AllThingsNeonatal

To be sure there are fans of both HFNC and CPAP out there. I have often heard from other Neonatologists that they use HFNC and find positive results while other centres refuse to use it in favour of the tried and true CPAP. Turning to the literature you will find some conflicting results with some studies suggesting equity and others more recently favouring CPAP. There has been speculation as to why one would be superior to the other and now we appear to have some answers as to where the differences lie. A Physiologic Study Liew et al published Physiological effects of high-flow nasal cannula therapy in preterm infants this month in an elegant study of 40 infants. The study was fairly simple in design either randomizing infants <37 weeks to starting with nCPAP +6 and then transitioning to 8 l/min HFNC followed by stepwise reductions of 1 l/min until 2 l/min was reached or the reverse, starting with 2 l/min and working their way up and then transitioning to nCPAP+6. All infants were on one or the other modality at the start and were all at least 3 days old, they were randomized to one or the other arm regardless of where they started off. Physiologic measurements were taken at each step including the following: Mv -Minute ventilation pEEP – nasopharyngeal end-expiratory pressure pEECO2 -nasopharyngeal end-expiratory CO2 RR – respiratory rate; SpO2 – oxygen saturation TCCO2 – transcutaneous CO2 Vt – tidal volume A Fabian device was used to deliver either HFNC or CPAP at the different flows for all patients. The Results The authors certainly found some interesting results that I think shed some light on why comparisons of HFNC and CPAP have been so inconsistent. Table 2 contains the results of the study and I will point out the main findings below. 1. Flow matters – Compared to nCPAP+6 which is fairly consistent flows below 6 l/min deliver pEEP that is below 6 cm H2O. 2. Keep the mouth shut – With CPAP whether the mouth is open or closed the Fabian device delivers +6 cm H2O. As you can see from the table, when the mouth is open transmitted pressures drop off substantially. The infant put on a flow of even 6-8 l/min of HFNC sees pressures less than +6 consistently. 3. As flows increase end expiratory CO2 decreases. HFNC seems to help wash out CO2 4. Low flow rates on HFNC do not seem to help with ventilation as much as higher flow rates. In order to maintain Mv these infants at 2 l/min flow become tachypneic. The low pressures produced likely cause some atelectasis and hence tachypnea. Size matters! Beware of excessive pressures. An additional finding of this study was that on “multiple linear regression, flow rate, mouth position, current weight and gestation but not prong-to-nares ratio significantly predicted pEEP and account for a significant amount of its variance (F(4431)=143.768, p<0.0001), R2=0.572, R2=adjusted 0.568).” Essentially, infants under 1000g in particular could see pEEP levels as high as 13 cm H2O with flows of 8 l/min. The variability in transmitted pressures with HFNC is shown nicely in this figure from the study. As flows increase above 6 l/min the actual pressures delivered become less reliable. Conclusions Looking at this data, it becomes evident why HFNC may be failing in its attempt to dethrone nCPAP. In order to achieve higher pressures and provide comparable distending pressure to nCPAP you need higher flows. With higher flows though come the problem of greater variability in delivered pressure. While the average pressure delivered may be equivalent or even higher than a CPAP of +6, in some infants (especially those below 1000g) one may be delivering significantly higher pressures than intended which may help with oxygenation and preventing intubation but others may be seeing far less than needed. What it comes down to is that nCPAP is better at delivering a consistent amount of pressure. Studies using lower flows of HFNC likely failed to show superiority to CPAP as they just didn’t deliver enough pressure. An example of this was the study by Roberts CT et al Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants, in which flows of 6-8 l/min were used. Other studies using higher pressures could have been problematic due to open mouths, or larger babies not receiving as much benefit. I am not saying that we should throw out HFNC entirely however. Depending on the unit you practice in you might not be able to use CPAP but HFNC may be allowed. If you had to choose between no support or HFNC I would likely go with the HFNC. For me at least, if I want to delivery reliable pressures in my tertiary care NICU I will be calling for the CPAP.

I have written about non-traditional methods of providing surfactant to newborns previously. The practice of intubating a preterm infant to administer surfactant and leaving the endotracheal tube in with a slow wean of ventilation is mostly a thing of the past (at least in my units). Strategies have evolved and have seen the development of the INSURE technique, LISA methods, use of an LMA to delivery surfactant and even simple deposition into the pharynx all with variable success. The Holy Grail To me at least, the Holy Grail of surfactant delivery has been aerosolization. A small non randomized study was done in by Finer et al in 2010 An open label, pilot study of Aerosurf® combined with nCPAP to prevent RDS in preterm neonates. This study noted a reduction in CPAP failure with nebulized surfactant but as a pilot was not large enough to move the needle. Since then the Cochrane group weighed in and declared that there was not enough evidence to support the practice. The CureNeb group anchored by Dr. Pillow though has now published a double blind RCT entitled Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomized controlled trial. It certainly sounds interesting and might help determine if the needle has indeed moved. The Study Poractant alfa at 200 mg/kg was used in this study and delivered via aerosolization using a vibrating membrane called the eFlow. The authors chose to look at infants from 29 0/7 to 33 6/7 weeks at birth and stratified them into two groups of 29 0/7 to 31 6/7 and 32 0/7 to 33 6/7 weeks. They estimated a need for 70 babies based on an anticipated failure rate of 30% in the control group vs 5% in the treatment group. Unfortunately, due to several reasons the study was only able to recruit 64 babies for randomization before being stopped due to the recruitment issues. The design of the study included adequate blinding with a sham procedure and there were predefined “failure criteria” necessitating intubation at the outset of the study. These criteria are acceptable to me as they are similar enough to my own practice and were: 1. FiO2 >0.35 over more than 30 min OR FiO2 >0.45 at anytime. 2. More than four apnoeas/hour OR two apnoeas requiring bag and mask ventilation. 3. Two capillary blood gas samples with a pH <7.2 and partial pressure of carbon dioxide >65 mm Hg (or partial pressure of carbon dioxide in arterial blood (PaCO2) >60 mm Hg if arterial blood gas sample). 4. Intubation deemed necessary by the attending physician. What did they find? The primary outcome CPAP failure within 72 hours of birth was indeed different in the two groups. CPAP failure by 72 hours CPAP + surfactant 11/32 (34%) CPAP 22/32 (69%) (RR (95% CI)=0.526 (0.292 to 0.950)) Clearly the event rates were quite off from what they expected in the power calculation but given that they found a difference as opposed to no difference at all the fact that they didn’t recruit the numbers they planned is of less importance. However, what is interesting is when they looked at the planned analysis by stratification an interesting finding emerged. Group 1 (29 0/7 to 31 6/7) CPAP failure by 72 hours CPAP + surfactant 12/21 (57%) CPAP 12/19 (63%) (RR (95% CI)=0.860 (0.389 to 1.90)) Group 2 (32 0/7 to 33 6/7 CPAP failure by 72 hours CPAP + surfactant 1/11 (9%) CPAP 10/13 (77%) (RR (95% CI)=0.254 (0.089 to 0.727)) There were a number of secondary outcomes looked at as well which may be of interest to you but as the numbers here are quite small I will not comment other than to say there was no increased incidence of complications with surfactant administration in this fashion. Also for those who ultimately failed CPAP the time when they did so was quite delayed compared to CPAP alone. Age at intubation for nCPAP failure, hours 4.9 (2.7–10.6) 11.6 (9.0–31.1) 0.008* What can we take from this? I believe these results are encouraging even if the study is a small one. The message I take from this study is that aerosolization of surfactant delivers some amount of product to the lungs. Those with more significant RDS or smaller lungs (those in the 29 0/7 to 31 6/7 group) may not get enough surfactant to treat their RDS sufficiently to avoid intubation. Those with less significant RDS or a larger number of alveoli get “enough” of a dose delivered to the alveoli to make a difference and avoid intubation. It is worth stressing that there can be no specific comment about using this strategy in even more immature infants as they weren’t tested. If I had to guess though, I would expect no difference given the findings in the smaller group. As a physician responsible for transport though I am interested in the potential benefits to those born in non-tertiary centres. Many centres lack individuals with the confidence and skill to regularly place endotracheal tubes. For these centres it may be that providing nebulized surfactant could delay the time to treatment failure, allowing more time for a trained transport team to arrive. Training of course would be needed in these centres on how to administer surfactant in this way but it is an interesting concept to consider. With a near tripling of the average time to treatment failure the extra hours on CPAP would be much appreciated when weather delays or difficulty securing air assets means long delays in transport team arrivals. To be sure this isn’t the last study of this kind but it certainly is an interesting start and one that will no doubt produce questions that will help formulate the next study design.

Just about all of our preterm infants born at <29 weeks start life out the same in terms of neurological injury. There are of course some infants who may have suffered ischemic injury in utero or an IVH but most are born with their story yet to be told. I think intuitively we have known for some time that the way we resuscitate matters. Establishing an FRC by inflating the lungs of these infants after delivery is a must but as the saying goes the devil is in the details. The Edmonton group led by Dr. Schmolzer has had several papers examined in these blogs and on this occasion I am reviewing an important paper that really is a follow-up study to a previous one looking at the impact of high tidal volume delivery after birth. I have written on this previous paper before in It's possibile! Resuscitation with volume ventilation after delivery. On this occasion the authors have 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 observational study had a simple enough premise. Will the use of Vt > 6 mL/kg in infants given PPV for at least two minutes lead to worse rates of IVH? All infants were < 29 weeks and if they had chest compressions or epinephrine were excluded. All infants were treated equally in terms of delayed cord clamping and antenatal steroid provision. Ventilation was done with a t-piece resuscitator and Vt measured with an NM3 monitor connected to the face mask. First ultrasounds were done for all at 3 days of age. What did the authors find? One hundred and sixty five infants comprised this cohort. Overall, 124 (75%) infants were in the high volume group compared to 41 (25%) with a mean VT<6 mL/kg. Median Vt were 5.3 (4.6-5.7) ml/kg for the low group and 8.7(7.3-10.6) mL/kg which were significantly different. When looking at the rates of IVH and the severity of those affected the results are striking as shown in the table. Hydrocephalus, following IVH developed in 7/49 (14%) and 2/16 (13%) in the >6 mL/kg and <6 mL/kg VT groups. Looking at other factors that could affect the outcome of interest the authors noted the following physiologic findings. Oxygen saturations were lower in the low volume group at 6, 13 and 14 min after birth while tissue oxygenation as measured by NIRS was similarly lower at 7,8 and 25 min after birth (P<0.001). Conversely, heart rate was significantly lower in the VT>6 mL/kg group at 5, 20 and 25 min after birth (P<0.001). Fraction of inspired oxygen was similar in both groups within the first 30 min. Systolic, diastolic and mean blood pressure was similar between the groups. What these results say to me is that despite having lower oxygen saturations and cerebral oxygen saturation at various time points in the first 25 minutes of life the infants seem to be better off given that HR was lower in those given higher volumes despite similar FiO2. Rates of volume support after admission were slightly higher in the high volume group but inotrope usage appears to be not significantly different. Prophylactic indomethacin was used equally in the two cohorts. Thoughts for the future Once a preterm infant is admitted to the NICU we start volume targeted ventilation from the start. In the delivery room we may think that we do the same by putting such infants on a volume guarantee mode after intubation but the period prior to that is generally done with a bag and mask. Whether you use a t-piece resuscitator or an anesthesia bag or even a self inflating bag, you are using a pressure and hoping not to overdistend the alveoli. What I think this study demonstrates similar to the previous work by this group is that there is another way. If we are so concerned about volutrauma in the NICU then why should we feel any differently about the first few minutes of life. Impairment of venous return from the head is likely to account for a higher risk of IVH and while a larger study may be wished for, the results here are fairly dramatic. Turning the question around, one could ask if there is harm in using a volume targeted strategy in the delivery room? I think we would be hard pressed to say that keeping the volumes under 6 mL/kg is a bad idea. The challenge as I see it now is whether we rig up devices to accomplish this or do the large medical equipment providers develop an all in one system to accomplish this? I think the time has come to do so and will be first in line to try it out if there is a possibility to do a trial.

We have all been there. After an uneventful pregnancy a mother presents to the labour floor in active labour. The families world is turned upside down and she goes on to deliver an infant at 27 weeks. If the infant is well and receives minimal resuscitation and is on CPAP we provide reassurance and have an optimistic tone. If however their infant is born apneic and bradycardic and goes on to receive chest compressions +/- epinephrine what do we tell them? This infant obviously is much sicker after delivery and when the family asks you “will my baby be ok?” what do you tell them? It is a human tendency to want to reassure and support but if they ask you what the chances are of a good outcome it has always been hard to estimate. What many of us would default to is making an assumption that the need for CPR at a time when the brain is so fragile may lead to bleeding or ischemia would lead to worse outcomes. You would mostly be right. One study by Finer et al entitled Intact survival in extremely low birth weight infants after delivery room resuscitation.demonstrated that survival for infants under 750g was better if they had a history of CPR after delivery. The thought here is that more aggressive resusctiation might be responsible for the better outcome by I would presume establishing adequate circulation sooner even if the neonates did not appear to need it immediately. The Canadian Neonatal Network In Canada we are fortunate to have a wonderful network called the Canadian Neonatal Network. So many questions have been answered by examining this rich database of NICUs across the county. Using this database the following paper was just published by Dr. A. Lodha and others; Extensive cardiopulmonary resuscitation of preterm neonates at birth and mortality and developmental outcomes. The paper asked a very specific and answerable question from the database. For infants born at <29 weeks gestational age who require extensive resuscitation (chest compressions, epinephrine or both) what is the likelihood of survival and/or neurodevelopmental impairment (NDI) at 18-24 months of age vs those that did not undergo such resuscitation? For NDI, the authors used a fairly standard definition as “any cerebral palsy (GMFCS1), Bayley-III score <85 on one or more of the cognitive, motor or language composite scores, sensorineural or mixed hearing impairment or unilateral or bilateral visual impairment.” Their secondary outcomes were significant neurodevelopmental impairment (sNDI), mortality, a Bayley-III score of <85 on any one of the components (cognitive, language, motor), sensorineural or mixed hearing loss,or visual impairment.sNDI was defined as the presence of one or more of the following: cerebral palsy with GMFCS 3, Bayley-III cognitive, language or motor composite score <70, hearing impairment requiring hearing aids or cochlear implant, or bilateral visual impairment” What did they discover? It is a fortunate thing that the database is so large as when you are looking at something like this the number of infants requiring extensive resuscitation is expected to be small. The authors collected data from January 1, 2010 and September 30, 2011 and had a total number of infants born at less than 29 weeks of 2760. After excluding those with congenital anomalies and those who were born moribund they were left with 2587. From these 80% had follow-up data and when applying the final filter of extensive resuscitation they were left with 190 (9.2%) who received delivery room CPR (DR-CPR) vs 1545 who did not receive this. Before delving into the actual outcomes it is important to note that neonates who did not receive DR-CPR were more likely to be born to mothers with hypertension and to have received antenatal steroids (89 vs 75%). With these caveats it is pretty clear that as opposed to the earlier study showing better outcomes after DR-CPR this was not the case here. The results are interesting in that it is pretty clear that receiving DR-CPR is not without consequence (higher rate of seizures, severe neurological injury, BPD). Looking at the longer term outcomes though is where things get a little more interesting. Mortality and mortality or neurodevelopmental impairment are statistically significant with respect to increased risk. When you take out NDI alone however the CI crosses one and is no longer significant. Neither is CP for that matter with the only statistically significant difference being the Bayley-III Motor composite score <85. The fact that only this one finding came out as significant at least to me raises the possibility that this could have been brought about by chance. It would seem that while these infants are at risk of some serious issues their brains in the long run may be benefiting for the neurological plasticity that we know these infants have. The study is remarkable to me in that an infant can have such a difficult start to life yet hope may remain even after dealing with some of the trials and tribulations of the NICU. Parents may need to wade through the troubling times of seizures, long term ventilation and CPAP and then onto a diagosis of BPD but their brains may be ok after all. This is one of the reasons I love what I do!

The metabolic syndrome describes the development as an adult of centripetal obesity, high blood pressure, high triglycerides, elevated blood sugar and low HDL cholesterol. These constellation of problems significantly increase the risk of cardiovascular disease, stroke and diabetes. The origins of this syndrome may begin in the newborn period as previous research has noted an association with infants who are born SGA and development of insulin resistance later in life as in the paper Insulin resistance in young adults born small for gestational age (SGA). A relationship to the metabolic syndrome has been also noted in the paper Small for gestational age and obesity related comorbidities. The theory here is that conditions in utero in which the fetus is chronically deprived of blood flow and nutrition lead to a tendency towards insulin resistance. The body is essentially trying to use any energy it is receiving to stay alive in an environment in which resources are scarce. Given that situation, resisting the effects of insulin by preventing storage of this needed energy serves a useful purpose but in the long run may be detrimental as the body become programmed to resist the effects of this hormone. What if this programming could be overcome? Breast milk certainly has many incredible properties and as we learn more we discover only more applications. My previous post on putting breast milk in the nasal cavity is just one such example (Can intranasal application of breastmilk cure severe IVH?). In 2019 Dr. Hair and Abram's group looked at this with respect to insulin resistance and with potential extrapolation to the metabolic syndrome in their paper Premature small for gestational age infants fed an exclusive human milk-based diet achieve catch-up growth without metabolic consequences at 2 years of age. Texas Children's Hospital uses an exclusive human milk diet for premature infants with the following criteria GA of <37 weeks, BW of ≤1250 g, with the diet maintained until approximately 34 weeks PMA. Exclusive human milk is provided through a combination of mother's own milk and Prolacta instead of a bovine based human milk fortifier. In this study they were able to prospectively track 51 preterm infants of which 33 were AGA and 18 SGA. The first visit (visit 1) was performed at 12–15 months CGA and the second visit (visit 2) was at 18–22 months CGA. The question at hand was whether these children would experience catch up growth at 2 years of age and secondly what their levels of insulin might look like at these times. Higher insulin levels might correlate with levels of insulin resistance with higher levels being needed to maintain euglycemia. As a measure of insuline resistance the authors used the calculation of the Non-fasting homeostatic model of assessment-insulin resistance (HOMA-IR) = (insulin × glucose)/22.5 which has been validated elsewhere. Protein intakes were equal for both groups at about 4 g/kg of human milk protein. The Results Please The SGA group had greater weight gain between visit 1 and 2 as evidenced by a significant difference in the change in BMI z-score, AGA −0.21±0.84 vs.SGA 0.25±1.10. I suppose this isn't too shocking as we know that many babies born SGA experience catch up growth after discharge. What is surprising and once again speaks to the power of breast milk is the impact observed on insulin levels and resistance to the same as measured by the HOMA-IR (AGA babies are the left column and SGA the right). The adjusted p vlaues for glucose were 0.06 with insulin and HOMA-IR being 0.02. What does this mean? Well, these are not fasting insulin levels which would be ideal but what it does say is that at fairly comparable glucose levels the level of insulin is higher in former AGA babies and the level of insulin resistance lower in the SGA infants! This result is quite the opposite of what previous studies have shown as referenced above. Aren't these growth restricted infants supposed to have had insulin resistance in utero and been programmed for life to have insulin resistance and as adults develop the metabolic syndrome? This study falls short of making any claims about the latter as these infants are only two years of age. What this study provides though is certainly a raised eyebrow. There will be those of course that look at the size of the study and dismiss it as being too small but at the very least this study will lead to further work in this area. This paper though adds to the mystery around the potential impacts of breast milk and certainly provides strength to the thought that perhaps breastmilk should be the exclusive source of nutrition for preterm infants in the NICU. While I understand that not all women are able to produce enough for their own infants or may choose not to for a variety of reasons, with access to donor milk supply this could become a reality. The cost savings to the health care system by preventing insulin resistance would be many fold greater than the cost of donor milk in the newborn period. Another intriguing question will be whether use of an exclusive human milk diet with use of only mother's own milk will have similar effects or even greater impact on glucose homestasis later in life. I think the authors are to be commended for their dedication to work in this field and I certainly look forward to the next publication from this group.

Recently the practice of keeping ELBW infants with a midline head position for the first three days of life has been recommended to reduce IVH as part of a bundle in many units. The evidence that this helps to reduce IVH has been somewhat circumstantial thus far. Studies finding that decreased sagittal sinus blood flow, increased cerebral blood volume with increased intracranial pressure all occur after head turns would theoretically increase the risk of IVH. Raising the head of the bed would help in theory with drainage of the venous blood from the head and in fact systemic oxygenation has been shown to improve with such positioning. This presumably is related to increased cardiac output from better systemic venous return. Bringing it to the bedside Interestingly, some of the above studies are from over thirty years ago. We now have some evidence to look at involving this practice. Kochan M et al published Elevated midline head positioning of extremely low birth weight infants: effects on cardiopulmonary function and the incidence of periventricular-intraventricular. The study involved maintaining ELBW infants in an elevated midline head position (ELEV- supine, head of bed elevated 30 degrees, head kept in midline) versus standard head positioning (FLAT–flat supine, head turned 180 degrees every 4 h) during the first 4 days of life to see if this would decrease in the incidence of IVH. Ninety infants were randomized into both arms of the study. In terms of baseline characteristics, BW of 725g in the FLAT vs 739 in ELEV were comparable as well as GA both at 25 weeks. Two differences on the maternal side existed of 40% ELEV vs 24.4% FLAT of mothers having preeclampsia and 23.3% FLAT vs 10% ELEV having prolonged rupture of membranes both of which were statistically significant. What did they find? Ultrasounds were performed at entry into the study and then daily for days 1-4 and then on day 7 with abnormal scans repeated weekly. In terms of IVH the authors noted no overall difference in rate of IVH. What they did find however was a statistically significant reduction in the rate of Grade IV IVH.The p value for the finding of lower rates of Grade IV IVH was 0.036 so not strikingly significant but different nonetheless. Given that the venous drainage of the head is also dependent on the resistance to flow from the pressure in the thorax one can’t infer that the intervention alone is responsible for this without ensuring that that respiratory findings are similar as well. Similarly without knowing inflow of blood into the head as measured by blood pressure it is difficult to say that the reduction in IVH isn’t related to differences in blood pressure. The authors helpfully looked at both of these things. For those infants on high frequency ventilation the mean airway pressure was higher on day one being 11.5 cm H2O (FLAT) vs 9.9 cm H2O (ELEV) neither of which are high although different. The rest of the three days were no different. For those on conventional ventilation the only difference was on day 4 where the MAP was higher for ELEV at 8 vs 7.4 cm H2O which again is fairly mild. Interestingly, as was found in other studies that oxygenation was improved with elevation of the head, the maximum FiO2 for the two groups was different on day 1 being 46% in the FLAT vs 37.5% in the ELEV. Looking at the hemodynamic side of things there were differences in the lowest mean BP recorded on day 1 and 3 but otherwise the groups were similar. It would have been nice to see mean results during this time rather than lowest but this is what we have. In terms of complications of preterm birth there were no differences found in rates of sepsis (important given the increase rate of prolonged rupture in the FLAT group), NEC or ROP. Although length of stay was no different 92 vs 109 days ELEV (NS), survival to discharge was at 88% vs 76% (p=0.033) which also may explain the longer length of stay. What Can We Learn From This Don’t worry. I am not about to throw the results out. There are a couple observations though that need to be addressed. The first is the increased rate of preecampsia in the ELEV group. This finding could have impacted the results. We know that fetuses exposed to this condition are stressed and are often born with better lungs than their non-exposed counterparts. The endogenous increase in steroids due to this stress is attributable and may explain the better oxygenation and lower mean airway pressures needed in the ELEV group rather than improvements in flow alone from positioning. The second issue is adherence to the protocol as there were some infants in the ELEV group who were placed flat for the final 1-2 days of the study. Having said that, this would serve to dilute the effect rather than strengthen it so perhaps it makes the results more believable. So where does this leave us? This study demonstrates improved survival and a reduction in Grade IV IVH without an overall reduction in IVH. There was nothing found to suggest that the intervention is harmful. Given the background studies demonstrating improved systemic oxygenation, reductions in ICP and cerebral blood volume the finding of reduced severe IVH seems plausible to me. This could be a practice changing study for some units who have perhaps only adopted midline positioning in the first few days of life. It will be interesting to see if this takes off but is certainly worth a good look at.

Choosing to provide postnatal systemic steroids to preterm infants for treatment of evolving BPD has given many to pause before choosing to administer them. Ever since K Barrington published his systematic review The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. and found a 186% increase in risk of CP among those who received these treatments, efforts have been made to minimize risk when these are given. Such efforts have included shortening the exposure from the length 42 day courses and also decreasing the cumulative dose of dexamethasone. Fortunately these efforts have led to findings that these two approaches have not been associated with adverse neurodevelopmental outcomes. Having said that, I doubt there is a Neonatologist that still doesn’t at least think about long term outcome when deciding to give dexamethasone. The systemic application certainly will have effects on the lung but the circulating steroid in the brain is what occupies our thoughts. What About Applying it Directly to the Lung If you wanted to prevent BPD the way to do it would be to minimize the time infants are exposed to positive pressure ventilation. Rather than giving steroids after a week or two maybe it would be best to give them early. Recent evidence supports this for systemic steroids and has been written about recently. Hydrocortisone after birth may benefit the smallest preemies the most! This still involves providing steroid systemically. Over the years, inhaled steroids have been tried as have intratracheal instillation of steroid with and without surfactant as a vehicle for distribution to the lung. This month colleagues of mine anchored by Dr. G. t’Jong (a founding member of the “Tall Men of Pediatrics #TMOP) published a systematic review and meta-analysis of all such RCTs in their paper Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and metaanalysis. The results of the study suggest that there may well be a role for this approach. All of the included studies used a prophylactic approach of giving between the first 4 hours and the 14th day of postnatal age doses of pulmonary steroids with the goal of preventing death or BPD. The GA of enrolled infants ranged from 26 to 34 weeks, and the birth weight ranged from 801 to 1591 g. Out of 870 possible articles only 12 made the cut and compromised the data for the analysis. Routes of steroid were by inhalation, liquid instillation though the endotracheal tube or by mixing in surfactant and administering through the ETT. What Did They Find? Using 36 weeks corrected age as a time point for BPD or death, the forrest plot demonstrated the following. A reduction in risk of BPD or death of 15% with a range of 24% to only a 4% reduction. Looking at the method of administration though is where I find things get particularly interesting. What this demonstrates is that how you give the steroids matters. If you use the inhalational or intratracheal instillation (without a vehicle to distribute the steroids) there is no benefit in reduction of BPD or death. If however you use a vehicle (in both Yeh studies it was surfactant) you find a significant reduction in this outcome. In fact if you just look at the studies by Yeh the reduction is 36% (CI 34 – 47%). In terms of reduction of risk these are big numbers. So big one needs to question if the numbers are real in the long run. Why might this work though? In the larger study by Yeh, budesonide was mixed with surfactant and delivered to intubated infants every 8 hours until FiO2 was less than 30%, they were extubated or a maximum of 6 doses were reached. We know that surfactant spreads throughout the lung very nicely so it stands to reason that the budesonide could have been delivered evenly throughout the lung. Compare this with inhalational steroid that most likely winds up on the plastic tubing or proximal airway. The anti-inflammatory nature of steroids should decrease damage in the distal airways offsetting the effects of positive pressure ventilation. Future Directions I am excited by these findings (if you couldn’t tell). What we don’t know though is whether the belief that the steroid stays in the lung is true. Are we just making ourselves feel better by believing that the steroid won’t be absorbed and move systemically. This needs to be tested and I believe results of such testing will be along in the near future. Secondly, we need a bigger study or at least another to add to the body of research being done. Such a study will also need long term follow-up to determine if this strategy does at least have equal neurodevelopmental outcomes to the children who don’t receive steroid. The meta-analysis above does show in a handful of studies that long term outcome was no different but given the history of steroids here I suspect we will need exceptionally strong evidence to see this practice go mainstream. What I do believe is whether you choose to use steroids prophylactically using hydrocortisone or using intratracheal surfactant delivered budesonide, we will see one or both of these strategies eventually utilized in NICUs before long.

The medical term for this is placentophagy and it is a real thing. If you follow the lay press you may have seen that originally this was promoted by Kourtney Kardashian who did this herself and then by Kim who planned on doing the same after delivery. See Did Kourtney Kardashian Eat Her Placenta? This is not completely without basis as many readers will be thinking already that they have heard about the health benefits of doing the same. Reports of improved mood and reductions in the baby blues following ingestion of placenta as well as improvements in breast milk production have led to this growing practice. The evidence for this up until recently though was quite old and fraught with poorly design of such studies. The bigger driver however has been word of mouth as many women having heard about the promises of better mood at the very least have thought “why not? Can’t hurt.” What I will do in this post is run through a little background and a few recent studies that have shed some light on how likely this is to actually work. Where did the idea come from? Animals eat their placentas after delivery. It turns out that unprocessed placenta is quite high in the hormone prolactin which is instrumental for breastfeeding. Given the large amount of this hormone as well as the number of other hormones present in such tissue it was thought that the same benefits would be found in humans. Eating unprocessed human tissue whether it is put in a capsule or not is unwise as unwanted bacteria can be consumed. In fact, a case of GBS sepsis has been linked to such a practice in which the source of the GBS was thought to be due to contaminated unprocessed maternal placenta that had been ingested. Buser GL, Mat´o S, Zhang AY, Metcalf BJ, Beall B, Thomas AR. Notes from the field: Late-onset infant group B streptococcus infection associated with maternal consumption of capsules containing dehydrated placenta. What happens when you process placenta by steaming and drying? This would be the most common way of getting it into capsules. This process which renders it safe to consume may have significant effects on reducing hormonal levels.This was found in a recent study that measured oxytocin and human placental lactogen (both involved positively in lactation) and found reductions in both of 99.5% and 89.2%, respectively compared versus raw placenta. I would assume that other hormones would be similarly affected so how much prolactin might actually wind up in these capsules after all? Clinical Randomized Double Blind Controlled Trial Twenty seven women from Las Vegas were recruited into a pilot trial (12 beef placebo vs 15 steamed and dried placenta) with the authors examining three different outcomes across three studies. The first study Effects of placentophagy on maternal salivary hormones: A pilot trial, part 1 looked at a large number of salivary hormones at four time points. Plasma samples were taken as well to determine the volume of distribution of the same. First samples were at week 36 of gestation then within 4 days (96 h) of birth followed by days 5–7 (120–168 h) postpartum and finally Days 21–27 (504–648 h) postpartum. All consumption of capsules was done in the home as was collection of samples. As per the authors in terms of consumption it was as follows “two 550 mg capsules three times daily for the first 4 days; two 550 mg capsules twice daily on days 5 through 12, and then to decrease the dose to two 550 mg capsules once daily for the remainder of the study (days 13 through approximately day 20 of supplementation). Outcomes No difference was found between salivary concentrations of hormones at any time point other than that with time they declined following birth. Curiously the volume of distribution of the hormones in serum was slightly higher in the placenta capsule groups but not enough to influence the salivary concentrations. It was felt moreover that the amount of incremental hormone level found in the serum was unlikely to lead to any clinical response. The second study was on mood Placentophagy’s effects on mood, bonding, and fatigue: A pilot trial, part 2. Overall there were no differences for the groups but they did find “some evidence of a decrease in depressive symptoms within the placenta group but not the placebo group, and reduced fatigue in placenta group participants at the end of the study compared to the placebo group.” The last paper published from the same cohort is Ingestion of Steamed and Dehydrated Placenta Capsules Does Not Affect Postpartum Plasma Prolactin Levels or Neonatal Weight Gain: Results from a Randomized, Double-Bind, Placebo-Controlled Pilot Study. This study specifically addressed the issue of prolactin levels and found no difference between the groups. Neonatal weight gain was used as a proxy for breastmilk production as it was thought that if there was an effect on breastmilk you would see better weight gain. About 80% in both groups exclusively breastfed so the influence of formula one can’t take out of the equation. In the end weight gain was no different between groups although a trend to better weight gain was seen in the placebo group. To eat or not to eat that is the question? What is clear to me is that the answer to this question remains unclear! What is clear is that I don’t think it is wise to consume raw placenta due to the risks of bacterial contamination. Secondly, the levels of hormones left in the placental preparation and the most common preparation of steaming and drying leave hormone levels that are unlikely to influence much at all from a biochemical standpoint. It also seems that breastmilk production and neonatal weight gain aren’t influenced much by consumption of these pills. The issue though in all of this is that while the previous research was of low quality, the current research while of better quality is at a low volume. These were pilot trials and not powered to find a difference likely. The finding in the subgroup of some effect on mood at the end of the study does leave some hope to those that believe in the power of the placenta to help. Would a larger study find benefit to this practice? My suspicion from a biochemical standpoint is not but that one may feel a benefit from a placebo response. Should you go out and have your placenta prepared for consumption? If you have Kardashian like wealth then go for it if you think it will help. If you don’t then I would suggest waiting for something more definitive before spending your money on placentophagy.

This post is very exciting to me. All of us in the field of Neonatology are used to staring at patient monitors. With each version of whatever product we are using there seems to be a new feature that is added to soothe our appetites for more data. The real estate on the screen is becoming more and more precious as various devices such as ventilators, NIRS and other machines become capable of displaying their information in a centralized place. The issue though is that there is only so much space available to display all of this information but underneath the hood so to speak is so much more! Come Along For The Ride One of our Neonatologists Dr. Yasser Elsayed has been very aware of these features embedded in the patient monitor. Through teaching on rounds, some of our staff have become aware of these features but delivering this content to the masses has been an issue. That is where this post and it’s linked content come into play. I have created a new Youtube playlist where all of this great content can be found. Each video is very watchable with most being 5-7 minutes long with the longest being 14:16. Each video starts with a demonstration on the patient monitor of the lesson being taught and how to access the data using the patient monitor (in this case a Phillips but I have no doubt many other monitors have the same tech – just ask your rep how to get it) followed by a brief voice-over powerpoint to deliver the essential concepts. However you wish to digest the information is up to you but as they are short we hope that you will be able to find the content you need quickly and apply the knowledge to patient care. How can you use the information? The next time a patient is giving you cause to worry try looking into some of the deeper trends that the monitor is hiding from plain sight. Is there a trend towards becoming hypotensive for the patient that can be revealed in their blood pressure histogram? Maybe the issue lies with the way the patient is being ventilated and examining trends in the pleth waveforms may reveal where the underlying problem lies. The Topics (click the links to go to Youtube) Complete List of Videos Part 1 – Using Histograms Part 2 – How to interpret blood pressure histograms Part 3 – Using vital signs as trends Part 4 – Impact of ventilation on pleth waveforms Part 5 – How to interpret arterial pressure waveforms Part 6 – Near Infrared Spectroscopy

A recent post on the intranasal application of breast milk Can intranasal application of breastmilk cure severe IVH? garnered a lot of attention and importantly comments. Many of the comments were related to other uses for breast milk (almost all of which I had no idea about). A quick search by google uncovered MANY articles from the lay press on such uses from treating ear infections to diaper dermatitis. One such article 6 Surprising Natural Uses For Breast Milk certainly makes this liquid gold sound like just that! This got me thinking as I read through the claims as to how much of this is backed by science and how much is based on experience of mothers who have tried using breast milk for a variety of unconventional treatments. I was intrigued by the claim about acne as with several family members nearing that wonderful period of the teenage years I wondered might there have been a treatment right under my nose all this time? Before going on I will tell you what this post is not. This is not going to be about telling everyone that this is a terrible idea. What this is about is breaking down the science that is behind the articles that have surfaced on the internet about its use. I thought it was interesting and I hope you do too! The Year Was 2009 The story begins here (or at least this is the point that I found some evidence). A group of nanoengineering researchers published a paper entitled The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes. The authors examined the antibacterial effect of three fatty acids one of which was lauric acid (which is found in coconut oil but also in breast milk) against Propionibacterium acnes (P. acnes) the bacterium responsible for acne in those teen years. The results in terms of dose response to lauric acid was quite significant. This is where the link in the story begins. Lauric acid kills P. Acne and it is found in high concentrations in breast milk so might topical application of breast milk treat acne? From what I can see this concept didn’t take off right away but a few years later it would. Next we move on to 2013 This same group published In vivo treatment of Propionibacterium acnes infection with liposomal lauric acids. in 2013. This time around they used a mouse model and demonstrated activity against P. Acnes using a liposomal gel delivery system to get the Lauric acid onto the skin of the mouse. Interestingly, the gel did not cause any irritation of the mouse skin but using the traditional benzoyl peroxide and salicylic acid caused severe irritation. From this it appears that the news story broke about using breast milk to treat acne as I note several lay press news stories about the same after 2013. Let’s be clear though about what the state of knowledge is at this point. Lauric acid kills P. Acne without irritating skin in a mouse model. As with many early discoveries people can get very excited and apply the same to humans after extrapolation. What Happened Since Then? Well, in late 2018 this study was released Design, preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies. This is another animal study but this time in the rat which demonstrated application of the gel led to “∼2 fold reduction in comedones count and cytokines (TNF-α and IL-1β) on co-application with curcumin and lauric acid liposomal gel compared to placebo treated group.” Essentially, comedones were reduced and markers of inflammation. So not only do we see an antimicrobial effect, once the bacteria are erradicated, there is a clinical reduction in acne lesions! Where do we go from here? This story is still evolving. Based on the animal research thus far here is what I believe. 1. Lauric acid a fatty acid found in breast milk can kill P. Acne. 2. Lauric acid provided in a gel form and topically applied to rodents with acne can achieve clinical benefits. 3. Whereas current standard treatments of benzoyl peroxide and salicylic acid cause inflammation of the skin with a red complexion, lauric acid does not seem to have that effect. These are pretty incredible findings and I have no doubt, pharmaceutical companies will be bringing forth treatments with lauric acid face creams (they already exist) with a target for acne soon enough. The question though is whether families should go the “natural route” and apply expressed breast milk to their teenagers face. Aside from the issue of whether or not your teenager would allow that if they knew what it was the other question is what might grow on the skin where breast milk is left. I am not aware of any further studies looking at other bacteria (since P. Acnes certainly isn’t welcome around breast milk) but that is one potential concern. In the end though I think the research is still a little premature. We don’t have human trials at this point although I suspect they are coming. Can I say this is a terrible idea if you are currently using breast milk in such a fashion? I suppose I can’t as there is some data presented above that would give some credibility to the strategy. I am curious for those who read this post what your experience has been if you have used breast milk for acne or for other skin conditions. Does it really work?!?

Hypoglycemia has been a frequent topic of posts over the last few years. Specifically, the use of dextrose gels to avoid admission for hypoglycemia and evidence that such a strategy in not associated with adverse outcomes in childhood. What we know is that dextrose gels work and for those centres that have embraced this strategy a reduction in IV treatment with dextrose has been noted as well. Dextrose gels however in the trials were designed to test the hypothesis that use of 0.5 mL/kg of 40% dextrose gel would be an effective strategy for managing hypoglycemia. In the Sugar Babies trial the dextrose gel was custom made and in so doing an element of quality control was made possible. In Canada we have had access to a couple products for use in the newborn; instaglucose and dex4. Both products are listed as being a 40% dextrose gel but since they are not made in house so to speak it leaves open the question of how consistent the product is. Researchers in British Columbia sought to examine how consistent the gels were in overall content and throughout the gel in the tube. The paper by A. Solimano et al is entitled Dextrose gels for neonatal transitional hypoglycemia: What are we giving our babies? As an aside, the lead author Alfonso was just announced as the 2019 recipient of the Canadian Pediatric Society Distinguished Neonatologist award so I couldn’t see a better time to provide some thoughts on this paper! What did they find? The study examined three tubes each of instaglucose and dex4. For each tube the researchers sampled dextrose gel from the top, middle and bottom and then the dextrose content per gram of gel determined as well as gel density. Glucose concentrations were analyzed high-pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and gas chromatography mass spectrometry (GCMS) were used to determine glucose concentrations and identify other carbohydrates, respectively. In terms of consistency the gels were found to be quite variable with dextrose content that for instaglucose could be as much as 81% and 43% different for dex4. Differences also existed between the different sections of the tubes so depending on the whether it was a fresh tube you were using or not the amount of dextrose could vary. The authors also discovered that while dex4 contained almost exclusively dextrose, instaglucose contained other carbohydrates not listed on the manufacturer’s ingredient list. What does it all mean? The differences are interesting for sure. If the glucose gels are not consistent though should we stop using them? I think the answer to that at least for me is no. Although the data is unpublished, our own centres experience has been that admissions for hypoglycemia have indeed fallen since the introduction of dextrose gel usage (we use instaglucose). What I can only surmise is that in some cases patients may be getting 40% but perhaps in others they are getting as little as 20% or as much as 60% (I don’t know exactly what the range would be but just using this as an example). In some cases of “gel failure” perhaps it is for some babies, receipt of low dextrose containing gel that is at fault or it may be they just have high glucose requirements that gel is not enough to overcome. Other infants who respond quickly to glucose gel may be getting a large dose of dextrose in comparison. Overall though, it still seems to be effective. What I take from this study is certainly that there is variation in the commercially prepared product. Producing the gel in the hospital pharmacy might allow for better quality control and would seem to be something worth pursuing.

It isn’t often in Neonatology these days that something truly innovative comes along. While the study I will be discussing is certainly small I think it represents the start of something bigger that we will see evolve over the coming years. There is no question that the benefits of mother’s own milk are extensive and include such positive outcomes as improved cognition in preterm infants and reductions in NEC. The benefits come from the immunological properties as well as the microbiome modifying nature of this source of nutrition and have been discussed many times over. Mother’s own milk contains a couple of very special things that form the basis of the reason for the study to be presented. What are neurotrophins and stem cells? Before discussing the study it is important to understand what these two classes of molecules and cells are capable of. Neurotrophins are molecules that have the capability of promoting growth and survival of neural cells. Included in this class are EGF, brain-derived neurotrophic factor, glial derived neurotrophic factor, nerve growth factor, insulin-like growth factor-1, and hepatic growth factor. It turns out that not only are these found in high concentrations in breast milk but that a woman who produces breast milk at early gestational ages has higher amounts of these substances in her milk. Pretty convenient that substances promoting development of the brain and survival of brain cells increase the earlier you deliver! Stem cells are pluripotent cells meaning that they can develop into pretty much any cell type that they need to in the body. This would come in handy for example if you needed some new cells in the brain after a neurological insult. These are also present in mother’s milk and in fact can represent as much as 30% of the population of cells in breast milk. The Nasal Cavity and the Brain Clearly, the distance from the nasal cavity to the brain is relatively short. Without going into exhaustive detail it has been demonstrated in animal models that provision of medications intranasally can reach the brain without traversing the blood stream. This affords the opportunity to provide substances to the neonate through the nasal cavity in the hopes that it will reach the brain and achieve the desired effect. When you think about it, newborns when feeding have contact between the whole nasopharyngeal cavity and milk (as evidenced by milk occasionally dripping out of the nose when feeding) so using an NG as we do in the NICU bypasses this part of the body. Is that a good thing? Intranasal application of breast milk Researchers in Germany led by Dr. Kribs published an early experience with this strategy in their article Intranasal breast milk for premature infants with severe intraventricular hemorrhage—an observation. In this paper the strategy;follows; 2 × 0.1 ml of his or her mother’s milk 3 to 8 times a day (0.6 to 1.6 ml total per day). The breast milk was freshly expressed, which means the milk was used within 2 h after expression. The daily application started within the first 5 days of life and was continued for at least 28 days to a maximum of 105 days. The outcome of interest was whether the severe IVH would improve over time compared to a cohort of infants with severe IVH who did not receive this treatment. Importantly this was not a randomized trial and the numbers are small. A total of 31 infants were included with 16 receiving this treatment and 15 not. The two groups were compared with the results as follows. The results don’t reach statistical significance but there is a trend at the bottom of the table above to having less progressive ventricular dilatation and surgery for the same. Again this is a very small study so take the results with a grain of salt! Is this practice changing? Not yet but it does beg the question of what a properly designed RCT might look like. The authors predict what it might look like with a sham nasal application versus fresh mother’s milk. I do wonder though if it may become a study that would be hard to recruit into as when families are approached and the potential benefit explained it may be hard to get them to say anything other than “Just give my baby the breast milk!” Such is the challenge with RCTs so it may be that a larger retrospective study will have to do first. Regardless, be on the lookout for this research as I suspect we may see more studies such as this coming and soon! * Featured image from the open access paper. (There couldn’t be a better picture of this out there!)

InSurE (Intubate, Surfactant, Extubate) has been the standard approach for some time when it comes to treating RDS. Less Invasive Surfactant Administration (LISA) or Minimally Invasive Surfactant Administration (MIST) have been growing in popularity as an alternative technique. More than just popular, the techniques have been shown to reduce some important short term and possibly long term outcomes when used instead of the InSurE approach. Aldana-Aquirre et al published the most recent systematic review on the topic in Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. They demonstrated that when looking at 6 RCTs with 895 infants, the overall results indicate that use of LISA instead of InSurE leads to a lower rate of death or bronchopulmonary dysplasia (BPD) at 36 weeks (risk ratio (RR)=0.75 (95% CI 0.59 to 0.94), p=0.01) and the need for mechanical ventilation within 72 hours of birth (RR=0.71 (0.53 to 0.96), p=0.02) or anytime during the patient stay in the NICU (RR=0.66 (0.47 to 0.93), p=0.02). This study has been out for two years this month and yet here we are at least in my centre still performing InSurE. Why is that? One reason likely has something to do with the expression "you can't teach an old dog new tricks". We know how to do InSurE and we are pretty good at it. Performing the LISA technique is not just about putting a catheter in the airway and instilling surfactant. There are several steps that need to be done in order to ensure that the surfactant goes where it is supposed to so there is training required but such training is available in videos posted on the internet or I am sure available from centres willing to share their methods. Still it takes someone declaring we need to change before anything will happen. The second reason for this insistence on the status quo has been the availability of only a large volume surfactant in Canada at 5 ml/kg while in European centres the volume administered was half that. Now a low volume surfactant is available in Canada but some centres have been slow to make a switch due to comfort with the current product. The drawback to the current product is the concern that you can't use it for LISA techniques since the centres practicing this technique use the low volume form. Can High Volume Be Used For Lisa? Researchers in London, Ontario performed a retrospective cohort study of 43 infants in their institution who underwent the MIST approach for surfactant administration in their study High-volume surfactant administration using a minimally invasive technique: Experience from a Canadian Neonatal Intensive Care Unit. In 2016, London instituted a change in practice to provide MIST for infants born at ≥28 weeks and/or with a birth weight ≥ 1,000 g with respiratory distress syndrome. Surfactant was provided over 1-3 minutes via a MAC catheter guided through the vocal cords with Magill forceps. What I like about this study is the reproducibility of it as the authors describe very nicely how the steps were done. What I also appreciate is the provision of sucrose and atropine prior to the procedure. Not a rapid sequence induction but it does do something to address the risk of bradycardia and discomfort with cannulation of the trachea. The results I think speak for themselves that this is indeed possible as 41/43 neonates underwent the procedure with successful instillation of surfactant confirmed by absence of recovered surfactant in aspirated stomach contents. All of these infants qualified for BLES based on an oxygen requirement on non-invasive support of 40% or more. These patients are similar to our own in Winnipeg in terms of qualifying criteria for surfactant but perhaps a little higher tolerance of FiO2 before intubating. Additional evidence that surfactant was indeed received was the reduction to room air in 85% of patients within 24 hours and also the need for a second dose of surfactant in only 10%. Aside from oxygen desaturation in about 50% during BLES administration the adverse effects were fairly limited and similar to what one would see with InSurE. What now? BLES can be administed via MIST despite concerns about the higher volume of surfactant. What many centres need to address I suspect is that while we think we are practicing InSurE, in many cases we are not. The goal of that procedure is to provide the surfactant over a few seconds and then get the ETT out right away. How often does that happen though in reality? Have you ever found yourself leaving the ETT in till the baby gets to NICU and extubating there? Seems safer right? What if in the elevator or hallway on the way to NICU the baby deteriorates and needs intubation? How long does the ETT stay in? Twenty minutes, 30, 45, 60 or longer? Thinking about that in a different way, what does that translate into in terms of number of PPV breaths? Well at a rate of 60 breaths a minute that means 1800, 2700, 3600 and more breaths before the ETT is removed. I have often wondered if this in itself explains why InSurE seems to be repeatedly identified as being inferior to MIST. If you intubated, gave the surfactant and pulled the ETT out right away in all cases might the two techniques actually be equivalent. The question now really is how do we get past our tendencies and embrace a change in practice that by design will not allow us to delivery any positive pressure breaths?!

In 2015 the Pediatric Endocrine Society (PES) published new recommendations for defining and managing hypoglycaemia in the newborn. A colleague of mine and I discussed the changes and came to the conclusion that the changes suggested were reasonable with some “tweaks”. The PES suggested a change from 2.6 mmol/L (47 mg/dL) at 48 hours of age as a minimum goal glucose to 3.3 mmol/L (60 mg/dL) as the big change in approach. The arguments for this change was largely based on data from normal preterm and term infants achieving the higher levels by 48-72 hours and some neuroendocrine data suggesting physiologically, the body would respond with counter regulatory hormones below 3.3 mmol/L. As it turned out, we were “early adopters” as we learned in the coming year that no other centre in Canada had paid much attention to the recommendations. The inertia to change was likely centred around a few main arguments. 1. How compelling was the data really that a target of 2.6 and above was a bad idea? 2. Fear! Would using a higher threshold result in many “well newborns” being admitted to NICU for treatment when they were really just experiencing a prolonged period of transitional hypoglycaemia. 3. If its not broken don’t fix it. In other word, people were resistant to change itself after everyone was finally accustomed to algorithms for treatment of hypoglcyemia in their own centres. What effect did it actually have? My colleagues along with one of our residents decided to do a before and after retrospective comparison to answer a few questions since we embraced this change. Their answers to what effect the change brought about are interesting and therefore at least a in my opinion worth sharing. If any of you are wondering what effect such change might have in your centre then read on! Skovrlj R, Marks S and C. Rodd published Frequency and etiology of persistent neonatal hypoglycemia using the more stringent 2015 Pediatric Endocrine Society hypoglycemia guidelines. They had a total of 58 infants in the study with a primary outcome being the number of endocrine consults before and after the change in practice. Not surprisingly as the graph demonstrates the number went up. Once the protocol was in place we went from arbitrary consults to mandatory so these results are not surprising. What is surprising though is that the median critical plasma glucose was 2.2 mmol/L, with no significant difference pre or post (2.0 mmol/L pre versus 2.6 mmol/L post, P=0.4) Ninety percent of the infants who were hypoglycemic beyond 72 hours of age were so in the first 72 hours. Of these infants, 90% were diagnosed with hyperinsulinemia. What this tells us is that those who are going to go on to have persistent hypoglycemia will demonstrate similar blood sugars whether you use the cutoff of 2.6 or 3.3 mmol/L. You will just catch more that present a little later using the higher thresholds. How would these kids do at home if discharged with true hyperinsulinemia that wasn’t treated? I can only speculate but that can’t be good for the brain… Now comes the really interesting part! Of the total infants in the study, thirteen infants or 40% had plasma glucose values of 2.6 to 3.2 mmol/L at the time of consultation after November 2015. Think about that for a moment. None of these infants would have been identified using the old protocol. Nine of these infants went on to require treatment with diazoxide for persistent hyperinsulinemia. All of these infants would have been missed using the old protocol. You might ask at this point “what about the admission rate?”. Curiously an internal audit of our admission rates for hypoglycemia during this period identified a decline in our admission rates. Concurrent with this change we also rolled out the use of dextrose gels so the reduction may have been due to that as one would have expected admission rates to rise otherwise. The other thing you might ask is whether in the end we did the right thing as who says that a plasma blood glucose threshold of 3.3 mmol/L is better than using the tried and true 2.6 mmol/L cutoff? While I don’t have a definitive answer to give you to that last question, I can leave you with something provocative to chew on. In the sugar babies study the goal glucose threshold for the first 7 days of life was 2.6 mmol/L. This cohort has been followed up and I have written about these studies before in Dextrose gel for hypoglycemia. Safe in the long run? One of the curious findings in this study was in the following table. Although the majority of the babies in the study had only mild neurosensory impairment detectable using sophisticated testing the question is why should so many have had anything at all? I have often wondered whether the goal of keeping the blood sugar above 2.6 mmol/L as opposed to a higher level of say 3.3 mmol/L may be at play. Time will tell if we begin to see centres adopt the higher thresholds and then follow these children up. I don’t know about you but a child with a blood sugar of 2.7 mmol/L at 5 or 6 days of age would raise my eyebrow. These levels that we have used for some time seem to make sense in the first few days but for discharge something higher seems sensible.

Use of caffeine in the NICU as a treatment for apnea of prematurity is a topic that has certainly seen it’s fair share of coverage on this blog. Just when you think there is an aspect of treatment with caffeine that hasn’t been covered before, along comes a new paper to change my mind. The Caffeine for Apnea of Prematurity study or CAP, demonstrated that caffeine given between 3-10 days of age reduced the incidence of BPD in those treated compared to those receiving placebo. As an added benefit, in follow-up studies of these patients there appeared to be a benefit to neurodevelopmental outcomes as well at 18-21 months but this was lost by school age with groups being equivalent. In recent years evidence has mounted that starting caffeine earlier in the time course (<3 days and in many cases in the first hour after birth) has led to less need for intubation and BPD. What has really not been known though is whether the use of caffeine in this way might have any long term benefits aside from these short term outcomes. Dr. Abhay Lodha from Calgary and a group of researchers led by Prakesh Shah from the Canadian Neonatal Network using our robust Canadian network data have tried to answer this with their paper Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants The group studied were <29 weeks’ gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network centres. As defined in the paper “Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months’ corrected age.” There were 2018 neonates included in the analysis with 1545 in the early group and 563 in the late. It is worth noting that there were 473 infants lost to follow-up meaning that there was about an 80% follow-up rate. Looking at the characteristics of those infants lost to follow-up there were no striking differences that one would expect between them and the group followed. What did they find? The odds of BPD (aOR 0.61; 95% CI 0.45–0.81), PDA (aOR 0.46; 95% CI 0.34–0.62), and Severe Neurologic Injury – parenchymal injury or GR III/IV IVH or PVL (aOR 0.66; 95% CI 0.45–0.97) were reduced in the early- caffeine group. The primary outcome was also found to be significantly different as per the table below demonstrating the odds after logistic regression analysis. So early caffeine seems to be good. Is that all then? I am very happy to see these results but a few questions remain. Before we get too enthusiastic, I find myself thinking back to the early 2000s after the initial CAP results showed an apparent difference in outcome. The question is whether the reduction in odds seen here for the primary outcome will persist as these children age. Will we see a tendency for the differences to vanish as these children enter school age? I suspect we might but that doesn’t mean all is lost here. What the authors have demonstrated clearly is that early caffeine is not harmful as there is no suggestion of those infants exposed to caffeine so shortly after birth fare worse than those treated later. Also as the authors state, what isn’t clear is how caffeine works to decrease the risk of developmental impairment. In the discussion they offer some insightful thoughts as to what may be at play and I agree that certainly an anti-inflammatory effect may be responsible for some of the effect. I do wonder though if one could tie the reductions to the lower likelihood of BPD. Development of BPD has been shown many times over to be associated with worse developmental outcomes. Aside from the anti-inflammatory effect mentioned, could the avoidance of early intubation and therefore reduced risk of BPD from positive pressure ventilation be the reason? In the end if the results persistent into school age, the reason won’t really matter and I hope it does. Will see what happens when we revisit this cohort in a few years but in the meantime I think this paper certainly confirms in my mind the need to give caffeine and make sure it’s provided early!