What is hypoglycaemia? Part 3. Part of the answer!

The only way that we can find the answer to the question of what threshold blood sugar we should use to treat babies with low blood sugars is a prospective RCT, and Behold! Look! Lo! How say you? (van Kempen A, et al. Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia. N Engl J Med. 2020;382(6):534-44) in the hypoEXIT trial 2024 “at risk” babies (late preterms 35 to 37 weeks, SGA <10%le, LGA >90%le or infants of diabetic mothers) were monitored and 698 of them developed a plasma glucose between 2.6 and 2.0 mmol/L; they were then randomized to one of 2 protocols, the first, the low threshold group, treated the infants by increasing their glucose intake (with feeds or IV glucose) whenever the plasma glucose was less than 2.0, the second treated the infants in the same way, but used a threshold of 2.6 mmol/L. The same threshold was used during the entire 48 hours of the trial.

The primary outcome of the trial was the developmental status at 18 months of age, using the BSID-3 cognitive and motor scales, and the trial was designed as a non-inferiority trial to determine whether the lower threshold was not inferior, looking for a difference of 0.5 SD, and was powered for the 4 at-risk groups individually. Around 85% of the babies came back for follow-up, which is pretty good, I think, for a trial in full-term babies that only lasted 48 hours: Bravo!

As you can see from the main result for the entire sample, there was absolutely no hint of a whisper of a difference between the groups. When you look at each of the strata there is also absolutely nothing there.

In case you think those mean scores of slightly over 100 disprove my previous comment about these at-risk groups having overall poorer scores than their not at-risk peers, these are the BSID-3, and in a society which is somewhat similar to Holland (where hypoEXIT was done), in Australia, term babies at 24 months had a mean cognitive score of over 108, and a mean motor score of 118, Anderson PJ, et al. Underestimation of Developmental Delay by the New Bayley-III Scale. Arch Pediatr Adolesc Med. 2010;164(4):352-6) when excluding babies under 37 weeks or under 2.5 kg; which suggests that these scores are indeed lower than population means.

After the initial randomization, the babies in the low threshold group were more likely to have a plasma glucose < 2.0 mmol/L (10% of them vs 5%), and were more likely to have recurrent episodes < 2.6 mmol/L; 9% compared to 2% went < 2.6 four or more times. The numbers affected with multiple episodes were too small to really affect the developmental outcome of the groups overall.

This is the only reliable information in the medical literature about which glucose threshold should be used to increase glucose intake.

Of note, the HypoEXIT study used a threshold for entry to the study of 2.6 mmol/L of plasma glucose, and added, in a revision of the protocol, that if whole blood glucose is used then the values for entry into the trial were between 1.7 and 2.2 mmol/L, because of the difference between whole blood and plasma values. Maybe this is why the proportion of at-risk infants in HypoEXIT who were eligible was less than the 1/2 in Harris’s study, more like 1/3; HypoEXIT, in fact, required a plasma glucose which was lower than the equivalent blood glucose in the Harris study.

Most of the guidelines, as I mentioned in part 2, have somewhat ignored this distinction, which makes a major difference to which babies we treat and how often they will be considered to be hypoglycaemic.

A whole blood glucose threshold of 2.6 is equivalent to a plasma glucose of about 3.0 mmol/L. A whole blood glucose of 2.0 is a plasma glucose of around 2.3 mmol/L.

Changing an approach to therapy based on only one study should be carefully considered, but, for early neonatal transitional hypoglycaemia, there are no previous data to compare it to. There is no previous prospective controlled data to suggest that screening the more than 30% of newborn infants who are considered to be at-risk and treating them at a threshold of 2.6 mmol/L is of any value to them compared to treating at a lower threshold. Among at-risk infants the proportion of babies who have at least one glucose under is about 50%; so by following many guidelines we label over 15% of newborn infants as being hypoglycaemic, and they then receive an intervention.

To return to where I started a few thousand words ago, the CPS guideline has been revised, although the text has changed only a little, the algorithm that accompanies it no longer has the lower threshold for intervention and retesting at 2 hours (2.0 mmol/L) that was in the previous version; subsequent tests were treated with a threshold of 2.6 mmol/L.

The new guidelines will mean that thousands of babies in Canada, if they followed the old algorithm, would simply have continued to have repeat tests; with the new algorithm, they will be labelled as being hypoglycemic and receive intervention. The usual intervention will simply be oral glucose gel, but retesting is then required after the gel. The threshold is also based on blood glucose rather than plasma glucose, which is likely to mean that about 50% of screened babies will be labelled hypoglycemic, whereas if plasma glucose was used it would be more like 30%. Screening, of course, causes pain, and intervention might possibly actually increase the risk of poor outcomes, as suggested by the increased problems noted in McKinlay’s study among those who had a more rapid correction of a low glucose.

Based on the only reliable data regarding different thresholds that we now have, I think that intervention during the 1st 48 hours of life can be safely withheld until the plasma glucose is < 2.0 mmol/L (blood glucose < 1.7 mmol/L), on one occasion. If plasma glucose is <2.6 on several occasions (blood glucose <2.2), or for a prolonged period, we do not have enough information to suggest that it is safe, and further intervention and testing may be warranted. We need more studies like HypoEXIT, with even larger sample sizes; for such a common phenomenon it si vital that we figure this out, once and for all.

Posted in Neonatal Research | Tagged , , | 4 Comments

What is hypoglycemia? part 2

The new statement from the CPS, and many others, don’t discuss which measurement that we are really interested in, is it blood glucose, or plasma glucose? The different data sources are discussed as if they were all measuring the same thing.

But this is where it gets a bit confusing. Whole blood glucose is lower than plasma glucose, by about 15%, depending on hematocrit. Even more confusing, some laboratories will convert glucose measurements even when they perform whole blood glucose, and report the results as if they were a plasma glucose. Most glucose reagent strips actually measure whole blood glucose, but pretend they are measuring plasma glucose and apply a conversion factor. So what you see on the screen is what was measured multiplied by 1.15 (or something similar)

Some studies, such as the excellent study from Auckland on the incidence of low blood sugars among at-risk infants (Harris DL, et al. Incidence of neonatal hypoglycemia in babies identified as at risk. J Pediatr. 2012;161(5):787-91) used a whole-blood glucose oxidase method, and defined hypoglycaemia as a whole blood glucose < 2.6 mmol/L. The other studies that I referenced from the same group, such as the McKinlay study, used the same reliable method, and were measuring whole blood glucose.

The study by Lucas that I mentioned in part 1, in contrast, studied plasma glucose concentrations, so the preterm babies that he found to have increased long term risks, with multiple days of plasma glucose < 2.6 mmol/L, had the equivalent of multiple days of blood glucose < 2.26 mmol/L.

The study by Duvanel in contrast used bedside reagent strips for most measures, and only performed blood glucose measurements if the bedside test was <2.0 mmol/L.

This is more than a detail; a plasma glucose of 2.6 is equivalent to a blood glucose concentration, of about 2.26 mmol/L. So using one or the other will have a major impact on how many babies are treated and re-tested.

The recent Swedish guidelines for hypoglycaemia monitoring and intervention (Wackernagel D, et al. Swedish national guideline for prevention and treatment of neonatal hypoglycaemia in newborn infants with gestational age >/= 35 weeks. Acta Paediatr. 2020) Discuss exclusively plasma glucose concentrations, this is the algorithm they suggest, which prescribes glucose gel application at a plasma glucose of <2.6, which is about 2.26 mmol/L for blood glucose.

Although this is a small difference, between plasma and blood glucose, in the ranges we are discussing, it means that tens of thousands more babies will be treated if we use a threshold of 2.6 mmol/L of blood glucose (for example) compared to the number who need treating at a threshold of 2.6 mmol/L of plasma glucose.

The criteria used for determining who is at risk also needs to be reconsidered.

All SGA babies are not growth restricted, many of them are just constitutionally small, and probably not at increased risk compared to AGA babies who are not growth restricted. How to identify these babies is challenging, but probably a baby with symmetrical growth over the third trimester following the same percentile throughout, and with normal antenatal dopplers in a normotensive mother is at very low risk of being growth restricted.

By the same reasoning, some babies over the 10th %le are growth restricted, they started out growing on a higher percentile and fell because of placental dysfunction, and have lower glycogen stores than their peers, and are at increased risk of early transitional low glucose.

At the other end of the spectrum, LGA infants who are not infants of diabetic mothers, but just constitutionally large are probably not at increased risk either, and, if we have a completely normal glucose loading test during pregnancy, could they be taken out of the screened groups? One registry study, which uses discharge diagnoses, found that less than 2% of LGA infants of non-diabetic mothers had hypoglycemia (referred to as a blood glucose < 2.6 mmol/L). On the other hand mild glucose intolerance, while not satisfying definitions for gestational diabetes, might increase the risk for neonatal hypoglycemia (not defined in this study). Some other studies show less hypoglycemia among LGA infants who are not infants of diabetic mothers, but continue to show over 5% incidence of hypoglycaemia, however, they might include mothers with mild glucose intolerance, so it isn’t really clear what is the risk for LGA infants of mothers with completely normal glucose tolerance.

The UK guidelines have taken all this to heart and only recommend screening for babies who are <2 percentile for birth weight or are clinically wasted, or infants of diabetic mothers. They do discuss plasma and blood glucose, but seem to think that blood gas machines report “plasma glucose equivalents”, which ours don’t.

The guidelines from the experts in Auckland, in contrast, refer to hypoglycemia as being “a serum glucose <2.6mM” (serum and plasma glucose being very similar), but the rest of their guideline refers to blood glucose. They recommend screening all infants <10th centile or >95th centile, and infants of diabetic mothers and preterm babies.

If you are getting confused by now you are not alone! Just try comparing the US guidelines from the AAP to the US guidelines from the Pediatric Endocrine Society, which are endorsed by the AAP.

“Oh! for an RCT of fire!” (Apologies to Will Shakespeare)

Posted in Neonatal Research | Tagged , | 1 Comment

What is hypoglycaemia? Part 1.

The Canadian Pediatric Society has just published new guidance for screening and treatment of infants at risk for neonatal hypoglycaemia. The older statement needed to be revised, in particular to include the use of oral glucose gel as an option, which had not been studied when the previous version was developed.

Prior to birth the infant receives a continuous supply of nutrients, including glucose, across the placenta. Immediately at birth, with interruption of this trans-placental supply, glucose concentrations fall and stimulate counter-regulatory mechanisms which take some time to affect glucose concentrations, and thus a fall in glucose concentrations during the first hours of life is a normal phenomenon.

Over 30% of newborn infants are considered to be “at-risk” as 10% of them are SGA, below the 10th percentile, 10% are LGA, about 10% are preterm, and 16% are born to mothers with gestational or pre-gestational diabetes.  There is some overlap, of course, so the total number of babies who are “at-risk” isn’t immediately clear to me, but it’s a lot.

During this hypoglycaemic slump glucose concentrations often fall to levels below those which cause symptoms in adults and older children. During this period some term infants, and few preterm infants, produce ketone bodies, here is an older figure from an observational study among healthy singleton infants, excluding infants of diabetic mothers and the SGA, published in 1992 (Hawdon JM, et al. Patterns of metabolic adaptation for preterm and term infants in the first neonatal week. Arch Dis Child. 1992;67(4 Spec No):357-65.). Ketone bodies here refers to the sum of acetoacetate and β-hydroxybutyrate, as you can see among term infants with hypoglycaemia, many do not produce a lot of ketone bodies, and none of the preterm infants do either.

So the previous dogma, that hypoglycaemia is more dangerous among infants with hyperinsulinaemia because they don’t produce ketone bodies, is probably not true, babies without hyperinsulinemia don’t produce them reliably either! It may well be that other fuels are used by the neonatal brain during hypoglycemia, such as possibly lactate.

At what level does asymptomatic hypoglycemia become dangerous? The best evidence would come from RCTs (of which more in part 2) and absent such evidence then the second-best would be from scrupulous prospective cohort studies with prospectively determined glucose sampling, using reliable glucose measurement methodology (i.e. not bedside test strips), and surveillance for both short and long term impacts.

One observational study which is often quoted (Duvanel CB, et al. Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational-age preterm infants. The Journal of Pediatrics. 1999;134(4):492-8) showed that multiple repeated episodes of a blood glucose under 2.6 mmol/L (on 6 occasions or more) were associated with smaller head circumference and motor delay among SGA preterm babies with an average birth weight of 1.1 kg, however, the majority of babies in that study with glucose <2.6 mmol/L mmol/L also had at least one blood glucose <1.6 mmol/L, and fewer episodes of glucose <2.6 were not significant. Other quoted studies, such as the classic study by Lucas in 1988 showed that persistently low blood glucose over several days may lead to problems, but his study, exclusively in preterm infants, showed a significant impact only when there were at least 5 days with values <2.6 mmol/L. In that study, the result was derived from a secondary analysis of blood glucose values collected for other reasons over the first several weeks of life, and in centres with variable treatment thresholds, which ranged between 1.5 and 2.5 mmol/L.

Another recent large cohort had routine, protocol-specified, glucose monitoring and was designed to prospectively evaluate a group of at-risk infants (McKinlay CJ, et al. Neonatal Glycemia and Neurodevelopmental Outcomes at 2 Years. NEJM. 2015;373;1507-18). The infants were followed to 2 years with tests of development (BSID-3) and executive and visual function. All the babies were ‘at-risk’ as defined by being over the 90th%le, under the 10th %le, an infant of a diabetic mother or preterm. and followed a protocol to intervene for low blood sugars at 2.6 mmol/L, but some were nevertheless found to have “severe hypoglycaemia” < 2.0, and some had multiple episodes of low sugar. That study did not show any additional risk of low blood sugars and they noted “Hypoglycemia… was not associated with an increased risk of the primary outcomes of neurosensory impairment (risk ratio, 0.95; 95% confidence interval [CI], 0.75 to 1.20; P=0.67) and processing difficulty, defined as an executive-function score or motion coherence threshold that was more than 1.5 SD from the mean (risk ratio, 0.92; 95% CI, 0.56 to 1.51; P=0.74). Risks were not increased among children with unrecognized hypoglycemia (a low interstitial glucose concentration only). The lowest blood glucose concentration, number of hypoglycemic episodes and events, and negative interstitial increment (area above the interstitial glucose concentration curve and below 47 mg per deciliter) also did not predict the outcome”  (47 mg/dl=2.6 mmol/L). In contrast, they did show an association of rapid correction of low glucose with adverse outcomes, babies whose blood glucose rose faster after they were treated for a blood glucose < 2.6 mmol/L had more neurosensory impairment. The range of blood sugars among these babies was a low as 0.5 mmol/L in the 1st 12 hours, and as low as 1.0 thereafter.

It seems that this group of “at-risk” infants, who are at some increased risk of lower blood sugars (in particular those who are small for gestational age) have an increased prevalence of developmental difficulties. The same article, just referred to, showed that the at-risk infants in the study had substantially lower scores of Bayley testing than population norms, whether or not they had episodes of blood glucose <2.6. That association may be because of the impacts of growth restriction or maternal diabetes; there is no good evidence that mild to moderate transiently low blood sugars contribute to that risk, indeed I can’t find any reliable evidence of that.

In the pivotal ‘sugarbabies’ trial, (Harris DL, et al. Outcome at 2 Years after Dextrose Gel Treatment for Neonatal Hypoglycemia: Follow-Up of a Randomized Trial. J Pediatr. 2016;170:54-9 e1-2) at-risk babies whose blood sugar fell below 2.6 mmol/L were randomized to receive oral glucose gel immediately, or they received placebo and were treated later if the blood sugar remained below 2.6 mmol/L thirty minutes later. The babies in the two groups had identical outcomes at 2 years of age, including neurodevelopmental assessment even though the placebo group, by protocol design, had a longer period of time with a blood sugar less than 2.6 mmol/L.

There is, therefore, no good observational data to show what threshold of low glucose levels might lead to developmental problems. Severe, prolonged, or repeated low blood sugars in some studies seem to be associated with poorer outcomes, but some studies can’t even show that.

There is also the observation from the CHYLD cohort that low sugars which recover faster are associated with more long term problems.

Hypoglycaemia could be defined as a statistically low glucose, as a glucose which causes short term CNS dysfunction, or as a glucose level which causes permanent CNS injury, or as a blood glucose level below which treatment improves outcomes. It seems unlikely that there is a single threshold that applies to all these potential definitions. I think the most practical way to define a threshold for hypoglycemia would be to find a threshold below which intervention is required in order to reduce adverse outcomes. In other words, to perform RCTs (which should not be difficult in such a common problem affecting 1/3 of all newborn babies).


Posted in Neonatal Research | Tagged , | 2 Comments

The jaundiced eye of the beholder

Well, this is disappointing, the amazing results from Iowa regarding the outcomes of infants born at 22 and at 23 weeks gestation have now been published in the February print edition of the Journal of Pediatrics. What is disappointing about it is the editorial comment from Dr deRegnier (deRegnier R-A. The eye of the beholder: Periviable outcomes in Iowa. The Journal of Pediatrics. 2020;217:1-3). In it, she suggests that “The reported outcomes will be interpreted as good or bad through the eye of the beholder”.

I don’t know what kind of beholder would see the survival of babies as a bad thing, even if the survival means that some of them might have cerebral palsy or developmental delay. (Watkins PL, et al. Outcomes at 18 to 22 Months of Corrected Age for Infants Born at 22 to 25 Weeks of Gestation in a Center Practicing Active Management. J Pediatr. 2019).

This is a group of babies, previously left to die and thus with a 100% mortality rate, who, the group in Iowa has shown us, can be rescued by high quality perinatal and neonatal care with the survival of 14 of 20 infants born at 22 weeks (14/24 if non-resuscitated babies and those not surviving initial resuscitation are included) and 41/50 at 23 weeks (14/52). Among the survivors evaluated, 11% had “severe NDI” which seems to have been almost entirely due to a Bayley-3 cognitive score less than 70.

The majority of survivors had no problems or minor problems. If there is an eye that beholds that as being a bad thing, then maybe the eye should be “plucked out” (sorry for the Christian reference; I am an atheist but with a Christian/protestant heritage).

Any reasonable human eye would surely behold a 60 to 70% survival, with encouraging long term outcomes, as a good thing. Other networks are also seeing progressive improvements in the survival of infants born at 23 weeks or less (the Canadian Neonatal Network for example) look at the figure below (from the 2018 annual report) for the survival among actively treated infants at 23 weeks and <23 weeks. Only 30% of babies under 23 weeks received active treatment, and there wasn’t much change in that over these years, but among babies born at 23 weeks the proportion receiving active treatment increased from about 60% to 70-80% over this period.

One day we hope to replicate the amazing success in Iowa, which I think only a very jaundiced eye could think was not a major advance in neonatology.

Posted in Neonatal Research | Tagged | 2 Comments

Giving bad news as it happens

A new publication from my great group at Sainte Justine. Lizotte MH, et al. Techniques to Communicate Better With Parents During End-of-Life Scenarios in Neonatology. Pediatrics. 2020:e20191925.

We have already published about what residents think about being part of a resuscitation simulation that fails. What we showed was that residents appreciated a resuscitation scenario where the baby dies despite them doing the right thing. (Lizotte M-H, et al. Trainee Perspectives on Manikin Death During Mock Codes. Pediatrics. 2015;136(1):e93-e8). What I mean by that is that one problem with resuscitation simulations is that usually, (for pedagogical purposes) if the trainee follows correct procedures, the patient recovers. In real life (IRL as the younguns say), you can do everything right, but the baby dies anyway. How do we teach residents the best way to convey the worst news possible while it is actually happening? And what is the best way anyway? In that previous study, residents noted that a simulated resuscitation that included simulated discussions with parents would be a good idea.

The idea behind the study was this: IRL sometimes babies die despite competent resuscitation. When that happens, it is usually without any preparation, and everyone is traumatized, the resus team and the obstetric team, but especially the parents. Can we describe, and then teach, the best behaviour in the worst of circumstances?

Our team decided to include bereaved parents, and not just medical ‘experts’, which was a very risky undertaking. Asking parents who had lost a child to evaluate the behaviour of medical trainees during the simulated death of a newborn had all sorts of potential problems; again we are ‘lucky’ to have Annie Janvier as part of the team; she has created links with many parents, including those who have lost a baby, and encouraged them to be part of our team improving quality in neonatal resuscitation. We had several levels of screening before finally collaborating with 6 bereaved parents in this study.

We were very careful to inform parents what they were getting into, to give them examples of what they might face, and then show them sample, fake, videos. At each stage, there were parents who didn’t feel able to continue, but finally, we were very fortunate to have several parents who wanted to help us teach residents how to give the worst possible news to parents.

In our simulation centre, we had 31 clinicians, who have to do neonatal resuscitation as part of their work, perform an extensive resuscitation where the manikin was programmed not to respond. Simulated parents were present and the resuscitation and the interaction with the parents was videoed and evaluated.

I can’t embed the video abstract here, but you can go and see it at this link: https://pediatrics.aappublications.org/content/early/2020/01/23/peds.2019-1925.long

Where you can watch Annie do her bit, and Ahmed join in speaking really quickly to be under the time limit.

We analyzed the interactions with the actor parents before, during and after the resuscitation, and then asked all the evaluators who they thought were the best communicators. The evaluators included a clinical psychologist, nurses, an NNP, an obstetrician and a few neonatal providers in addition to the parents and the 2 actors.

The scores given by the parents were routinely a bit lower than the providers, and the actors scored most people higher. There was a lot of agreement about who were the best communicators; we then analyzed the details of how they interacted with the parents to identify simple teachable skills that were associated with being a good communicator. Many of those skills were overtly identified by evaluators as being positive.

These are what we identified as positive behaviours and examples of things to say to the parents.

Interestingly many of the residents did not know the details of what happens to the body after death, some were juniors who had never really been involved in a death yet during their training; others had, but often still didn’t really know what the procedures were. The nurses all knew in detail.

Many of these behaviours are simple to learn and remember, some of them you probably already do, if you are involved in looking after critically ill children. But on a busy night on call, when you need to get back to the NICU for your other patients, and you are already tired and a bit frazzled, we can all forget things which in our best moments would be natural. I’ve been involved in many baby deaths. Most parents only experience it once. Being compassionate, supportive and caring are essential, and most of us in the field are there because we have those characteristics in our natures. Following these simple suggestions will help parents to feel cared for at the worst time in their lives.

Posted in Neonatal Research | Tagged , , | Leave a comment

Preventing prematurity for pennies, and perinatal death.

This is amazing and somewhat surprising, at least to me. When I saw the title of this article, Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial. I scanned over the methods and read the results, expecting to see yet another article with a null result. Maybe I am getting cynical but the idea that you could find a way to improve perinatal outcomes in the developing world at an affordable price seemed just inherently unlikely.

How wrong I was! After seeing the results I rushed back to the methods and read in much more detail. In seven sites in 6 countries (two in India and one each in the Democratic
Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia) 12,000 nulliparous women with singleton pregnancies were enrolled between 6 and 14 weeks of gestation and received 81 mg of aspirin or a placebo every day until they reached 37 weeks.

Preterm birth decreased from 13.1% with placebo to 11·6% with aspirin (RR 0·89 [95% CI 0·81 to 0·98]). There were also reductions in perinatal mortality (0·86 [0·73–1·00]), fetal loss (0·86 [0·74–1·00]), early preterm delivery (<34 weeks; 0·75 [0·61–0·93]), and delivery before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17–0·85]). Other adverse maternal and neonatal events were similar between the two groups.

I can’t see any real downside to introducing this intervention everywhere in low- and middle-income countries, other studies in multiple pregnancies are needed, and among singletons, a comparison with higher doses is required. I also don’t understand why this should work in nulliparous women, but not in multipara, so either trials in multiparous women should be performed, or there is some reason which I don’t understand to not do so.

On the maternal side, there was a small reduction in maternal hypertensive disorders, and no clear adverse impact.

A relative reduction of 14% in perinatal mortality, from 54/1000 to 46/1000 is an enormous change in mortality, with a potential to save hundreds of thousands of lives every year.

Even writing that makes me feel a bit humble; perinatal mortality of 54 per 1000, that is more than 5%! A small reduction in that mortality is a huge potential impact around the world.

I must, at this point, feel grateful to the sponsors of this study which was funded by the NIH. A study which might well have no real impact in the USA, but which was funded by the NICHD, and includes as one of its authors, almost hidden among the others the amazing Wally Carlo. This study is one reason to continue to hold in high esteem the principles on which the USA was founded, and its profile around the world. Even if these days it is hard to believe that those principles are being pursued, this study is proof that even in the heart of darkness there continues to beat a great light.

Posted in Neonatal Research | 1 Comment

Cephalhaematomas, just leave them alone?

I remember going from Edmonton to Ukraine, to Kiev, not long after Chernobyl, as part of what started as the Chernobyl Children’s Project and had by then been renamed “Osvita”, “education” in Ukrainian. There are many Albertans of Ukrainian background, including paediatricians, and the project was set up as an international program to promote collaboration after the break-up of the Soviet Union.

One of the interactions I had with the neonatal physicians there was at the bedside of a baby with a large cephalhaematoma. They asked me what we would do in Canada, and I said: absolutely nothing. I was informed that their practice was to drain the haematoma as if not there was “a risk of serious infection”. I told them (with a touch of superiority, given my first-world education) that, no, draining it introduced a risk of infection, and it would be better just to not touch it.

I realized afterwards that they had just been quoting what they had been taught, and I was just quoting what I had been taught, but that I didn’t actually really know who was right! (Except, of course, for the fact that I am always right….).

Large cephalhaematomas can take months to completely resolve, and in the meantime, marginal calcification can occur, and deformation of the skull can sometimes follow. A new publication reports the results of needle aspiration of large cephalhaematomas still present after 2 weeks of age without signs of resorption. (Blanc F, et al. Early needle aspiration of large infant cephalohematoma: a safe procedure to avoid esthetic complications. Eur J Pediatr. 2020;179(2):265-9). They note that there were no complications, they did this with local anaesthesia and sucrose, and it might actually, I think, be a reasonable idea.

One of the problems I see, with this common situation, is that almost all of the references given in the article are case reports. I cannot tell from the literature how often a cephalhaematoma might cause problems in the long term, with or without drainage. Of course, a randomized controlled trial would be the way to answer the question of what to do, but I have no idea how you would calculate the sample size. You could just guess a number and say if after a hundred babies in each group didn’t show a difference, then the choice of intervention could be left to the parents. Lacking that (which I think is unlikely to happen) some large case series with and without drainage could at least give us an idea. For such a common problem which probably causes parents to worry, and which also makes babies’ heads look funny, it would be great to have some good data.

Posted in Neonatal Research | 1 Comment

Does acidosis affect contractility of the neonatal heart? And does bicarbonate help?

I sometimes write posts which are not based on a new publication but to address a clinical issue that I think is important, and may not be clear to everyone. Often triggered by something that has happened in my own practice.

If you are a specialist in the domain you probably already know that the answers to the 2 parts of the question in the title are 1: very little, and 2: probably not.

To give a bit more detail:

The impacts of acidosis on myocardial function were first investigated to my knowledge in the 1960s in several papers published mostly in the American Journal of Physiology, it was shown that acidosis decreased contractility of isolated myocardial strips and ventricular preparations. If you go back to those articles you can find what we would consider medically profound extreme acidosis, pH typically of 6.0, induced often by adding HCl to the fluid surrounding the preparation.

Clearly, hydrochloric acid acidosis is not common in clinical practice, and a pH of 6.0 is usually only found post-mortem.

More recent studies have investigated more clinically important types of acidosis, more reasonable pH ranges, and the relative impacts on adult and neonatal myocardium.

Here is one example, using an isolated perfused adult rabbit heart, with a pH of 7.4 for the controls and pH=7.03 for each of the 3 models of acidosis. (Berger DS, et al. Disparate effects of three types of extracellular acidosis on left ventricular function. Am J Physiol. 1999;276(2):H582-94). As you can see respiratory acidosis had impacts similar to the HCl, leading to a 22% reduction in maximal pressure generation, whereas lactic acidosis only reduced pressure generation by about 8%. Elastance of the ventricle (the inverse of compliance) was not affected by lactic acidosis.

Even in the adult, therefore, organic acidosis has a much more modest effect than inorganic acidosis (there are other studies showing essentially the same thing), and respiratory acidosis is much more potent. Studies of hypercarbia without acidosis, on the other hand, show a smaller effect which is not sustained. The impact, as are most things related to contraction of muscles, seems to be mediated by changes in calcium flux. That becomes important when you start to think of neonatal myocardium, because it is very different.

Excitation of the cardiomyocyte is coupled to contraction by the flux of calcium into the cell which normally stimulates calcium release from the sarcoplasmic reticulum, the link between the sarcolemmal membrane and the SR being the t-tubule. There is also trans-sarcolemmal Na/Ca exchange which kicks in. T-tubules are absent in the newborn and there is very little SR, which basically means that you cannot extrapolate anything about myocardial function from the adult to the newborn. SR is probably still quite important, and recent data show a high concentration of calcium within the relatively sparse SR. However all the mechanisms underlying calcium flux are quantitatively, if not qualitatively, different, and you really need to test any intervention or abnormality in neonatal myocardium before assuming that it applies to the newborn.

This figure, as one example, (Nakanishi T, et al. Effect of acidosis on contractile function in the newborn rabbit heart. Pediatr Res. 1985;19(5):482-8) shows the impact of respiratory acidosis pH=6.8 on the calcium tension relationship in rat hearts, compared ot the adult. There is almost no detectable impact of a very low pH in the newborn.

In the same study, Toshio Nakanishi and his co-workers induced a metabolic acidosis (which was an inorganic acidosis) and found no effect on the neonatal myocardium

At the end of the acidotic period, there was a fall in developed tension (DT, a measure of contractility), which occurred when the acidotic perfusing solution was changed back to a neutral standard solution, containing bicarbonate. (The fall in DT at this point might be relevant, see below).

Despite my comments at the start, even in the 1960s there were studies using medically relevant models of acidosis, such as this one from Yale (Talner NS, et al. Influence of acidemia on left ventricular function in the newborn lamb. Pediatrics. 1966;38(3):457-64)
using an in situ heart preparation in newborn lambs,

SV10 is the stroke volume, MER10 is the mean ejection rate, and you can see that acidosis, which was induced by infusion of lactic acid to a pH of 6.9, had no effect on cardiac function, and no effect on the response to norepinephrine, if anything, the SV response to norepinephrine was greater with acidosis.

Does Bicarbonate improve cardiac function in acidosis?  Bicarbonate plus acidosis, of course, generates CO2 (HCO3- + H+ = H2CO3 = H2O + CO2) which diffuses rapidly across cell membranes and reacts with water to generate carbonic acid, reversing that equation, which releases H+. Bicarbonate administration, therefore, worsens intracellular acidosis when you administer it to acidotic subjects. It doesn’t seem likely that it would improve myocardial function.

Indeed most of the studies confirm the lack of benefit or an adverse effect. In this study for example, (Shapiro JI. Functional and metabolic responses of isolated hearts to acidosis: effects of sodium bicarbonate and Carbicarb. Am J Physiol. 1990;258(6 Pt 2):H1835-9) pH was progressively reduced to 6.8 by using buffers with lower bicarbonate concentrations, and then either saline, bicarbonate or carbicarb (an iso-osmolar mixture of NaHCO3 and Na2CO3 which buffers acid without producing CO2) were added. As you can see, Bicarbonate caused intracellular pH to fall slightly and had no effect on contractility (dp/dt max) whereas carbicarb did the opposite.

I don’t think there are entirely similar studies in the newborn, but there are studies in intact animals which generally show that metabolic acidosis is associated with an increase in dp/dt max, as they are intact animals it may be that there are changes in preload associated with this, so it may not be entirely a contractility change, but there is at least no evidence of a depression of contractility in these models. Basir MA, et al. Effects of Carbicarb and sodium bicarbonate on hypoxic lactic acidosis in newborn pigs. Journal of investigative medicine. 1996;44(2):70-4. Nudel DB, et al. Comparative effects of bicarbonate, tris-(hydroxymethyl)aminomethane and dichloroacetate in newborn swine with normoxic lactic acidosis. Dev Pharmacol Ther. 1993;20(1-2):20-5.

In these models, the increase in cardiac output or dp/dt max occurring with acidosis decreased when bicarbonate was administered.

So to summarize, metabolic acidosis in the newborn has little or no effect on myocardial contractility in several mammalian animal models of isolated myocardial preparations (lambs, rabbits and rats). Even in the mature myocardium, the impact of organic acidosis is relatively modest. And there is no evidence that response to catecholamines in the newborn myocardium is affected by acidosis.

In that context looking for a benefit of bicarbonate in the newborn would be a bit of a lost cause, which may be why there are no relevant studies that I could find. But even in the mature myocardium, the impact of bicarbonate use during acidosis has usually been shown to be a negative effect on contractility. What data there are in the newborn intact mammalian models show that cardiac function in some models is actually increased in acidosis, and decreased by the use of bicarbonate.

Posted in Neonatal Research | Tagged , , | Leave a comment

Do Probiotics work in the UK?

Seems like a dumb question I know, if they work in one country, surely they should work everywhere? It is sometimes difficult, however, to institute change based on studies that are done elsewhere, usually because there is an idea, or some evidence, that risk factors and other co-interventions may be different in published trials from local practice. Based on the results of the high-quality PIPS trial (multicenter RCT in the UK testing B. breve against placebo for prevention of NEC which did not show an impact), many centres in the UK have been reluctant to introduce probiotic supplementation.

A newly published cohort study from Norwich shows that there are some UK centres that have nevertheless introduced routine probiotic supplementation (Robertson C, et al. Incidence of necrotising enterocolitis before and after introducing routine prophylactic Lactobacillus and Bifidobacterium probiotics. Arch Dis Child Fetal Neonatal Ed. 2019:fetalneonatal-2019-317346). In 2013 they introduced probiotic prophylaxis, and they have seen an immediate and persistent reduction in NEC, using, at first, a preparation with 2 organisms, and more recently a preparation with 3 organisms, including a B longum sbsp infantis. They found more than a 50% fall in NEC after introducing probiotics, a decrease which was sustained, and did not seem to be associated with any other changes in practice. Breastfeeding frequency was stable, and they performed multiple analysis to try and confirm whether or not the probiotics were likely to be the main change associated with NEC reduction, no other obvious explanation was found. They evaluated the effects in multiple subgroups.

For the impact of diet, there were no cases of NEC among babies who received exclusively donor milk, but before you get excited about that, there were only 9 of them; there also weren’t many who got only formula (the group with the most dramatic impact in the figures above); 50 infants pre-probiotics, and 23 post. The majority had either exclusive breast milk or a mix of breast-milk and other sources.

There is some reason to believe that B. infantis is one of the most important of the probiotic organisms, and systematic reviews now generally show that a combination of probiotic organisms is more effective than a single strain. (Hagen PC, Skelley JW. Efficacy of Bifidobacterium Species in Prevention of Necrotizing Enterocolitis in Very-Low Birth Weight Infants. A Systematic Review. J Pediatr Pharmacol Ther. 2019;24(1):10-5).
Many of those combinations contain a Bifidobacterium which is at least similar to B infantis.

Promoting and supporting colonization with B. infantis and doing what we can to normalise the intestinal microbiome of the very preterm infant is a goal which seems to bear fruit. Finding better ways of doing this and reducing colonization with pathogens are important goals for the future. Testing the appropriate prebiotic molecules to support the growth of B. infantis, such as 2′-fucosyl-lactose should be a priority.


Posted in Neonatal Research | Tagged , | Leave a comment

Breathe baby, breathe!

Annie’s book is now available in English.

It is a distillation of the notes she made while our daughter was in the NICU, as well as additions written later, chapters written by caregivers, reprints of some of Annie’s narrative articles, and even a poem.

It is published by the University of Toronto Press. If you click here you will be taken to a page where you can order a printed book or an ebook. The front cover may look familiar, which means I am now a published photographer!

It is also available on Amazon, at least in Canada and in the USA and in the UK, there is also a Kindle edition on those websites. In other countries, I don’t know the availability.

The reviews on the U of T press website are copied below:

Breathe, Baby, Breathe! is incredibly honest, and there are times when you are brought to tears. Dr. Janvier not only discusses what it is like to be the mother of a premature baby, but its impact on her own sense of self-worth and the challenges to her family.”

Lainie Ross, Professor of Clinical Medical Ethics and Pediatrician, University of Chicago

Breathe, Baby, Breathe! is a book about resignation, resilience, and transformation.”

Nicolas Krawiecki, MD, Professor Emeritus of Pediatrics, Emory University

“Annie Janvier has written the best book by far about prematurity for parents and health care providers. As a neonatologist, bioethicist, and mother of an extremely preterm infant, her voice is unique, and we should all listen to her wise and eloquent words. Her intensely honest account of giving birth to Violette at 24 weeks’ gestation and her subsequent experiences as a mother in the NICU is quite remarkable. This amazing book is written from Annie’s heart but also from her brain and her gut.”

Edward Bell, MD, Vice Chair for Faculty Development, Department of Pediatrics, Professor of Pediatrics – Neonatology, University of Iowa Health Care

Posted in Neonatal Research | Leave a comment