What can I say? I have had a love affair with research on hypoglycemia. I suppose ever since my colleague and I began the quest of rewriting the Canadian Pediatric Society statement The screening and management of newborns at risk for low blood glucose it has become an interest. Embedded in the statement is commentary on the use of glucose gels for management of neonatal hypoglycemia and based on the sugar babies trial that found treatment of hypoglycemia with dextrose gel reduced admission for hypoglycemia and improved rates of breastfeeding after discharge I have been a proponent. A new approach has arisen in a large study in neonates that warrants some discussion. It tackles hypoglycemia from a preventative approach rather than as a treatment per se and is presented below.
The hPOD Study
The same group from Auckland led by Jane Harding published a preventative trial in January entitled Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): Amulticenter, double-blind randomized controlled trial. The study approached the problem of hypoglycemia by looking at whether provision of dextrose gel at 1 hour of age along with a breastfeed could reduce admission to NICU. The targeted population were babies with risk factors for hypoglcyemia such as maternal diabetes, late preterms and SGA or LGA infants. Remarkably this multicentre study managed to randomize 2149 infants into dextrose (1078) and placebo 1071) arms which for a neonatal study is pretty big! Blood glucose levels were analyzed on all at risk infants at 2 hours of age and were then followed up every 2-4 hours for the first 12 hours of age and until there were 3 consecutive measurements greater than or equal to 2.6 mmol/L. Given the size of the study it should come as no surprise that the two groups were similar in terms of baseline characteristics. The most common risk factor for hypoglycemia in each group was maternal diabetes at 81% in each group.
In the end the only thing that was different between the two groups was a diagnosis of hypoglycemia with about a 5% reduction in the outcome. Admission to NICU was no different whether it was for any reason or hypoglycemia alone. Treatment with IV therapy was also no different between groups and in addition breastfeeding rates were exceptionally high at discharge at about 96% for both groups. So the conclusion here is that prophylactic glucose gel doesn’t matter much but I have a few thoughts despite this being a VERY large trial and the authors really doing a good job of answering an important question.
My Thoughts on the Outcomes
The study demonstrates that one dose of glucose gel does not affect admission for any reason or for hypoglycemia. I can’t help but wonder if allowing the dextrose gel group to receive one or two more doses could have changed that outcome.
No difference in admission is not surprising since there are many reasons that a baby could be admitted with those underlying risk factors. Low birth weight, TTN, RDS etc would be some reasons and I wouldn’t think would be any different. It might have been better to power the study for admission for hypoglycemia as that to me is the only reason for admission that could be impacted by such prophylaxis.
When your breastfeeding rate in the placebo arm is at 95.9% there really isn’t much room for improvement so not sure a lack of improvement with dextrose gels can really be called here. There really wasn’t anywhere to go but down and previous work suggested that rates can go up. As the saying goes, can you apply the results of the study to my population. I can only wonder what would have happened if the authors were to replicate this study in a population with breastfeeding rates of 80%.
Is the outcome of reduced hypoglycemia a good enough outcome alone to adopt prophylactic dextrose gel? I don’t think so as there was no difference in groups between recurrent or severe hypoglycemia which is what likely matters most to neurodevelopmental outcome. Curiously the mean initial blood glucose was 2.97 and 3.16 in the placebo and glucose gel arms respectively so I am not sure how hypoglycemic this population really was. Yes there were about 40% in each arm that were hypoglycemic but only 10% were severe and almost 90% never had another episode. It’s possible that just by chance these children were on a very mild spectrum and therefore prophylaxis had little effect since they really were only going to have transient hypoglycemia.
In spite of my comments above I believe the authors did a fine job trying to answer an important question which to be honest others have wondered about before. For now I won’t be recommending this in my own institution but I do wonder what project will come next from this group that keeps on producing great work in the area of neonatal hypoglycemia.
This post is special to me. A redemption of sorts. When I was a fellow in Edmonton in the early 2000s my fellowship project was to see whether heliox (helium/oxygen) given to piglets with meconium aspiration syndrome (MAS) would improve ventilation and measures of pulmonary hypertension vs controls. Why heliox? There had been work done with this gas for other conditions and the lower viscosity of the gas (who hasn’t sucked on a helium balloon to see the effect of helium) means that the flow of the gas in a tube is more linear that regular air. Turbulent flow as with air/oxygen mixtures creates more resistance to flow than linear flow with heliox. Imagine if you will this linear flow slipping more easily past particles of meconium partially blocking airways and you get the idea of why heliox might work. One thing to bear in mind though is that as your FiO2 goes up the percentage of helium drops so the properties described work best at low FiO2 so flow is more linear.
I collected meconium from diapers in the NICU and created a NS slurry of meconium and then instilled it into the trachea’s of these piglets through a tracheostomy (they were too small to intubate for me at least). A flow probe was put around the pulmonary artery to look for evidence of pulmonary hypertension. We saw some interesting trends but the paper never saw the light of day for a variety of reasons that I won’t go in to here. Originally I had wanted to do the study as a small RCT in humans but I was advised that although heliox is an inert gas I should do the animal study first. That was the end of the heliox story as far as I was concerned as I hadn’t thought much about it since that time. I will admit though that anytime I had a baby with bad meconium aspiration syndrome though the thought did pop into my head.
The Study Has Arrived
Imagine my surprise when this week an RCT from China entitled A randomized single‐center controlled trial of synchronized intermittent mandatory ventilation with heliox in newborn infants with meconium aspiration syndrome came across my inbox. The authors used a power calculation based on some previous work in RDS using heliox to determine they needed 28 neonates in each arm to show a difference. In the end they managed 71 total with 35 in the heliox and 36 in the control arm. Inclusion criteria were a diagnosis of MAS on x-ray, GA ≥37 weeks and ≤42 weeks, need for intubation due to a pH <7.2/PCO2 >60 mmHg. The study could not be blinded as one would not be able to hide the large tanks for heliox so for any study like this it would be unavoidable. One thing that differs in terms of management from my own practice is that the authors in this study used SIMV pressure limited ventilation as the ventilatory strategy as opposed to AC/VG that my unit would typically use. Initial ventilator PIP of 15–28 cmH2O, PEEP of 4–10 cmH2O, and RR of 15–45 breaths/min; FiO2 of 0.21 to 1 to reach the target oxygen saturation (SpO2) of 90%–95%. The intervention group received heliox for 6 hours and then switched over to air/oxygen while the control group was ventilated with air/oxygen from the start. The extubation criteria included PIP ≤15 cmH2O, gradually enhanced effective spontaneous breathing, a ventilator breathing frequency ≤10/min, and normal blood gas analysis results. The main outcomes were PaO2/FiO2 (P/F), the extubation time and the hospital length of stay in the NICU. Aside from measuring the ventilatory responses and time of extubation the authors also examined the effect of heliox as an anti-inflammatory agent based on previous results demonstrating markers of inflammation can be attenuated by use of the gas.
The Results
To start with, the babies in both arms were equivalent at the start of the study in terms of inflammatory markers and some clinical variables.
As you will see from the following figures a number of important findings are noted. The main marker of oxygenation used for this study was the PaO2/FiO2 ratio and this was statistically different (301 ± 22 vs. 260.64 ± 24.83, p < .001). Secondly, extubation time (78 ± 30 vs. 114 ± 28.07, p < .001 and length of hospital stay in days were also shorter 15.3 ± 4.2 vs. 19.11 ± 4.01, p < .001.
The authors state that the following markers of pO2, pH and pCO2 shown in the graphs were all significantly improved in the heliox group but looking at the first two I find that hard to believe as the curves look almost superimposed. pCO2 however could be different in particular given the linear flow described above so ventilation might be improved.
Finally, across the board, markers of inflammation were noted to improve with administration of heliox as well as markers of myocardial injury. The gas may have done what it was supposed to do.
I wish the conclusions were that easy
I want to like this paper so badly. Sadly, I have some pretty significant reservations. It is helpful to see that the two groups began at a similar PaO2/FiO2 ratio. What is missing though is the ventilatory requirements to get to that point. There is no information provided as to the mean airway pressures or PIP/PEEP for each group over time to get a sense of whether the two groups in terms of severity of illness were the same. Yes we know that the inflammatory markers at the start were similar but could the difference in changes of inflammation relate to a progressive rise in the control group that were just sicker rather than a protective effect of heliox to reduce inflammation? Also when one looks at the change in pCO2 how do you interpret that without knowing the minute ventilation to achieve those data points? It is really unfortunate that the authors did not use oxygenation index (MAP X FiO2/PaO2) as this would have taken the ventilation component at least into account. Would be helpful as well to know the weaning strategy in each group as without blinding might the authors have reacted more aggresively with weaning of the ventilator to get to extubatable settings knowing that the babies were receiving the intervention. As there was no weaning strategy planned out from the start we can only guess. Lastly, one could have possibly gotten around the inability to hide the heliox tanks by having a Neonatologist not on service take each blood gas data and sight unseen suggest changes to ventilation without being able to see which arm a baby was in.
I will end on a positive note though. It has been almost twenty years since I did the piglet study using heliox. I had always hoped that this research would see the light of day in a human model although my piglet data didn’t show much benefit however the intervention was shorter than this study. I think this study is worthy of being repeated using a different mode of ventilation that does not rely on manual changes to PIP but rather by using a VG mode the baby would be gradually weaned as compliance improves. Any further study needs to address differences that were missing from this paper as well. I don’t think this is the last we will see of heliox and I look forward to seeing another paper although if it takes another twenty years I may be out of this line of work.
I had the opportunity recently to give a talk on strategies to reduce BPD in our preemie population. For the talk, I used as a springboard the recommendations for reducing BPD as laid out by the Evidence Based Practice for Improving Quality (EPIQ) group. There are far too many recommendations for optimal care to go through but the point of this post is to highlight one strategy that I think is deserving of discussion.
That volume targeted ventilation is recommended is no surprise. Setting a desired volume and allowing pressures to fluctuate rather than fixing a pressure and allowing volumes to fluctuate reduces the risk of both atelectotrauma and volutrauma. A recent paper Early volume targeted ventilation in preterm infants born at 22-25 weeks of gestational age has added further arguments in those at the smallest gestational ages by reducing episodes of hypocapnia and increasing likelihood of extubation by 24 hours compared to those on pressure limited ventilation.
Are Bigger Volumes Better With Time?
It is the second highlighted piece above that has left me scratching my head. Going way back to my residency I was taught that the ideal tidal volume is somewhere between 3.5 – 4.5 mL/kg and we should try and keep PIPs less than 35 cm H2O as an absolute maximum. In reality we typically would switch to the high frequency jet ventilator if pressures were increasing above 25 cm H2O in an effort to avoid volutrauma by increasing volumes further or barotrauma from excessive pressure. The main thrust of the argument was that big volumes hurt the lung so one is better off being gentle and inflating the lung with PEEP and then using the more gentle pulse of the HFJV after that. To be sure in the early stages of the neonatal course excessive volumes and pressure can commit the patient to a significant risk of BPD and meticulous attention to respiratory care is needed. The question for today is whether after 2 or 3 weeks of age, babies with developing lung injury need more volume on conventional ventilation or whether continuing on the HFJV is the way to go. I will let you in on a secret right away though. There is a systematic review on the subject.
The problem is it only includes one study from 1991 which is before antenatal steroids and surfactant as standards of care so not much to take from this paper.
As shown in the table above the needed tidal volumes rise over time. The PIPs remain acceptable (below the set limits) but the volumes rise to close to 6 mL/kg by three weeks of age. If these results are generalizable to our own population this would mean that using our units current levels of 3.5 – 4.5 mL/kg would leave these older infants short. If so is it any wonder we see high pCO2 triggering a need for HFJV. The authors conclude here that the progressive dilation of the trachea and proximal bronchi over time from ventilation increase dead space and are responsible for the rise in needed Vt.
The next study Volume targeting levels and work of breathing in infants with evolving or established bronchopulmonary dysplasia was published in 2019 by Hunt et al. This study looked at 18 infants less than 32 weeks and randomly assigned them once older than one week of age and still ventilated to 20 minute periods on 4,5,6 and 7 mL/kg of Vt in random fashion. The median GA was 26 weeks and day of study 18 days. The outcome of interest was measurement of work of breathing using the Pressure-time product of the diaphragm (PTPdi). The findings are below.
One did not see a significant improvement in work of breathing until 7 mL/kg was reached and you can see a progressive rise in minute ventilation needed to maintain normocapnia over time. This study supports the previous one in suggesting that over time there is an increase in dead space and if we want to reduce air hunger which could be represented by work of breathing we need to consider higher volumes.
The Damage is Done
Its an imperfect science that we are looking at and there is no doubt there will be readers of this post that will cringe at the volumes being discussed. I think what this really comes down to is whether you think the damage is done by 2-3 weeks. We of course don’t officially classify babies as having BPD until 36 weeks but if we are being honest we often know or can predict which ones are destined to get it. Is it better for the babies to be put on high frequency ventilation for weeks or to be given some larger volumes on conventional ventilation? Hard to say based on the evidence as there really isn’t much to go by. One thing that does need to be considered is long term high frequency ventilation and the need for sedation. Many of our kids on weeks of such therapy need progressively more sedation and what effect does that have on the developing brain. On the other hand if excessive volumes even at 2-3 weeks lead to increased damage to the lungs are you risking a prolongation on the ventilator or increasing the need at some point for a tracheostomy?
In the end I don’t think at the moment anyone knows. If you move from one center to another though and see completely different approaches I hope that by reading this post you will at least understand where the differences in practice come from.
In the end we are all just trying to do what we believe is best for the baby.
As readers of this blog will know I am a big fan of anything that challenges my practice. It’s something that I think in general is a good practice to live by. For many years now when a preterm infant in particular is hypotensive it has been our practice to draw a serum cortisol level and then determine whether the stress response is adequate before starting hydrocortisone for blood pressure support. Having said that, sometimes we start the hydrocortisone and then use the level afterwards to determine if we need to continue. is this approach right though?
Evidence That Shakes Up Our Approach
It turns out the evidence that preterm infants may not be able to produce a robust cortisol response after birth has been around for sometime. In 1994 Hingre et al published Adrenal steroidogenesis in very low birth weight preterm infants. In this paper they documented the diminished ability of infants born < 30 weeks gestational age to produce cortisol finding preterm newborns had low basal cortisol levels “(mean +/- SEM, 207.4 +/- 23.5 nmol/L), and their levels were similar to basal levels reported for healthy full-term newborns (170.7 +/- 26.8 nmol/L; P = 0.31”. It is worth noting here that commonly held beliefs have been that an adequate adrenal response is in the range of 400 – 450 nmol/L or about 15 microgram/dL and these levels are lower than that. Moreover, when the authors measaured precursors of cortisol and found elevations consistent with a deficiency of decreased activity of 11 beta-hydroxylase (11 beta OH). Knowing this then, the use of a baseline cortisol to determine if an appropriate stress response is present before starting hydrocortisone is questionable. Having said that the practice has been that when it is low we assist with hydrocortisone and when it is high we can ease off the support. A new study that has just come out though I think may turn that thinking on its head!
High Cortisol Levels Are Concerning. Not the Lows!
Absence of relationship between serum cortisol and critical illness in premature infants by Prelipcean I et al was just published and looked at 224 infants at the University of Florida who were born under 30 weeks and had baseline cortisol levels drawn for clinical indications prior to 36 weeks PMA. Like many centres the baseline cortisol was done prior to starting hydrocortisone for hypotension. A baseline level under 15 mcg/dL was considered low which equates to about 413 nmol/L for those using those units (like my own hospital). The Simplified Score for Neonatal Acute Physiology II SNAP-II score , neonatal Sequential Organ Failure Assessment (nSOFA) and Vasoactive-Inotrope Score (VIS) were calculated and used as measures of illness severity against the the cortisol levels obtained in a retrospective fashion. Cortisol levels were taken at a median of 3.8 days with an IQR of 1.2 to 14 days). Hydrocortisone was givne to 71% of patients in the study as well.
What emerged from these results might be counterintuitive. From the figure below it was found that those infants with higher baseline cortisol levels were less likely to survive. This result just reached statistical significance. Thinking about this for a moment, we have traditionally worried about the infants with low cortisol and rushed to supplement them. The babies at real risk though here are the ones with a robust pituitary adrenal axis response. Notably another factor that leads to lower cortisol levels in the first few days of life is provision of antenatal steroids so it may be at least in part that the higher baseline levels might be seen in those without the benefit of antenatal steroids and therefore are at higher risk of adverse outcome. Bottom line though, a robust cortisol level would not necessarily appear to be marker of a good thing.
The second thing to be identified is the scatter of results for these infants across birth weight, day of life and gestational age. The authors discovered using a multivariable model that birth weight was the only statistically significant variable to explain cortisol variation. Interestingly for every 100g increase in birth weight cortisol increased an average of 10%.
Additionally, differences in average cortisol level were affected by chorioamnionitis and antenatal steroids. The presence of chorioamnionitis as a variable is not surprising I suppose given the results from the prophylactic steroid trials for BPD that have consistently found chorio predicts a higher rate of BPD.
Where things get really interesting is in the bottom half of the figure below. While weak linear associations with SNAP-II, nSOFA were found ,no correlation between serum cortisol concentration and concurrent critical illness severity objectively measured by SNAP-II and nSOFA scores at time points beyond the first day of life and prior to 36 weeks PMA in these infants were found. Most intriguing was the complete lack of relationship between the VIS and cortisol levels.
This presents a predicament about what to do with these levels. Based on this research the degree of illness and the amount of inotrope one is on (VIS takes into account doses of dopamine, dobutamine, vasopressin, milrinone, epinephrine and norepinephrine) has no relationship to cortisol level. If you are like our centre though you have been considering whether to use hydrocortisone based on the level of cortisol at baseline. Based on this research the message would be that if one wants to know a baseline cortisol it might be useful as a tool to determine how concerned one should be with an infant as risk of mortality is higher if baseline levels are above 413 nmol/L. In terms of determining whether one should support with hydrocortisone though in the face of a sick preterm infant and more specifically a hypotensive one the utility of the baseline measurement I would question. Adding to this the research from 1994 and one has to question if the level is low is that simply because the infant doesn’t have the metabolic machinery yet to produce enough rather than has an abnormal response to stress.
Some qualifiers as with any study like this need to be acknowledged. It is not a study of 1000 patients so the individual numbers of patients at different weight levels will be lower and therefore there could be unusual patients here influencing the results. Having said that, when you combine this information in this study with what is known from before about these preterm infants should we be surprised that there is no relationship between baseline cortisol and illness. If you don’t have the capacity to make it except when exceptionally stressed it would appear that all these baseline cortisols may in fact be good for telling ourselves how stressed we should be about the patient.
