks and 4 days that now as a three year old is reaching appropriate milestones without any significant impairments.  It is a story that is filled with inspiration and so I am not mistaken I am delighted for this child and their family that this outcome has occurred.  When the lay press latches onto stories like this there is no doubt a great deal of sensationalism to them and in turn that gathers a lot of attention.  This in turn is a great thing for media. A Few Caveats Though With the exception of pregnancies conceived through IVF the best dating we have is only good to about +/- 5 days when an early first trimester ultrasound is performed or the date of the last menstrual period is fairly certain.  A baby though who is born at 21 weeks + 4 days may in fact be 22 +3 days or even more depending on when the dating was done (second trimester worse).  Let’s not take away though from the outcome being this good even at 22 weeks.  That is a pretty perfect outcome for this family but the point is that this baby may in fact be older than 21 weeks. Secondly, there are millions of babies born each year in North America.  Some of these infants are born at 22 weeks.  How do they fare overall?  From the paper by Rysavy et al from 2015 the results are as follows. If you look at the overall rate of survival it is on an average of 5.1%.  If you take a look though at those infants in whom resuscitation is provided that number increases to a mean of 23%.  Intact survival is 9% overall.  The odds aren’t great but they are there and I suspect the infant in the article is one of those babies.  Flipping the argument though to the glass is half empty, 91% of infants born at 22 weeks by best estimate who are offered resuscitation will have a moderate or severe disability if they survive.  I am not saying what one should do in this situation but depending on how a family processes the data they will either see the 110 chance of intact survival as a good thing or a 9/10 chance of death or disability as a very bad thing.  What a family chooses though is anyone’s best guess. Should we resuscitate below 22 weeks if the family wishes? I guess in the end this really depends on a couple things.  First off, how certain are the dates?  If there is any degree of uncertainty then perhaps the answer is yes.  If the dates are firm then I at least believe there is a barrier at which futility is reached.  Perhaps this isn’t at 21 weeks as some patients may indeed be older but think about what you would offer if a family presented at 20 weeks and wanted everything done.  What if it were 19 weeks?  I suspect the point of futility for all lies somewhere between 19-21 weeks. As I prepare to attend the annual meeting in Ottawa tomorrow for the Fetus and Newborn Committee I think it is prudent to point out just how difficult all of this is.  The current statement on Counselling and management for anticipated extremely preterm birth I think hits on many of these issues.  The statement is the product on not only the think tank that exists on this committee but was the product of a national consultation.  I know I may be biased since I sit on the committee but I do believe it really hits the mark. Should we be thinking about resuscitating at 21 weeks?  For me the answer is one clouded by a whole host of variables and not one that can be easily answered here.  What I do think though is that the answer in the future may be a yes provided such infants can be put onto an artificial placenta.  Even getting a few more weeks of growth before aerating those lungs is necessary may make all the difference.  The NICUs of tomorrow certainly may look quite different than they do now.      

AllThingsNeonatal

AllThingsNeonatal

 

In the Opioid Crisis is Burprenorphine The Answer?

It would seem that the Opioid crisis is continuing to be front and centre in the news.  Just today the President of the United States declared an Opioid Epidemic Emergency. Of course he was speaking primarily about the damage these drugs do on the family unit and those around them, the impact on the unborn child is significant as well.  If this sounds familiar it is because I have written about this topic recently and in the past in the posts A Magic Bullet to Reduce Duration of Treatment and Hospital Stays for Newborns With NAS and Mandatory Drug-Testing ni PRegnancy: Lesson learned.  I suppose I write about this topic often as at least where I work this is a problem which just won’t go away and takes up a tremendous amount of resources. What Can a Large Data Set Tell us? Pediatrix medical group that you may well be familiar with has a lot of data that can be mined from the hospitals in their network.  When it comes to buprenorphine there is a lot of data to look at.  In this case the question posed by VN Tolia et al in thier paper Antenatal methadone vs buprenorphine exposure and length of hospital stay in infants admitted to the intensive care unit with neonatal abstinence syndrome was whether there is a difference in infants born to mothers who have been exposed to methadone vs burprenorphine.  Specifically they chose to use length of stay as the primary outcome in a retrospective review of 3364 infants admitted for management of NAS.  Of these infants, 2202 (65%) were exposed to methadone and 1162 (34%) to buprenorphine.  Before we get into what the results actually were it is important to highlight what this study will not tell us.  By looking only at admissions for NAS we do not know whether the use of buprenorphine in mothers actually reduced admission for NAS so we are only speaking of the babies who were afflicted with NAS. When looking at the two groups, the median length of stay was 24 days for the methadone group and 21 for the buprenorphine which was found to be significantly different.  In the secondary analysis another interesting finding (at least to me) was noted.  When looking at the percentage of babies with a length of stay > 30 days the difference was significant at 34% vs 22% for buprenorphine.  The authors here did a good job of doing their best to control for factors which could have influenced the results as they did a regression analysis to determine whether other factors such as gestational age, sex, type of treatment provided etc would explain the shortened length of stay and they found that it remained significant controlling for a wide variety of factors. Is three days worth it? It would be tempting to look at the 3 day median difference and shrug it off as no big deal.  Remember though that we are in an epidemic are we not?  What the study does not account for as well are the number of babies who could have been managed in a postpartum ward and also had a shortened length of stay.  Let’s look at a city though where about 100 babies are admitted a year with NAS.  A three day reduction in length of stay would translate into 300 patient days per year.  By simply changing the medication a woman is being treated with in pregnancy from methadone to buprenorphine we could save almost one NICU bed for the whole year.  That is nothing to sneeze at!  Moreover if the reduction in admission rates are also true another one, two or more beds per year could be spared depending on the effectiveness of the drug. In the last post that spoke of using buprenorphine to treat NAS in babies I was concerned about the alcohol content of the syrup for administration in babies.  Here we are talking about treating women rather than babies so this is not a concern (plus they would not be taking the pediatric suspension).  I see little downside to using buprenorphine over methadone so the real question is how do we get the care providers for the mothers to make the switch?  I have a feeling that is coming sooner rather than later.

AllThingsNeonatal

AllThingsNeonatal

 

Looking for a place to happen

This past week, Canada lost a rock icon in Gord Downie of the Tragically Hip.  My late high school, university and medical school days seem to have him and the band forever enmeshed in memories from that time.  In honour of his passing I thought it suitable to pay tribute to him by using one of the band’s famous song titles as the title for this post.  No this isn’t a post about the band but rather a controversial ventilation strategy.  While CPAP has been around for some time to support our infants after extubation, a new method using high frequency nasal ventilation has arrived and just doesn’t want to go away.  Depending on your viewpoint, maybe it should or maybe it is worth a closer look.  I have written about the modality before in High Frequency Nasal Ventilation: What Are We Waiting For?  While it remains a promising technology questions still remain as to whether it actually delivers as promised. Better CO2 elimination? For those who have used a high frequency oscillator, you would know that it does a marvelous job of removing CO2 from the lungs.  If it does so well when using an endotracheal tube, why wouldn’t it do just as good a job when used in a non-invasive way?   That is the hypothesis that a group of German Neonatologists put forth in their paper this month entitled Non-invasive high-frequency oscillatory ventilation in preterm infants: a randomised controlled crossover trial.  In this relatively small study of 26 preterm infants who were all less than 32 weeks at delivery, babies following extubation or less invasive surfactant application were randomized to either receive nHFOV then CPAP for four hours each or the reverse order for the same duration.  The primary outcome here was reduction in pCO2 with the goal of seeking a difference of 5% or more in favour of nHFOV.  Based on their power calculation they thought they would need 24 infants total and therefore exceeded that number in their enrollment. The babies in both arms were a bit different which may have confounded the results.  The group randomized to CPAP first were larger (mean BW 1083 vs 814g), and there was a much greater proportion of males in the CPAP group.  As well, the group randomized first to CPAP had higher baseline O2 saturation of 95% compared to 92% in the nHFOV group.  Lastly and perhaps most importantly, there was a much higher rate of capillary blood sampling instead of arterial in the CPAP first group (38% vs 15%).  In all cases the numbers are small but when looking for such a small difference in pCO2 and the above mentioned factors tipping the scales one way or the other in terms of illness severity and accuracy of measurement it does give one reason to pause when looking at the results. The Results No difference was found in the mean pCO2 from the two groups.  As expected, pCO2 obtained from capillary blood gases nearly met significance for being higher than arterial samples (50 vs 47; p=0.052).  A similar rate of babies had to drop out of the study (3 on the nCPAP first and 2 on the nHFOV side). In the end should we really be surprised by the results?  I do believe that in the right baby who is about to fail nCPAP a trial of nHFOV may indeed work.  By what means I really don’t understand.  Is it the fact that the mean airway pressure is generally set higher than on nCPAP in some studies?  Could it be the oscillatory vibration being a kind of noxious stimulus that prevents apneic events through irritation of the infant? While traditional invasive HFOV does a marvelous job of clearing out CO2 I have to wonder how the presence of secretions and a nasopharynx that the oscillatory wave has to avoid (almost like a magic wave that takes a 90 degree turn and then moves down the airway) allows much of any of the wave to reach the distal alveoli.  It would be similar to what we know of inhaled steroids being deposited 90 or so percent in the oral cavity and pharynx.  There is just a lot of “stuff” in the way from the nostril to the alveolus. This leads me to my conclusion that if it is pCO2 you are trying to lower, I wouldn’t expect any miracles with nHFOV.  Is it totally useless? I don’t think so but for now as a respiratory modality I think for the time being it will continue to be “looking for a place to happen”

AllThingsNeonatal

AllThingsNeonatal

 

Can a chest x-ray predict the future?

If you work in Neonatology then chances are you have ordered or assisted with obtaining many chest x-rays in your time.  If you look at home many chest x-rays some of our patients get, especially the ones who are with us the longest it can be in the hundreds. I am happy to say the tide though is changing as we move more and more to using other imaging modalities such as ultrasound to replace some instances in which we would have ordered a chest x-ray.  This has been covered before on this site a few times; see Point of Care Ultrasound in the NICU, Reducing Radiation Exposure in Neonates: Replacing Radiographs With Bedside Ultrasound. and Point of Care Ultrasound: Changing Practice For The Better in NICU.This post though is about something altogether different. If you do a test then know what you will do with the result before you order it. If there is one thing I tend to harp on with students it is to think about every test you do before you order it.  If the result is positive how will this help you and if negative what does it tell you as well.  In essence the question is how will this change your current management. If you really can’t think of a good answer to that question then perhaps you should spare the infant the poke or radiation exposure depending on what is being investigated.  When it comes to the baby born before 30 weeks these infants are the ones with the highest risk of developing chronic lung disease.  So many x-rays are done through their course in hospital but usually in response to an event such as an increase in oxygen requirements or a new tube with a position that needs to be identified.  This is all reactionary but what if you could do one x-ray and take action based on the result in a prospective fashion? What an x-ray at 7 days may tell you How many times have you caught yourself looking at an x-ray and saying out loud “looks like evolving chronic lung disease”.  It turns out that Kim et al in their publication Interstitial pneumonia pattern on day 7 chest radiograph predicts bronchopulmonary dysplasia in preterm infants.believe that we can maybe do something proactively with such information. In this study they looked retrospectively at 336 preterm infants weighing less than 1500g and less than 32 weeks at birth.  Armed with the knowledge that many infants who have an early abnormal x-ray early in life who go on to develop BPD, this group decided to test the hypothesis that an x-ray demonstrating a pneumonia like pattern at day 7 of life predicts development of BPD.  The patterns they were looking at are demonstrated in this figure from the paper.  Essentially what the authors noted was that having the worst pattern of the lot predicted the development of later BPD.  The odds ratio was 4.0 with a confidence interval of 1.1 – 14.4 for this marker of BPD.  Moreover, birthweight below 1000g, gestational age < 28 weeks and need for invasive ventilation at 7 days were also linked to the development of the interstitial pneumonia pattern. What do we do with such information? I suppose the paper tells us something that we have really already known for awhile.  Bad lungs early on predict bad lungs at a later date and in particular at 36 weeks giving a diagnosis of BPD.  What this study adds if anything is that one can tell quite early whether they are destined to develop this condition or not.  The issue then is what to do with such information.  The authors suggest that by knowing the x-ray findings this early we can do something about it to perhaps modify the course.  What exactly is that though?  I guess it is possible that we can use steroids postnatally in this cohort and target such infants as this. I am not sure how far ahead this would get us though as if I had to guess I would say that these are the same infants that more often than not are current recipients of dexamethasone. Would another dose of surfactant help?  The evidence for late surfactant isn’t so hot itself so that isn’t likely to offer much in the way of benefit either. In the end the truth is I am not sure if knowing concretely that a patient will develop BPD really offers much in the way of options to modify the outcome at this point.  Having said that the future may well bring the use of stem cells for the treatment of BPD and that is where I think such information might truly be helpful.  Perhaps a screening x-ray at 7 days might help us choose in the future which babies should receive stem cell therapy (should it be proven to work) and which should not.  I am proud to say I had a chance to work with a pioneer in this field of research who may one day cure BPD.  Dr. Thebaud has written many papers of the subject and if you are looking for recent review here is one Stem cell biology and regenerative medicine for neonatal lung diseases.Do I think that this one paper is going to help us eradicate BPD?  I do not but one day this strategy in combination with work such as Dr. Thebaud is doing may lead us to talk about BPD at some point using phrases like “remember when we used to see bad BPD”.  One can only hope.  

AllThingsNeonatal

AllThingsNeonatal

 

Automated control of FiO2; one step closer

It has been over two years since I have written on this subject and it continues to be something that I get excited about whenever a publication comes my way on the topic.  The last time I looked at this topic it was after the publication of a randomized trial comparing in which one arm was provided automated FiO2 adjustments while on ventilatory support and the other by manual change.  Automated adjustments of FiO2. Ready for prime time? In this post I concluded that the technology was promising but like many new strategies needed to be proven in the real world. The study that the post was based on examined a 24 hour period and while the results were indeed impressive it left one wondering whether longer periods of use would demonstrate the same results.  Moreover, one also has to be wary of the Hawthorne Effect whereby the results during a study may be improved simply by being part of a study. The Real World Demonstration So the same group decided to look at this again but in this case did a before and after comparison.  The study looked at a group of preterm infants under 30 weeks gestational age born from May – August 2015 and compared them to August to January 2016.  The change in practice with the implementation of the CLiO2 system with the Avea ventilator occurred in August which allowed two groups to be looked at over a relatively short period of time with staff that would have seen little change before and after.  The study in question is by Van Zanten HA The effect of implementing an automated oxygen control on oxygen saturation in preterm infants. For the study the target range of FiO2 for both time periods was 90 – 95% and the primary outcome was the percentage of time spent in this range.  Secondary outcomes included time with FiO2 at > 95% (Hyperoxemia) and < 90, <85 and < 80% (hypoxemia). Data were collected when infants received respiratory support by the AVEA and onlyincluded for analysis when supplemental oxygen was given, until the infants reached a GA of 32 weeks As you might expect since a computer was controlling the FiO2 using a feedback loop from the saturation monitor it would be a little more accurate and immediate in manipulating FiO2 than a bedside nurse who has many other tasks to manage during the care of an infant.  As such the median saturation was right in the middle of the range at 93% when automated and 94% when manual control was used. Not much difference there but as was seen in the shorter 24 hour study, the distribution around the median was tighter with automation.  Specifically with respect to ranges, hyperoxemia and hypoxemia the following was noted (first number is manual and second comparison automated in each case). Time spent in target range: 48.4 (41.5–56.4)% vs 61.9 (48.5–72.3)%; p<0.01 Hyperoxemia  >95%: 41.9 (30.6–49.4)% vs 19.3 (11.5–24.5)%; p<0.001 < 90%: 8.6 (7.2–11.7)% vs 15.1 (14.0–21.1)%;p<0.0001 < 85%: 2.7 (1.4–4.0)% vs 3.2 (1.8–5.1)%; ns Hypoxemia < 80%: 1.1 (0.4–1.7)% vs 0.9 (0.5–2.1)%; ns What does it all mean? I find it quite interesting that while hyperoxemia is reduced, the incidence of saturations under 90% is increased with automation.  I suspect the answer to this lies in the algorithmic control of the FiO2. With manual control the person at the bedside may turn up a patient (and leave them there a little while) who in particular has quite labile saturations which might explain the tendency towards higher oxygen saturations.  This would have the effect of shifting the curve upwards and likely explains in part why the oxygen saturation median is slightly higher with manual control.  With the algorithm in the CLiO2 there is likely a tendency to respond more gradually to changes in oxygen saturation so as not to overshoot and hyperoxygenate the patient.  For a patient with labile oxygen saturations this would have a similar effect on the bottom end of the range such that patients might be expected to drift a little lower then the target of 90% as the automation corrects for the downward trend.  This is supported by the fact that when you look at what is causing the increase in percentage of time below 90% it really is the category of 85-89%. Is this safe? There will no doubt be people reading this that see the last line and immediately have flashbacks to the SUPPORT trial which created a great deal of stress in the scientific community when the patients in the 85-89% arm of the trial experienced higher than expected mortality.  It remains unclear what the cause of this increased mortality was and in truth in our own unit we accept 88 – 92% as an acceptable range.  I have no doubt there are units that in an attempt to lessen the rate of ROP may allow saturations to drop as low as 85% so I continue to think this strategy of using automation is a viable one. For now the issue is one of a ventilator that is capable of doing this.  If not for the ventilated patient at least for patients on CPAP.  In our centre we don’t use the Avea model so that system is out.  With the system we use for ventilation there is also no option.  We are anxiously awaiting the availability of an automated system for our CPAP device.  I hope to be able to share our own experience positively when that comes to the market.  From my standpoint there is enough to do at the bedside.  Having a reliable system to control the FiO2 and minimize oxidative stress is something that may make a real difference for the babies we care for and is something I am eager to see.

AllThingsNeonatal

AllThingsNeonatal

 

Maybe we shouldn’t be in such a rush to stop caffeine.

Given that many preterm infants as they near term equivalent age are ready to go home it is common practice to discontinue caffeine sometime between 33-34 weeks PMA.  We do this as we try to time the readiness for discharge in terms of feeding, to the desire to see how infants fare off caffeine.  In general, most units I believe try to send babies home without caffeine so we do our best to judge the right timing in stopping this medication.  After a period of 5-7 days we generally declare the infant safe to be off caffeine and then move on to other issues preventing them from going home to their families.  This strategy generally works well for those infants who are born at later gestations but as Rhein LM et al demonstrated in their paper Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial., after caffeine is stopped, the number of intermittent hypoxic (IH) events are not trivial between 35-39 weeks.  Caffeine it would seem may still offer some benefit to those infants who seem otherwise ready to discontinue the medication.  What the authors noted in this randomized controlled trial was that the difference caffeine made when continued past 34 weeks was limited to reducing these IH events only from 35-36 weeks but the effect didn’t last past that.  Why might that have been?  Well it could be that the babies after 36 weeks don’t have enough events to really show a difference or it could be that the dose of caffeine isn’t enough by that point.  The latter may well be the case as the metabolism of caffeine ramps up during later gestations and changes from a half life greater than a day in the smallest infants to many hours closer to term.  Maybe the caffeine just clears faster? Follow-up Study attempts to answer that very question. Recognizing the possibility that levels of caffeine were falling too low after 36 weeks the authors of the previous study begun anew to ask the same question but this time looking at caffeine levels in saliva to ensure that sufficient levels were obtained to demonstrate a difference in the outcome of frequency of IH.  In this study, they compared the original cohort of patients who did not receive caffeine after planned discontinuation (N=53) to 27 infants who were randomized to one of two caffeine treatments once the decision to stop caffeine was made.  Until 36 weeks PMA each patient was given a standard 10 mg/kg of caffeine case and then randomized to two different strategies.  The two dosing strategies were 14 mg/kg of caffeine citrate (equals 7 mg/kg of caffeine base) vs 20 mg/kg (10 mg/kg caffeine base) which both started once the patient reached 36 weeks in anticipation of increased clearance.  Salivary caffeine levels were measured just prior to stopping the usual dose of caffeine and then one week after starting 10 mg/kg dosing and then at 37 and 38 weeks respectively on the higher dosing.  Adequate serum levels are understood to be > 20 mcg/ml and salivary and plasma concentrations have been shown to have a high level of agreement previously so salivary measurement seems like a good approach.  Given that it was a small study it is work noting that the average age of the group that did not receive caffeine was 29.1 weeks compared to the caffeine groups at 27.9 weeks.  This becomes important in the context of the results in that earlier gestational age patients would be expected to have more apnea which is not what was observed suggesting a beneficial effect of caffeine even at this later gestational age.  Each patient was to be monitored with an oximeter until 40 weeks as per unit guidelines. So does caffeine make a difference once term gestation is reached? A total of 32 infants were enrolled with 12 infants receiving the 14 mg/kg and 14 the 20 mg/kg dosing.  All infants irrespective of assigned group had caffeine concentrations above 20 mcg/mL ensuring that a therapeutic dose had been received.  The intent had been to look at babies out to 40 weeks with pulse oximetry even when discharged but owing to drop off in compliance with monitoring for a minimum of 10 hours per PMA week the analysis was restricted to infants at 37 and 38 weeks which still meant extension past 36 weeks as had been looked at already in the previous study.  The design of this study then compared infants receiving known therapeutic dosing at this GA range with a previous cohort from the last study that did not receive caffeine after clinicians had determined it was no longer needed. The outcomes here were measured in seconds per 24 hours of intermittent hypoxia (An IH event was defined as a decrease in SaO2 by ⩾ 10% from baseline and lasting for ⩾5 s).  For graphical purposes the authors chose to display the number of seconds oxygen saturation fell below 90% per day and grouped the two caffeine patients together given that the salivary levels in both were therapeutic.  As shown a significant difference in events was seen at all gestational ages. Putting it into context The scale used I find interesting and I can’t help but wonder if it was done intentionally to provide impact.  The outcome here is measured in seconds and when you are speaking about a mean of 1200 vs 600 seconds it sounds very dramatic but changing that into minutes you are talking about 20 vs 10 minutes a day.  Even allowing for the interquartile ranges it really is not more than 50 minutes of saturation less than 90% at 36 weeks.  The difference of course as you increase in gestation becomes less as well.  When looking at the amount of time spent under 80% for the groups at the three different gestational ages there is still a difference but the amount of time at 36, 27 and 38 weeks was 229, 118 and 84 seconds respectively without caffeine (about 4, 2 and 1 minute per day respectively) vs 83, 41, and 22 seconds in the caffeine groups. I can’t help but think this is a case of statistical significance with questionable clinical significance.  The authors don’t indicate that any patients were readmitted with “blue spells” who were being monitored at home which then leaves the sole question in my mind being “Do these brief periods of hypoxemia matter?”  In the absence of a long-term follow-up study I would have to say I don’t know but while I have always been a fan of caffeine I am just not sure. Should we be in a rush to stop caffeine?  Well, given that the long term results of the CAP study suggest the drug is safe in the preterm population I would suggest there is no reason to be concerned about continuing caffeine a little longer. If the goal is getting patients home and discharging on caffeine is something you are comfortable with then continuing past 35 weeks is something that may have clinical impact.  At the very least I remain comfortable in my own practice of not being in a rush to stop this medication and on occasion sending a patient home with it as well.    

AllThingsNeonatal

AllThingsNeonatal

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