Linezolid seems safe for preterms, probably

A few years ago we started having difficulty clearing Coagulase-Negative Staphylococcal (CoNS) sepsis from the blood cultures of some babies in our NICU, children with CoNS also seemed to be sicker, and to more often have thrombocytopenia. It was at that time that I learnt about heteroresistance. This is a phenomenon, as I understand it, where within a colony of vancomycin susceptible CoNS there are a few individuals which are much less sensitive, sub-cultures of the original strain continue to show this heterogenicity of vancomycin sensitivity. This makes it difficult to eradicate the condition with vancomycin.

As a result, we started using linezolid as an alternative for a few cases, and for a short time, it even became our standard anti-CoNS antibiotic, but especially for babies presenting with moderate-to-severe illness severity and thrombocytopenia.

There was very little to base dosing on in the preterm, and little or no knowledge about toxicity in the newborn. There is apparently a risk of peripheral neuropathy in adults after prolonged use, which is usually reversible, so we were concerned that there were potential neurological impacts. The long term safety of many treatments is not clear in the preterm infant, which is not an excuse for introducing more interventions of unknown safety, but does help to put this in context.

We had actually used linezolid once or twice before this occurrence, as it is well absorbed orally, so we had decided, for some babies with difficult IV access and in whom the only indication for IV access was for administration of antibiotics, to finish their antistaphylococcal treatment with oral linezolid.

There does seem to be an increased risk of neurologic impairment and developmental delay in infants who have had a CoNS sepsis, but it is probably less important for that outcome than gram-negative sepsis. We decided we had better investigate the impact of treating CoNS with linezolid, so we decided to compare our outcomes with those of 2 other large Canadian NICUs in the CNN, Mount Sinai in Toronto and BC Children’s in Vancouver.  Sicard M, et al. Neonatal and Neurodevelopmental Outcomes Following Linezolid for Coagulase-negative Staphylococcal Infection: Real World Evidence. Pediatr Infect Dis J. 2020. In the period covered, Sinai had not used linezolid at all, BCCH had used it a few times, and we treated 3/4 of our cases with the stuff.

The baseline data show that babies who received linezolid were indeed sicker, more getting vasopressors, and more receiving a transfusion of something (mostly platelets). We, therefore, corrected for these factors in the analysis of survival and of neurological impairment or developmental delay. In terms of survival, this was a bit lower in the infants who received linezolid in the first 30 days after the episode, but the difference was not great and disappeared after adjusting for severity of illness.

Long term neurological and developmental outcomes were very similar after adjusting for severity of illness. Even though there were more deaths in the very long term after linezolid use, as mentioned there was no difference in the first 30 days after using the medication, so it seems very unlikely to be causative.

Since this period our CoNS sepsis has again become less virulent, and we don’t seem to be having the heteroresistant strains any longer, so we now only use linezolid in rare cases. I wish I knew why changes like that happened!

Why not use linezolid more? It can be given orally, monitoring levels is fairly easy, and not clearly required. We now have about as much data about the safety of linezolid as about many other drugs that we use in the newborn; vancomycin, for example, is described as having about a 5% frequency of nephrotoxicity, and we have no idea about long term safety, but it seems no worse than linezolid from our study. A randomized comparison of vancomycin vs linezolid, examining long term outcomes in preterm infants with CoNS would be the best approach but seem unlikely to be done in the near future. Good quality registry RCTs could answer the question quickly and cheaply, but would still require some funding. In the meantime, observational studies like ours will help to allay some fears, but risk missing some adverse impacts, especially as we did not collect some data, for example acute creatinine changes.

I guess that the common response in such situations is that we have been using vancomycin for a long time, we think we know it, and its possible complications, and introducing a new agent, which does not have overwhelming advantages, is something we try and avoid.

 

 

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What to do about early postnatal steroids?

Steroid metabolism in the very immature infant is… immature. Adrenal function is still developing in the fetus between 20 and 26 weeks, and a source of precursors from the placenta is important, but obviously disappears at delivery. Very preterm babies might have limited responses to stress, and therefore might benefit from administration of steroids. Some studies seem to show that extreme preterms who have lower cortisol levels, and/or lower responses to ACTH stimulation tests, have more mortality, or perhaps more BPD, but those data are confusing, and somewhat inconsistent. Babies exposed to chorioamnionitis have higher cortisol concentrations over the first week of life at least.

This micro-summary of the evidence underlying the rationale for replacement trials does suggest that some form of replacement is worth investigating, but for whom, and when?

There are a number of possible approaches to the very early use of hydrocortisone.

1) Immediate replacement therapy for all extreme preterm infants.

2) Immediate replacement therapy for selected infants

3) Slightly delayed (12 to 48H) therapy for selected infants with ongoing respiratory problems, or other diagnoses.

4) More delayed therapy (48h to 7 days) for selected infants with ongoing respiratory problems, perhaps with larger doses.

5) Therapy after 7 days of age, when lung inflammation has set in, with larger hydrocortisone doses.

A recent individual patient meta-analysis of studies which were referred to as “prophylactic” included 4 trials which, from this viewpoint, were in categories 1 and 3. (Shaffer ML, et al. Effect of Prophylaxis for Early Adrenal Insufficiency Using Low-Dose Hydrocortisone in Very Preterm Infants: An Individual Patient Data Meta-Analysis. The Journal of pediatrics. 2019;207:136-42 e5). I think that the implications of those 4 trials is quite different between group 1 (which is only the PREMILOC trial of 521 babies), and the other 3 trials which include 360 babies from Kristi Watterberg’s trial, and 100 total from 2 other trials, those three trials are in my category 3.

The PREMILOC trial (Baud O, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. The Lancet. 2016;387(10030):1827-36) did not have any postnatal illness criteria, but did exclude infants with severe growth restriction (<3%le), early rupture of membranes (<22wks). asphyxia (5-min Apgar <4) and congenital anomalies seen before birth. The growth restriction criteria would probably have eliminated more than 3% of babies from eligibility, depending on the definitions used. The other exclusions, probably fewer than that. The study did not include any babies of 23 or 22 weeks best-guess gestational age (BGGA).

Those other 3 trials included in this IPD meta-analysis are :

1. Watterberg, included infants of 500-999g if they were ventilated between 18h and 48h; they were randomized at an average age of 33 h. (Watterberg KL, et al. Prophylaxis of Early Adrenal Insufficiency to Prevent Bronchopulmonary Dysplasia: A Multicenter Trial. Pediatrics. 2004;114(6):1649-57). The 360 randomized infants received 1 mg/kg/d for 12 days, then 0.5 for 3 days, or placebo.

2. Peltoniemi 2005, who randomized 51 infants of 23 to 30 weeks and 500-1250 g birth weight, ventilated before 24 h (the larger babies were ventilated for >24h with O2). they received 2mg/kg/day for 2 days, then 1.5 for 2 days, then 0.75 for 6 days. (Peltoniemi O, et al. Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants. The Journal of pediatrics. 2005;146(5):632-7). Hydrocortisone was started before 36 hours of age, but I can’t find the average postnatal age of administration.

3. Bonsante 2007, included 50 infants born at 24 to 30 weeks, and 500 to 1250 g, ventilated after surfactant, at less than 48h of life. They received 1 mg/kg/d for 9 d, then 0.5 for 3 days. (Bonsante F, et al. Early Low-Dose Hydrocortisone in Very Preterm Infants: A Randomized, Placebo-Controlled Trial. Neonatology. 2007;91:217-21). The actual age when the hydrocortisone was started is not clear.

Although I do think that including all of these trials in an IPD-SR is not unreasonable as a way of investigating the issues, it makes figuring out the implications for practice difficult;  Premiloc asks the question: is it safe and effective to give all infants between 24 and 28 weeks BGGA low dose hydrocortisone within the first 24 hours of life? Will it likely improve outcomes without increasing hazards? Or more than the increase in hazards? The 3 trials in category 3 inform a response to a somewhat different question; is it safe and effective to give steroids to all infants of less than 28 weeks who remain intubated for respiratory problems at around about 24 hours of age?

If we divide the trials in this way we end up with much less power, and with results with wider confidence intervals as a result. The results of the PREMILOC trial must also be evaluated with reference to the much higher mortality in that trial than in my practice, or indeed in Canada overall. In PREMILOC the mortality for the combined group of 24 to 25 weeks gestation was 43% (almost identical between groups, 42% hydrocortisone and 44% control). In 2016 in the CNN report the mortality at 24 weeks was 27%, and at 25 weeks was 19%; 23% for the 2 GA weeks combined. (As a side issue, survival continues to increase, in the 2018 report mortality at 24 weeks is down to 22%, and at 25 weeks remains stable at 18%, for an overall of 20% mortality for the two weeks combined).

It is hard to know what to do with the results of a good quality trial like PREMILOC when the intervention group, who had better results after early universal postnatal hydrocortisone than the controls, have much worse results than our babies without routine hydrocortisone; indeed, double the mortality.

When the mortality is twice as high in the better group in a trial than our mortality without the intervention, can we expect any beneficial impact of the intervention on our outcomes? PREMILOC also showed a dramatically higher risk of late-onset sepsis with hydrocortisone than controls among the more immature group, 40% compared to 23%. It is also worth mentioning that 30% of the 24 and 25 weeks babies received hydrocortisone after the study period (slightly fewer in the hydrocortisone group than controls) and 11% of the HC babies and 13% of controls received post-study betamethasone, it isn’t stated how many received both.

The results in the other trials also need to be taken in context, but as they are a selected subgroup of babies it is much harder to compare with local or national results. In Watterberg, for example, the mortality was 17% before discharge, and not different between groups. The original publication notes that the survival without BPD was basically identical between groups, 34% and 35%, or 43 and 42% using a physiologic definition. The IPD meta-analysis, in contrast, gives a slightly larger difference, and numbers which are different to either of the two reported numbers, 38% vs 41%. But in any case, if we put all the trials into a standard-type meta-analysis it looks like this, for the result of death or BPD:

If we take out the group 1 trial (Baud) and just look at those with early selective treatment of babies being ventilated after the first few hours of life, it looks like this ;

And if we take out the small trials, which are much more likely to show positive effects which are routinely exaggerated compared to larger trials, and take out the trial with co-intervention of hydrocortisone and T3 you are left with this:

There has been quite a lot of debate recently about systematic reviews and the fact that the Cochrane approach, of including all randomized babies, risks exaggerating the benefits of treatments, as smaller trials are much more likely to have positive results. Lower quality trials are also much more likely to have positive results.

I don’t like the idea of just eliminating smaller trials from the analyses, but sensitivity analyses focussed on larger trials, and on higher-quality trials, sometimes give different results to those obtained when all trials are included, and should be routine, I think, in a systematic review. Analyses could also be limited to trials which were registered prior to being performed, and further limited to trials where the primary outcome in the registration document is the same as the one in the final publication, to give an objective way of only including trials of high quality, even if they are small.

To return to the original question, what to do about postnatal steroids, I haven’t mentioned group 4 and 5 trials, but the Dutch multicenter trial of Wes Onland et al I discussed when it first came out, is in my group 5. It does seem to show a decrease in mortality with higher dose hydrocortisone after the end of the first week. There are some problems with extrapolatability for this trial also, I can’t find any published Dutch survival and BPD data more recent than 2011, but this article (de Kluiver E, et al. [Perinatal policy in cases of extreme prematurity; an investigation into the implementation of the guidelines]. Ned Tijdschr Geneeskd. 2013;157(38):A6362), after the change in Dutch guidelines to promote active treatment at 24 weeks gestation (thank you Google translate!), reported a 43% survival at 24 weeks, and 61% at 25 weeks, much lower than contemporary Canadian results, and 64% BPD incidence among survivors at 24 weeks, and 44% at 25 weeks. The Onland trial started in 2011, so these figures have some relevance. In the Flanders region of Belgium in 2011 (Draper ES, et al. Variability in Very Preterm Stillbirth and In-Hospital Mortality Across Europe. Pediatrics. 2017) survival at 24 and 25 weeks combined was only 40% and was 0 at 22 and 23 weeks.

For this trial, it is much harder to think about whether it may be relevant to my practice, the babies included were already receiving intensive care and had survived to a week of age, I don’t know whether the results of a similar group of babies in my current practice would be similar enough for me to be able to expect a similar impact on survival. But I am concerned that a mortality of 24% in the control group seems very high. If you use the online BPD calculator of the NICHD, using data from 2000 to 2004 (based on the publication by Matt Laughon), you can input data from a virtual baby similar to the average infant in the control group (male, 26 weeks, 710g, and 35% oxygen); the predicted mortality is 9.5%. substantially less than the mortality before discharge of the intervention group in Onland et al, which was 15.5%.

I know that comparing a point prediction from the online tool for a single baby similar to the mean baby in the Onland trial is not directly comparable to their findings, but it does give me pause to see so much higher mortality among the controls in the trial.

I think that I am not ready to give routine hydrocortisone to all babies between 24 and 28 weeks based on these data, nor to give them to 22 or 23 week BGGA babies. There are no clear data that giving them to babies at 24 hours of age who are still ventilated is beneficial either. I think, prior to changing practice and instituting a potentially hazardous treatment (increase in late-onset sepsis) I need a trial similar to Permiloc, which includes babies of under 24 weeks, in an environment with mortality more similar to current mortality in Canada, the USA, the UK, Germany, Australia and New Zealand, or Scandinavia (not an exclusive list!)

Perhaps a reasonable approach for the present would be to consider hydrocortisone therapy at 7 days of age if an individual baby’s predicted mortality is over say 24%. The Onland trial would suggest that this had a chance of reducing mortality, with little adverse consequence.

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We are all treaty peoples

We are all treaty peoples if we live in North America!

We, at least the “we” who are concerned about such things, have a tendency to think that the treaty people are only the aboriginal descendants of those who had their lands expropriated by the European invaders. We think that term only relates to the people who then signed treaties to protect the small areas that were left. But a treaty is an agreement between 2 peoples, that creates a requirement on both sides to abide by that agreement. Just because the treaties were signed over the last 300 years doesn’t relieve me of my responsibility, as an immigrant to Canada, to be bound by those treaties.

Some years ago Annie and I wrote an article with Brett Schrewe, one of our brightest residents. It was about a case of near-death in an otherwise healthy full-term infant placed in skin to skin with his mother, who suffered an arrest. Since then I have been very interested in that particular phenomenon, and I try to keep up with the literature.

Brett, on the other hand, has moved on to other things and is now a paediatrician in British Columbia.

I was delighted to read his recent article (Schrewe B. Who matters? Paediatr Child Health. 2019) about the provision of health care to indigenous children, even though some of the terminology (“allyship”, really Brett?) is a bit beyond me, the basic message, and the emotion behind it, is clear and extremely important.

Non-Indigenous Canadians cannot know the intricacies of the hurt or ever claim to know what it has been like to live this history from that perspective. Yet these events nonetheless bind together those of non-Indigenous and Indigenous heritages, for in this story we have all lost: what happened and continues to happen has deprived every single Canadian of the benefits of an equitable country. This matters morally as human beings, but it also matters as citizens: we are, by Canadian law, treaty persons, compelled to acknowledge historical title to unceded lands that comprise the majority of British Columbia as we are to honour the 97 treaties and Land Claim Agreements made by the Crown since 1701. Being a treaty person means having lifelong obligations to those with whom we live in treaty as well as a duty to ask why their benefits continue to be asymmetrically distributed. To ignore these existential relationships is akin to assuming our bodies could exist without their hearts or that the book of our history is comprehensive despite chapters obviously torn out.

The descendants and heritors of those who signed these treaties continue to be bound by their conditions. The injury to our society which is evident from the profound deprivation of many aboriginal children, and their families, is an injustice which has impacts on all of us, whether you are a first nations person, or not.

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They really are CRAP! C-ReActive Protein: “Hazardous Waste”.

I have railed against the use of C-Reactive Protein, CRP, on this blog previously, it was my analysis that the CRP is sensitive, but with very poor specificity, both for early-onset sepsis, and for late-onset sepsis. A new systematic review in JAMA Pediatrics (Brown JVE, et al. Assessment of C-Reactive Protein Diagnostic Test Accuracy for Late-Onset Infection in Newborn Infants: A Systematic Review and Meta-analysis. JAMA Pediatr. 2020)
suggests that I was wrong (gasp!), CRP is not very sensitive either.

Analyzing 22 publications including over 2000 infants using CRP to diagnose culture-positive sepsis among mostly preterm infants after 72 hours of age. Among the infants in the studies who presented with clinical signs suggestive of sepsis, the systematic review overall included articles where positive cultures were found in 40%.

The results show a test that is of virtually no value at all, whatever threshold was used for deciding that a CRP result was positive. After analysis of the results, they found: “At the reported median specificity (0.74), sensitivity was 0.62 (95% CI, 0.50-0.72); at the reported lower quartile specificity (0.61), sensitivity was 0.76 (95% CI, 0.66-0.83); at the reported upper quartile specificity (0.84), sensitivity was 0.45 (95% CI, 0.34-0.57)”.

Sensitivity and specificity refer to the performance of the test, the meaning and usefulness of a test depend on the prevalence of the condition among those tested, which will then lead to the positive and negative predictive values. This is illustrated by the great editorial, with a Barrington-esque subtitle, which accompanies the systematic review, (Cantey JB, Bultmann CR. C-Reactive Protein Testing in Late-Onset Neonatal Sepsis: Hazardous Waste. JAMA Pediatr. 2020)

If a baby presents with signs suggestive of sepsis you could do one of 2 things, send 0.4 mL of precious blood to the lab for a CRP when you do the blood culture, or save the baby’s blood (or add it to the blood in the culture bottle to increase the yield) and flip a coin instead. This table from the editorial shows the relative value of a CRP test and a coin flip.

Flipping a coin saves blood, saves money, and is just as useful as performing a CRP!

One adverse consequence of measuring CRP is that there is sometimes an assumption that, even when the culture is negative, if the baby had an elevated CRP they must have “culture-negative sepsis” and they then receive multiple days of unnecessary antibiotics. I think the argument on rounds that we should continue the antibiotics “because it was a ‘heads'” would be laughed at, we should do the same thing when someone says we should continue antibiotics because the CRP was elevated.

Measuring CRP in the evaluation of late-onset sepsis should be abandoned. The big question to answer now is whether we consider ‘heads’ or ‘tails’ to be a positive test!

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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.

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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)

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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).

 

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