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 a written as a tribute to John Minski RRT who taught me much about ventilation over the years and has been a champion for innovation in our unit. As he prepares to move on to the next phase of his life I thought it would be a nice send off to talk about something that he has been passionate about for some time. That passion is inhaled nitric oxide for more than just pulmonary hypertension.
This is actually nothing really new. For a review on the background behind the theory you can read The potential of nitric oxide releasing therapies as antimicrobial agents. While we think of iNO as being a drug for pulmonary hypertension it has other capabilities. It can diffuse across cell membranes and damage pathogens by causing nitrosative and oxidative damage. The amount of iNO needed though to accomplish this bactericidal action is much higher than the typical levels of 20 – 40 ppm that we use. Last year in August Bogdanovski et al published Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease. They describe a protocol of providing 30 minute doses of 160 ppm for 21 days in a 24 year old patient with cystic fibrosis who was infected with mycobacterium abscessus. While they were not able to eradicate the organism, they were able to demonstrate functional improvement in the patient. Also notable was the absence of adverse effects in terms of methemoglobin levels. Other prior research in-vitro has shown iNO at high levels to be truly bacteriocidal as per the review above.
In this paper they describe the use of iNO at 160 ppm in 5 spontaneously breathing patients with confirmed COVID19 infection. This was provided as a rescue therapy in the absence of any high quality therapies for this disease. The protocol was to give them the same dose of 160 ppm for 30 minutes at a time until resolution of their symptoms with those that received multiple treatments getting anywhere from 5-9 courses. In each case after each 30 minute period the treating physicians measured levels of methemoglobin and nitrogen dioxide and found in each patient acceptable levels after these brief exposures.
Of the 5 patients treated 2 died from COVID19 and three survived. The two patients who died interestingly were the ones who each only received one treatment each. The other three received 5, 8 and 9 treatments respectively. The authors recorded mean arterial pressure, heart rate, respiratory rate, SpO2/FiO2 and finally measurements of inflammatory markers in the two patients who died (E) and the 3 who survived in (F) in the figure below.
What is interesting from the figure above is the reduction in respiratory rate during treatment (certainly could be placebo from believing they will get better) but the oxygenation during the treatment improved as well. Could this be from a reduction in associated pulmonary hypertension? Certainly could be. Looking at the patients who died in (E) vs the ones in (F) who survived (patient 3 not shown) demonstrate that use of iNO stopped the rise in CRP and in the case of those who died reduced it significantly. There could be an argument made then that the changes in respiratory pattern observed during treatment are associated with a concomitant attenuation of inflammation. This treatment just might work but of course needs far more studies to be certain of that. On that note a review of iNO for this type of indication reveals there are currently 16 studies enrolling in this area of research so I imagine there will be more info to come with this story.
What about the neonate with pneumonia?
I sent this paper around to my colleagues and it generated some great discussion. I am no Ethicist but the question raised was could this be considered a “last ditch” treatment for the neonate succumbing to a pneumonia? I have no doubt if you are reading this that you will have seen in neonatal units around the world that there are infants who develop pneumonia unresponsive to traditional treatments such as iNO at regular doses, antibiotics, higher PEEP, surfactant etc. If we have this knowledge with respect to the potential use of iNO at high dose and a positive impact on pulmonary infective disease is this something that should be offered to parents?
We have no date to my knowledge in babies on the use of this type of dosing but it comes down to a question of what is the alternative? If a patient is dying on the ventilator are we at the point of knowledge here that it is worth offering the family this treatment? One could do so with full disclosure about the lack of neonatal data both for effectiveness and safety. Or do you fall on the side of it could be harmful and expedite death so should not be used. If you use it though and wait till the patient is in extremus on 100% oxygen might it be too late? Do parents have the right to know when they ask the question “is there anything else you can do?” For me I think the answer is that there should be a discussion with this evolving research out there. I am comfortable with it as long as the parents understand the potential for it to make things worse and shorten their time with their child. Alternatively if they choose not to that is their prerogative but should they have the choice when the competing outcome is death?
I can’t tell you whether you should or shouldn’t offer this in your institution but my suspicion is that you will be discussing this among colleagues before long. Who knows you might just one day say you saw it here first!
Thanks John M for the inspiration and keep sending those articles!
If you work in NICU you will have seen many babies who have passed through the stages of apnea, weaned off respiratory support and have reached a sufficient weight for discharge but alas will just not feed. Different strategies have been employed to get these infants feeding that rely in many cases on a cue based approach but in the end there are some that just won’t or can’t do it. Many of these babies will be sent home either with NG feedings or if it appears to be a more long term situation a gastrostomy tube. For this blog post I am going to present to you some novel research that suggests there may be another way to approach this and would like to thank one of the followers of my social media for alerting me to this work. You know who you are as the saying goes!
This was an open label Phase 0 trial (few patients as a pilot) using taVNS to help improve feeding in ex-preterm or 3 recovering from HIE infants who were now past term and all headed towards a gastrostomy tube. The hospital carrying out the study entitled Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study by Badran BW et al did not come out of thin air. Prior research in adult patients recovering from stroke found in multiple studies (all referenced in the paper) that motor stimulation accompanied by VNS improves motor function recovery. The objective here then was to see if stimulation of the auricular nerve along with assessment and motor treatments from an occupational therapist once a day could help improve feeding and avoid GT placement. The trial overview is as shown below.
The centre in which the study was done had a historical rate in this population of <10% of such patients avoiding a GT (all reaching term equivalent age and not showing an improvement in feeds). This was demonstrated in previous work by at the Medical University of South Carolina (MUSC). “Preterm infants who have not reached full PO feeds by 40-week gestational age (GA) and/or after 40 days of attempting PO feeds have a >90% chance of eventually needing G-tube implantation to achieve full enteral feeds (Ryan and Gehle, 2019).”
taVNS was done once a day during a bottle feed and timed with observed suckling and swallowing by an OT. The stimulation was stopped during a pause in feeding.
As you read this you may be concerned about side effects (as I was) of passing an electrical current to the ear and stimulating the auricular branch of the vagus nerve. This has been shown in other work to activate both afferent and efferent pathways of the vagus nerve and enhance plasticity and functional motor recovery. Could you then apply the same to improving development of the motor pathways of the preterm newborn or patient recovering from HIE? The authors examined skin irritation, pain scores and incidence of bradycardia before and during feeding while stimulation was occurring and found no difference in any of the measures. In order to minimize pain the authors increased the current by 0.1 mA until they perceived stimulation by change in facial expression, shrugging or fidgety movements. In the event of an increase in pain scoring by 3 the dose was decreased by the same amount. in the end the intervention was deemed safe without any adverse effects.
The primary outcome was ability to increase and maintain full daily PO intake for 4 days (>120 mL/kg/d and maintain a weight gain of >20 g/day until discharge.
Why you should care about the results
If you work in a hospital like mine you would probably find that once the discussion about a GT placement begins, few miraculously avoid it. In this study they found that 8 of the 14 patients or 57% avoided the GT. Their historical achievement in this regard was <10%. This could be by chance of course since the study is a small one but when looking at the PO intake between non-responders and responders they demonstrate the following.
The authors found no statistically significant increase in the non-responders after the taVNS in PO feeds but also note there were three infants born to mothers with diabetes in this group. I have commented before on the effect of diabetes on successful feeding so this certainly could have affected the success of this group. If you look at the change over time in the responder group they look graphically like there was an upwards trend in the feeding ability prior to the intervention although the increase or slope of the improvement due to small numbers was not significant. The takeoff in feeding afterwards was.
The findings in this study are extremely exciting to me. As units across the globe struggle with patient flow, one of the most common reasons for these patients to stay in hospital is no longer BPD or apnea but inability to feed. The idea that such a simple intervention that is done once daily for 30 minutes might influence the development of feeding coordination in these at risk infants is phenomenal in terms of its impact on patient flow.
If you wonder about whether this is a one off study, there is a lot of active research in this area. A quick search of clinicaltrials.gov uncovers 61 studies on taVNS recruiting at the moment for a variety of ailments. In fact the next study is a Phase 1 trial aiming to recruit 40 patients and is underway. If interested the link to the study is here.
In the book Outliers by Malcolm Gladwell he talked about 10000 hours being the threshold at which if you practiced or gained that much experience with something you could become an expert. In Sweden the approach to 22 week pregnancies and above is to resuscitate all as a strategy. I wrote about this before in At 22 weeks of gestation does your faith matter most to outcome? The information gleaned from that paper was that if you have a policy of resuscitation at these gestational ages and you compare outcomes to a centre that is selective in who they resuscitate the outcomes are better when you believe all should be resuscitated.
New Study Expands Data
The same group has published this time around the results of the same cohort from 2006-2015 but this time with developmental outcome data. The paper is entitled Outcomes of a uniformly active approach to infants born at 22-24 weeks of gestation In this paper they discuss outcomes at 234 and 24 weeks respectively in addition to the findings for 22 weeks which they covered in the paper mentioned above. The reason for sharing this study is that if I asked you to imagine going into a room right now and talking to a family at 22 – 24 weeks and predicting the outcome of their infant, my hunch is that you would not provide as rosy a picture as the group in Uppsala, Sweden.
The authors looked at a group of infants with the following breakdown by gestational age.
Not surprisingly as gestational age declines the incidence of complications rise but looking at Table 3 even at 22 weeks there was no difference in rate of NEC or need for PDA surgery. Nor was there a difference in rates of severe IVH/PVL. Rates of BPD were higher and likely attributable to the longer durations of positive pressure ventilation. Are these rates for these complications terrible though when the other option is non-intervention which for certain means death?
What about outcome?
Looking at the outcome at 2.5 years, the rate of cerebral palsy is about 1:10 to 1:20 for all GA. Hearing impairment is almost non-existent and while developmental delay is detected in 50 percent of survivors at 22 weeks only about a quarter of the infants have severe impairment.
Deciding what to do
There is no question that many of you seeing what this post was about would simply say “NO WAY” but in the end isn’t it really about a shared decision with the family? It wasn’t that long ago that we had to have a real paradigm shift in thinking about resuscitating 23 week infants. The amount of mental energy spent for teams worldwide coming to this decision was tremendous and now if you were to suggest compassionate care at 24 weeks you get a look back like you are crazy! It wasn’t that long ago that 24 weeks was considered viability in many places and now that 23 is the new 24 this is the struggle some people have now. Should we go to 22 weeks everywhere as the Swedes have? Clearly this is a decision that institutions need to look at critically and determine if they have the space to accomodate. Each infant should they survive will occupy a bed for at least 6 months. This needs to be looked at before one can just say sure this is a good idea.
In the end what the study demonstrates I believe is that the outcome at 22 and 23 weeks for that matter need not be universally dismal. There certainly is a good chance that a surviving infant will have one or more deficits but in the end I would advocate this is a conversation all units need to be having and critically look at whether each institution has the capactity to consider.
My bet is that five years from now this discussion will be moot as we will be mostly in that direction but at this time I think we are still in evolution.
This could turn into a book one day I suppose but I have become interested in chalenging some of my long held beliefs these days. Recently I had the honour of presenting a webinar on “Dogmas of Neonatology” for the Indian Academy of Pediatrics which examined a few practices that I have called into question (which you can watch in link). Today I turn my attention to a practice that I have been following for at least twenty years. I have to also admit it is something I have never really questioned until now! In our institution and I suspect many others, infants born under 1250g have been fed every two hours while those above every three. The rationale for this has been that a two hour volume is smaller and causes less gastric distention. This in theory would benefit these small infants by helping to not compromise ventilation or lead to reflux. Overwhelming the intestine with large distending boluses would also in theory lead to less necrotizing enterocolitis. All of this of course has been theoretical and I can thank those who preceded me in Neonatology for coming up with these rules!
Study Challenges This Old Belief
Yadav A et al published Two-hourly versus Three-hourly Feeding in Very Low Birthweight Neonates: A Randomized Controlled Trial out of India (well timed given my recent talk!). The authors randomized 175 babies born between 1000-1500g to either be fed q2h vs q3h once they began protocol feeding. The primary outcome was time to full feedings. Curiously, the paper indicates they decided to do a preplanned subgroup analysis of the 1000-1250 and 1251 -1500g groups but in the discussion it sounds like this is going to be done as a separate paper so we don’t have that data here.
The study controlled conditions for determining feeding intolerance fairly well. As per the authors:
“Full enteral feed was defined as 150 mL/Kg/day of enteral feeds, hypoglycaemia was defined as blood glucose concentration <45mg/dL . Feed intolerance was defined as abdominal distension (abdominal girth ≥2 cm), with blood or bile stained aspirates or vomiting or pre-feed gastric residual volume more than 50% of feed volume; the latter checked only once feeds reached 5 mL/kg volume . NEC was defined as per the modified Bells staging.”
We don’t use gastric residuals in our unit to guide cessation of feedings anymore but the groups both had residuals treated the same way so that is different but not somethign that I think would invalidate the study. The patients in the study had the baseline characteristics shown below and were comparable.
It will be little surprise to you that the results indicate no difference in time to full feedings as shown in Figure 2 from the paper.
The curves for feeding advancement are essentially superimposed. Feeding every two vs three hours made no difference whatsoever. Looking at secondary outcomes there were no differences as well in rates of NEC or hypoglycemia. Importantly when examining rates of feeding intolerance 7.4% of babies in the 2 hour and 6.9% in the 3 hour groups had this issue with no difference in risk observed.
Taking the results as they are from this study there doens’t seem to be much basis for drawing the line at 1250g although it would still be nice to see the preplanned subgroup analysis to see if there were any concerns in the 1000-1250 group.
Supporting this study though is a large systematic review by Dr. A. Razak (whom I have collaborated with before). In his systematic review Two-hourly versus three-hourly feeding in very low-birth-weight infants: A systematic review and metaanalysis. he concluded there was no difference in time to full feeds but did note a positive benefit of q3h feeding in the 962 pooled infants with infants fed 3-hourly regainin birth weight earlier than infants fed 2-hourly (3 RCTs; 350 participants; mean difference [95% confidence interval] -1.12 [-2.16 to -0.08]; I2 = 0%; p = 0.04). This new study is a large one and will certainly strengthen the evidence from these smaller pooled studies.
The practice of switching to q2h feedings under 1250g is certainly being challenged. The question will be whether the mental barriers to changing this practice can be broken. There are many people that will read this and think “if it’s not broken don’t fix it” or resist change due to change itself. The evidence that is out there though I would submit should cause us all to think about this aspect of our practice. I will!