Creating smoke-free homes for preterm babies

In response to my previous post about preterms smoking I was directed to a recent publication about the issue, Notley C, et al. Development of a Smoke-Free Home Intervention for Families of Babies Admitted to Neonatal Intensive Care. Int J Environ Res Public Health. 2022;19(6). Although the title of this post refers to preterm babies, because I linked my previous concerns to the potential deterioration of lung health in former preterm born adults, the publication deals with all babies in the NICU. As the authors of this study note, maternal smoking during pregnancy increases the chances that their infants will be admitted to the NICU. And even though smoking has become much less frequent over the last couple of decades, there are still between 10 and 18% of adults who smoke in Quebec depending on age group (2020 data from Stats Canada). Probably, therefore, around 20% or more of NICU parents smoke here, and improving the respiratory health of all our NICU graduates will be very dependent on protecting them from environmental smoke.

The smoke-free intervention that was evaluated was as evidence-based as possible, following a systematic review (Brown TJ, et al. Systematic Review of Behaviour Change Techniques within Interventions to Reduce Environmental Tobacco Smoke Exposure for Children. 2020;17(21):7731). Most stopping smoking interventions are disappointing in terms of efficacy, so any intervention should be as evidence-based as possible, to select those features for an intervention which might work. Nicotine is incredibly addictive, with most smokers having great difficulties in quitting. Brief advice, group support or individual “buddy” support, nicotine replacement therapy and a couple of medications have been shown to have some effect. Increasing cigarette prices is one of the most effective, but not something we can have much impact on! Interestingly, it seems that brief advice (less than 30 seconds) is at almost as effective as longer lectures… Probably a more widespread lesson there.

At a minimum, we should ensure that all parents taking home a baby from the NICU have been questioned about their smoking status, have brief advice to inform them that it is a risk factor for themselves and for their baby, and are given access to smoking cessation resources. In the paper which I reference at the beginning of this post, they held interviews and focus groups with parents and health professionals; “Findings demonstrated that both parents and healthcare professionals supported the need for intervention. They felt it should be positioned around the promotion of smoke-free homes, but to achieve that end goal might incorporate direct cessation support during the NICU stay, support to stay smoke free (relapse prevention), and support and guidance for discussing smoking with family and household visitors.” In general, parents will likely be open to being questioned about smoking, and will appreciate a more global approach to the health of their family after discharge.

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Evidence-based neonatology, or science based neonatology?

To many followers of this blog, the title may seem a little strange; is there any difference? Surely science underlies all of our field, and testing treatments in adequately designed trials leads to progressive improvements through the application of evidence-based therapies.

In general, the evidence-based therapies that we have in our field have been based on scientific understanding, basic biochemistry, developmental biology, and so forth, which has led to the development of therapies (I am thinking of surfactant replacement as the shining example) which have then been proven effective in clinical trials. This particular therapy was developed from observations of the role of surfactant in the lung, evidence that infants with HMD lack surfactant, investigations of the various components and development of stable mixtures, which were then tested in animal models, and finally in large multicentre RCTs and showed efficacy. The vital importance of EBM is shown by some counter examples; as one example, the use of immunoglobulins as a treatment of neonatal sepsis had a reasonable scientific basis, with preterm babies have very low Ig concentrations, and knowing that immunoglobulin deficient older children were at very high risk from sepsis. However, the pivotal trial of IgG supplementation was negative.

The problem with evidence-based neonatology, without a science-based foundation, is that interventions without any prior plausibility can be tested, just because someone thinks that maybe it could be a good idea, but without a reasonable scientific basis. Because there has not been an RCT it could be considered that there is no evidence to decide whether an intervention is effective or not. This can lead to the ridiculous situation of performing RCTs of interventions with as much scientific plausibility as a Harry Potter spell. By which I mean homeopathy, acupuncture, osteopathic or chiropractic manipulations, aromatherapy, and any other quackery that you can think of.

Evidence-based medicine has sometimes become divorced from the scientific baseline that should underlie it all. When an intervention is tested that has no real prior plausibility, there is always a risk of a spurious positive result just from random effects. Add to that the fact that, very often, investigations of unscientific interventions are often designed and performed by “true believers”, leading to methodology and interpretation biases. Positive trials can then be interpreted as proving that an intervention which cannot possibly work has actually been shown to be effective.

There are a few recent examples in neonatology of unscientific nonsensical interventions being published as showing that they are effective. Fortunately, I don’t think that applies to homeopathy, at least, I just did a search of Pubmed for randomized trial of homeopathy in the newborn and I found nothing from an NICU, although there were a couple of trials in older children. For anyone not aware, homeopathy requires the administration of enormously diluted substances, which, in their undiluted state, reproduce the symptoms of the disease being treated. Dilutions are usually so extreme that most often, when someone takes a homeopathic medication, they are not getting even a single molecule of the original substance. According to the nonsensical theories that underlie homeopathy this makes them more effective, the more diluted they are, the stronger the effect. Sometimes the medications that are actually sold as being homeopathic remedies do, in reality, contain active ingredients, which may be toxic. Death from atropine contamination of a supposed homeopathic teething remedy has been reported, and hundreds of adverse effects have been noted, which are, of course, not because truly homeopathic remedies are toxic, they are not, they are just water, but it is because some of what are sold as homeopathic remedies actually contain toxins.

Acupuncture is just as unscientific as homeopathy, being based on ideas about a life force (Qi, a very useful word if you are playing Scrabble, but not a scientific concept) which is conducted in meridians. Neither Qi nor the meridians actually exist. There are many RCTs of acupuncture in the literature, and objective evaluations have shown that the better the controls the less the efficacy of acupuncture, for any outcome. Controlled trials have shown that it doesn’t matter where you put the needles, or even if the needles actually puncture the skin. Acupuncture is most often studied as an analgesic, and is sometimes “enhanced” by passing an electrical current between the needles, this is often touted as being a variety of acupuncture, but is actually a variety of TENS. In other words, acupuncture is just a theatrical placebo, and one we should not subject our patients to, it has zero prior plausibility, given the lack of any scientific evidence for the existence of Qi, or the existence of meridians.

It is indeed unfortunate that otherwise sensible physicians can be misled into performing research studies of this nonsense, it becomes a despicable failure when they are performing painful procedures on babies and not giving them appropriate analgesia. The supposed justification for this “research” is that acupuncture is used a lot, even in children, and some studies seem to show analgesia. But, as I already mentioned, the apparent effect of acupuncture on pain gradually becomes less as the studies are better designed.

The most recent investigation of quackupuncture that I saw from an NICU was an investigation of what is called laser acupuncture! (Stadler J, et al. Laser acupuncture versus oral glucose administration for pain prevention in term neonates. Acupunct Med. 2021). That is, shining a light on the skin of the baby, which was supposed to be worth investigating as analgesia prior to heel pokes. But wait, they used the quackupuncture point LI4, which is well known to be the magical non-existent point, “Large Intestine 4” so what could go wrong? What went wrong of course was that the intervention was not blinded (although the person evaluating the videos of the babies responses to the heel poke was supposedly masked) the control intervention was “30% glucose solution over a period of 30 seconds”, but no dose is noted, there is no mention of soother or swaddling or skin-to-skin contact, all of which are effective in markedly reducing pain responses to heel pokes. The PIPP scores increased to a median of 12 in each group, which shows there was inadequate analgesia in both groups. PIPP scores over 7 imply that the pain is substantial, and good analgesic approaches, with swaddling and sucrose and a soother, or with kangaroo care, for example, will usually maintain PIPP scores less than 8, in this study for example, with a higher dose of 0.5 mL of sucrose the median PIPP score was 5 during the procedure, compared to 7 with the lower dose of 0.2 mL. In another study the effects of kangaroo care and sucrose were shown to be equivalent, and the median PIPP score hardly changed across the study, with a median of around 6.

The result of the Stadler et al trial, therefore, showed that acupuncture was basically useless, and so was the control intervention. Of course, as they usually will, the believers in acupuncture try to find some signal in the noise to pretend that maybe shining a light on the babies skin did indeed have an analgesic effect, and they come up with the observation that the heart rate slowed down faster after the laser light “therapy” than after inadequate glucose therapy.

What about ear acupuncture? Well, just as ridiculous as the above trial, is an investigation of sticking magnets to the babies ear, which is touted as being a safer form of TCM (Traditional Chinese Medicine). (Gan KML, et al. Magnetic Non-invasive Auricular Acupuncture During Eye-Exam for Retinopathy of Prematurity in Preterm Infants: A Multicentre Randomized Controlled Trial. Front Pediatr. 2020) Ear acupuncture actually has nothing to do with TCM, it was invented in 1957 by a French physician, Paul Nogier, who thought that the folds in the outer ear resembled a fetus, so he thought that sticking a needle in the stomach of the “fetus” would be good for stomachache. Since then, other points have been made up, which are supposed to represent specific parts of the brain. Because, I guess, people shied away from sticking needles in the ears of the babies, they decided to glue tiny magnets to them instead, the justification given for this, in a previous article, was that magnetic fields have been shown to have biologic effects. Which is true, but the review article they gave as a reference refers to fields up to 8 Tesla! Which is about 8 times more than an MRI and about a trillion times more than the tiny beads that they stuck on the babies ears. And even if there were some measurable effect on blood flow in the skin under the magnetic bead (for example), so what?

The beads were actually moved around the ear, in a procedure laughably called “Battlefield acupuncture”! Supposedly, the name is derived from use in the battlefield of medical practice, and the myth has grown up that it is used by quackupuncturists for acute pain from injuries. The magnetic beads are moved around the ear sequentially, to points which have been invented to represent: (1) Cingulate Gyrus, (2) Thalamus, (3) Shenmen, (4) Cranial Nerve-5 (Ophthalmic branch). This reminds me of witchcraft, casting spells using nonsensical words designed to impress. In this particular case the magic spell was invented in 2001, and the evidence for its efficacy, according to the practitioner that invented it, is that people attending the inventor’s course give him laudatory comments! Who needs science when you have evidence like that! I wonder if, like magic spells, if the beads are moved around in the wrong order, or backwards, then that reverses the effects and may cause mayhem!

Why anyone with a training in medical science would give any credence to this nonsense is beyond me, still less to organise a multi-centre trial of sticking magnets to the ear for pain relief during retinopathy screening. Nevertheless, that happened, and the trivial differences in PIPP scores between the groups, (which are presented as mean and SD, even though this is an ordinal scale) were means of 13.5 and 11.9, with SD of around 4 in each group. The results are actually presented with an incomprehensible table which includes the value of something called the “intercept” and seems to show that the baseline scores were also different between groups, by 0.7.

But doesn’t the “significant” p-value mean that the authors showed an effect, you might ask? Let us for the moment assume (and it is a very big assumption) that the analysis of the videos was indeed completely masked to study group. As mentioned above, the people doing the trial are clearly “true believers”, so it would be completely unsurprising if there had been some “leakage” of information, with some degree of partial unblinding. The person who applied the stickers was unmasked, which scould easily have some impact on the proceedings.

The prior probability of the analgesic efficacy of moving tiny sticky magnets around various made-up spots in the ear is about as close to 0 as it is possible to be; but let us be generous and propose that there is a 0.01% chance that sticking tiny magnets to the ears of preterm babies could affect pain responses, by some undescribed mechanism, dependent on unknown biochemical, cellular, and anatomical pathways. In that case, using Bayesian reasoning, even with a p-value of 0.03, it remains incredibly unlikely that the finding represents a real phenomenon.

I think it is shameful that this study was performed. It is shameful that the ethics review committees of these hospitals approved this study, the Royal Hospital for Women, Sydney, the Royal Alexandra Hospital, Edmonton, and the University Malaya Medical Center, Kuala Lumpur, have a lot to answer for, research is only ethically acceptable if it is scientifically valid. Wasting the resources involved in performing this study, and impacting the lives of the families who consented is shameful. Frontiers in Pediatrics should be ashamed to have published it.

Adequate pain relief for retinopathy screening is a major problem for our patients, and we really need to investigate science-based methods to reduce they distress they experience.

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Antenatal steroids prior to late preterm delivery; still many questions, but a major shift in practice.

It can sometimes take years for major advances in medicine, based on clear evidence of improved outcomes, to lead to shifts in practice. One example is the initial demonstration by Liggins and Howie that antenatal steroids (ANS) improved survival of preterm infants, it took 23 years before the American College of OB/GYN supported their use, and low rates of ANS treatment are evident in the data from trials (that is, even from active academic centres) well into the 1990’s. Sometimes the opposite happens, there is a huge shift in practice, even affecting patients for whom there is no good evidence, when the advantages are questionable, and adverse effects have not yet been ruled out.

Perhaps because of their tardiness in accepting ANS prior to very preterm delivery, our US Obstetric colleagues seem extremely keen to use ANS prior to late term delivery. Remember that, in the pivotal ALPS trial (Antenatal Late Preterm Steroids) although “statistically significant”, there was a relatively modest impact on the primary adverse outcome (death or respiratory disease needing over 30% oxygen or positive pressure), an absolute 3% reduction, which was mostly due to an absolute 3% reduction in need for CPAP/Highflow cannula; there were no deaths in either group. That trial also showed an absolute 3% decrease in NICU admission, and an absolute 9% increase in hypoglycaemia, with an NNT of 33 to prevent an additional baby needing CPAP, and an NNH of 11 to have one more baby developing hypoglycaemia.

This new publication demonstrates how much ANS prior to late preterm delivery has changed since then, and the “spill-over” into use for deliveries at term.

Kearsey EOR, et al. The Impact of the Antenatal Late Preterm Steroids Trial on the administration of Antenatal Corticosteroids. Am J Obstet Gynecol. 2022.

These data from a birth certificate database show an immediate dramatic increase in ANS usage, and ongoing increases in use since then, with the shaded part of the graphs starting in Feb 2016 when the trial was published in the NEJM.

Women with diabetes diagnosed prior to pregnancy were not eligible for the ALPS trial, but that hasn’t prevented a major increase in use of ANS for those women, prior to late preterm delivery. The trial also excluded women presenting at full term.


It is really unclear whether ANS are safe for this group of mothers and babies, despite what I said recently about hypoglycaemia, I don’t think we should be trying to create more of it! Particularly among mothers who would not have been eligible for ALPS (term or diabetic) the risk/benefit ratio is completely unknown.

Why ANS might increase hypoglycaemia is studied in another on-line first article in the same journal (Battarbee AN, et al. Mechanism of neonatal hypoglycemia after late preterm steroids: are fetal metabolic effects responsible? Am J Obstet Gynecol. 2022). One would guess that it might be due to endocrine effects, and specifically that betamethasone, which obviously crosses the placenta and has potent glucocorticoid effects in the foetus (that’s why it is being given), would lead to foetal hyperglycaemia and to downstream secondary hyperinsulinaemia. Which is what this study was examining. It was an analysis of data from a subset of babies in the ALPS trial who had umbilical cord blood stored; C-peptide, insulin, leptin, and insulin-like growth factor binding protein 1 (IGFBP-1) were measured in just over 200 babies, about 30% of whom developed hypoglycaemia, 33% in the ANS group and 27% of the controls. The C-peptide, insulin and leptin levels were higher in the ANS babies, and were strongly associated with hypoglycaemia, especially high insulin concentrations above the 90th percentile which had an Odds Ratio for hypoglycaemia of over 6.0.

Should we be giving ANS prior to expected or planned late preterm deliveries? There have been a number of concerns cited and, despite my snide comments about the ACOG earlier on, the current advice regarding late preterm ANS is well written and discusses the potential risks in detail, with a helpful “summary of Evidence” table in an appendix. I must say I disagree with their final conclusion, which is “We recommend offering a single course of antenatal corticosteroids (2 doses of 12 mg of intramuscular betamethasone 24 h apart) to patients who meet the inclusion criteria of the ALPS trial, ie, those with a singleton pregnancy between 34 0/7 and 36 6/7 weeks of gestation who are at high risk of preterm birth within the next 7 d and before 37 weeks of gestation”. They do also recommend, within the document, “against the use of late preterm corticosteroids in pregnant patients with pregestational diabetes mellitus, given the risk of worsening neonatal hypoglycemia”, although the increase in neonatal hypoglycaemia was demonstrated in the ALPS trial which excluded mothers with pregestational diabetes, and therefore applies to all the newborns who are exposed. They have a reasonable discussion of the potential adverse impacts on brain development and they “recommend that patients at risk of late preterm delivery be thoroughly counseled regarding the potential risks and benefits of antenatal corticosteroid administration and be advised that the long-term risks remain uncertain”.

How many obstetricians are really equipped to thoroughly counsel expectant mothers about the possible adverse impact of ANS prior to late preterm birth and the uncertainty of the scientific evidence? How many mothers are equipped to understand and make an informed choice? If I were in that situation (easy to say for someone who could never have been) I would just about be able to comprehend the data and the implications of the data, and that is with a subspecialty in neonatology and years perusing the literature! Perhaps ACOG, and their society for maternal fetal medicine who authored the guidelines, could produce a YouTube video for parents that summarizes the information in a way that most could understand.

If you examine the data from ALPS in detail (the online supplementary appendix) you find that there was no advantage to ANS if the woman was randomized at or after 36 weeks, there was exactly the same incidence of the primary outcome, 7.1%.

The benefit of the steroids was much greater with planned cesarean; 26% primary outcome in controls reduced to 16% with steroids, compared to planned vaginal delivery where the difference was 12.4% to 10.7%. The benefits were also much greater in the group with indicated preterm delivery (induction or cesarean), compared to preterm labour or ruptured membranes, below are the numbers and percentage of the adverse primary outcome according to indication, from the supplementary appendix, the first column of results being the betamethasone group, the second being control, the 3rd is the relative risk and compatibility intervals, and the final figure being the interaction p-value.

You can see that the absolute reduction in the primary outcome is about 1.5% for the first 2 indications, and about 4% for those with induced labour or planned cesarean deliveries.

The ACOG statement reviews some of the evidence suggesting a possibility of long term impacts on brain development, and comes to no clear conclusion as to whether this intervention is safe or not, which I think is the correct interpretation, there is no clear conclusion.

As I said above, I disagree with their final conclusion that ANS should be offered to all women with increased risk of preterm delivery at 34 to 36 6/7 weeks. The evidence of benefit at 36 weeks is lacking, and those babies are just being exposed to an increase in hypoglycaemia and the unknown long-term effects without a benefit. The benefits are also quite small in ruptured membranes or preterm labour, with an NNT of about 67, and that should be taken into account in the decision making.

Nevertheless, there has been widespread uptake of ANS prior to late preterm delivery, hopefully there will be good long term follow up of the babies in ALPS, that is the only way we will tell in the future whether this major change in practice is actually improving outcomes for babies, or not.

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Preterm babies, PLEASE don’t smoke!

One of the most addictive and harmful drugs of all is perfectly legal. Tobacco, and the nicotine it contains, are subject to prohibition for adults nowhere in the world, despite millions of deaths, prolonged severe disability, and being probably as addictive as cocaine or heroin. We have long thought that the lung injury that preterm babies experience will probably lead to worse outcomes in adulthood, with a chance of increased COPD, this study tests that belief. (Bui DS, et al. Association between very to moderate preterm births, lung function deficits, and COPD at age 53 years: analysis of a prospective cohort study. The Lancet Respiratory Medicine. 2022). In fact, overall, the results from this study of follow up at 53 years of age are quite encouraging. Although there were very few of the very preterm babies, 28 to <32 weeks, (there weren’t many survivors less than 32 weeks in 1961) when added with the moderate preterm, 32 to <34 weeks they had a cohort of 46 babies to compare with over 1400 full term infants, and 172 late preterms.

The post-bronchodilator forced expiratory flows were a bit lower in the very to moderately preterm-born subjects, but only among those who also smoked. The non-smokers look identical between the preterm and the term born subjects.

Our current NICU survivors, who often have chronic lung disease, will probably have a very different profile in their long term than the babies in this study, we can imagine the potentially horrific effects of cigarette smoke on their pulmonary function in late adulthood.

Assuring good long-term health of former preterms looks like it will be critically dependent on finding ways to stop them smoking. Perhaps the proposed ban in New Zealand, which, starting in 2027 will make it illegal to supply cigarettes to anyone born after 2008, is the way to go. I think we should probably start sooner than that, and, as we know that parental smoking is a strong predictor of whether their children start smoking, stopping-smoking interventions for parents of preterms should be a priority.

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We need to rethink neonatal hypoglycaemia

A great deal of time and effort is expended to detect and treat low blood sugars in the newborn. Studies to determine risk factors, monitoring schedules, and treatment strategies have taken a great deal of effort, and implementing the recommended protocols requires much effort, resources, and often separates healthy babies from their families, or at least makes them think the baby is sick. The whole point of all this is to prevent brain injury from hypoglycaemia, with the underlying premise that low blood sugars, below a certain threshold, may cause damage which will have an impact on the baby’s future, therefore it is important to detect and immediately treat the phenomenon.

Two new publications from studies co-ordinated by the Auckland group continue to challenge some of our assumptions.

The hPOD trial (Harding JE, et al. Evaluation of oral dextrose gel for prevention of neonatal hypoglycemia (hPOD): A multicenter, double-blind randomized controlled trial. PLoS Med. 2021;18(1):e1003411) showed that you could reduce the incidence of hypoglycaemia with prophylactic oral dextrose gel; that was a multicentre RCT of over 2000 newborns who were in at-risk groups. 42% of the control group developed a blood sugar under 2.6 mmol/L, compared to 37% of the treated babies. There wasn’t much effect on “severe hypoglycaemia” (<2.0) however, 9.9% vs 9.3%, on on NICU admission, which was the primary outcome variable, 9.4% vs 10.4%. At 2 years the New Zealand cohort from the study had follow up testing, 88% of them completed the assessment, a truly remarkable achievement after a short-term trial in otherwise healthy babies! (Edwards T, et al. Prophylactic Oral Dextrose Gel and Neurosensory Impairment at 2-Year Follow-up of Participants in the hPOD Randomized Trial. JAMA. 2022;327(12):1149-57). This is the table with the main results:

The small differences in outcome are all in favour of the placebo group. With, in particular, motor delay being more common in the dextrose group, 2.5% compared to 0.7%.

The average scores on each composite of the BayleyIII scores were higher in the placebo group, and, although the differences were very small, some of the 95% compatibility intervals for the unadjusted and adjusted mean differences did not include 0.

There were also tests of executive function which showed practically identical results in the 2 groups. On other words, no advantage at all, and some hints of an adverse impact of the oral gel when used as prophylaxis.

The other publication is from the CHYLD team, (Shah R, et al. Association of Neonatal Hypoglycemia With Academic Performance in Mid-Childhood. JAMA. 2022;327(12):1158-70). This is an evaluation of academic achievement in 480 infants from a prospective cohort, at 9 to 10 years after enrolment, which is 82% of the potentially eligible children. The children had initially been participants in either the BABIES study or SUGAR-BABIES: BABIES was a prospective cohort study of EEG monitoring in neonates at risk of hypoglycaemia, which showed no impact of hypoglycaemia on EEG activity; SUGAR-BABIES was the randomized trial of oral glucose gel as treatment for hypoglycaemia, which showed that the intervention was effective as treatment. Previous publications at 2 years showed no apparent impact of hypoglycaemia, whereas at 4.5 years there was some evidence of an association between hypoglycaemia and poor executive function. To recall in the 4.5 year follow up there were no differences in neurological outcomes or on Wechsler full scale IQ, and mean executive function scores were practically identical in the 2 groups, 13.5 (SD 6) compared to 13.3 (SD 5.7), but there was an excess of babies with scores more than 1.5 SD below the mean, 11% vs 5%, suggesting a slightly skewed distribution with an excess of lower scores in the hypoglycaemic group.

These 4.5 year findings reinforced the importance of performing this new evaluation at 9 to 10 years. Academic achievement, executive function, visual-motor integration, motor function, visual processing and behavioural problems were evaluated. No differences were found between infants with hypoglycaemia (either one blood glucose <2.6 mM/L (47 mg/dl) or an interstitial glucose <2.6 for over 10 minutes) and those who never had documented hypoglycaemia.

The differences in outcomes were small, with minor differences generally favouring the hypoglycaemia group, the only outcome for which compatibility intervals did not include no difference was the teachers evaluation of reading ability, that also favoured the hypoglycaemia children. They also evaluated the subgroup with severe (<2.0 mM/L (37 mg/dl)) or recurrent (3 or more) hypoglycaemia, and the subgroup with recurrent hypoglycaemia (3 or more episodes). None of the results look different from non-hypoglycaemic children. Here is the first part of the first results table:

What is somewhat surprising, is how frequent low educational achievement was in all of the groups, with almost half of all the participants being “below the normative curriculum level” or “well below”, below seems to mean that they were operating at a level at least 1 year behind their peers, and well below means more than 2 years behind. This isn’t totally clear in the publication, but the statistical analysis plan in the supplement defines “below” as performing at a level 4 to 7 school terms below the peer group and, according to Google, each school year in New Zealand consists of 4 terms. “Well below” is defined as performing at a level 8 or more terms behind the school year and term norms.

The power calculations were based on the prediction that 20% of children would have this outcome. Poor educational achievement was therefore very frequent in all groups, and more than twice as frequent as expected, even though achievement was not affected by whether the children had actually developed hypoglycaemia or not.

It seems therefore likely, that the same factors that lead to an increase in risk of hypoglycaemia also lead to an increased risk of poor academic performance, and also poor outcomes in visual-motor integration, executive function and behavioural domains. These findings emphasize the need for control groups in studies of long term potential impacts of hypoglycaemia to be babies with the same profile of risk factors, but who did not develop hypoglycaemia. That has not always been the case and may have misled us as to the importance of hypoglycaemia. Obviously, if you compare at-risk babies who develop hypoglycaemia to the general population, then they would seem to have much worse outcomes. It appears that being small for gestational age or an infant of a diabetic mother, and late preterm birth are risk factors for poor outcomes on the variables that were studied. There is also a question about the background frequency of social deprivation, and the population appears a little more deprived than the general NZ population, with about 40% of the participants’ families being in the most deprived 3 deciles (it should of course be 30%), but that doesn’t to seem to me to be a big enough finding to explain most of the results.

The most dramatic interpretation of these data would be that hypoglycaemia, to <2.6 or even <2.0 mM/l is unimportant in the transitional period. Single episodes or even multiple episodes below these thresholds don’t seem to increase risk of poor outcomes, over and above just being in an at-risk group. One possible explanation of the results could have been that we miss a lot of hypoglycaemia events, and the poor outcomes might be due to undetected hypoglycaemia. However, many of the children in CHYLD had continuous interstitial glucose measurements performed and the analysis, presented in the supplement, of only babies with continuous monitoring also showed that babies who were continuously normo-glycaemic had identical poor outcomes to those with documented hypoglycaemia, and to those with hypoglycaemia during their continuous monitoring period, 48% of normo-glycaemic infants having poor educational achievement.

These data suggest that we should maybe focus on detecting and treating more severe and prolonged hypoglycaemia. It has already been shown that using 2.0 as a limit rather than 2.6 mM/l (36 rather than 47 mg/dl) does not affect long term outcomes, these new data imply that even 2.0 is too high a threshold, using dextrose gel as prophylaxis actually slightly worsened outcomes compared to placebo, and babies with documented hypoglycaemia actually did slightly better than normoglycaemic infants.

Could it be that all our screening and interventions for mild and moderate hypoglycaemia in term and near term babies are actually making things worse? Is there any way of predicting which babies are at risk of more severe hypoglycaemia? What threshold of hypoglycaemia is associated with worse outcomes? Does treating hypoglycaemia when it fall below that threshold improve outcomes? Is it possible to focus prophylaxis to prevent more severe hypoglycaemia? If so, does that improve outcomes?

And for our obstetric colleagues, can we prevent gestational diabetes, intra-uterine growth restriction, excessive intra-uterine growth, and late preterm delivery? If so, does that improve long term outcomes of these babies?

So many questions, so few answers.

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Steroids to improve pulmonary outcomes in preterm infants.

When we consider using steroids in a preterm infant, ventilator dependent, with evolving lung disease, what outcomes are we most interested in? Survival, surely, is the first outcome that we want to improve, and secondly long-term pulmonary health. The adverse outcome we are most interested in avoiding is worsened development or adverse neurologic impacts.

Does it really matter if an individual baby still needs oxygen at 36 weeks post-menstrual age, that outcome is only of interest if it is a good predictor of respiratory health in the long term. Which it is not. When Andrew Shennan first proposed oxygen dependency at 36 weeks PMA as the definition of BPD, rather than the original definition of oxygen dependency at 28 days of age, it was because there seemed to be a good correlation with longer term respiratory symptoms after discharge. With the major advances in survival at extremely low gestational ages since then, the majority of our survivors of the earliest gestational ages still have some need for respiratory support, oxygen or positive pressure at 36 weeks, and many have respiratory problems ongoing after discharge.

More recent attempts to improve the usefulness of the diagnosis of BPD still concentrate on making the decision at 36 weeks, but why? Is it because many babies are often discharged shortly after 36 weeks, so, to make it a clean outcome for research, we like to have a yes/no outcome before the babies go home and start to be lost to follow up? That might make some sort of sense from a research design point of view, but we really should be studying things that have impacts on families and the future life of our patients.

The updated NICHD definition of BPD was shown in a publication from 2005 to be statistically significantly associated with readmission for respiratory illness, and with the use of respiratory medications up to 18 to 22 months corrected age. But statistically significant does not mean clinically useful; of babies in the NICHD database “without BPD” 24% were rehospitalised for respiratory indications and 27% received chronic respiratory medications. Among those with mild BPD the relevant figures were 27% and 30%, with moderate BPD, 33% and 41%, and those with severe BPD, 39% and 47%. There is therefore a significant trend to worse outcomes with worse grade of BPD, but the discriminatory power is not very good. One concern about these figures is that the use of chronic respiratory medications is very variable, as, in general, they don’t work! Diuretics, brochodilators and inhaled steroids are of questionable efficacy in infants with established BPD. Some physicians will use them more liberally than others, introducing variability that makes medication use problematic as an outcome variable.

A reduction in the frequency of BPD might, then, in a large study be an overall predictor of a probable improvement in respiratory health over the first year of life; a reduction in severe BPD being much more important than a reduction in mild BPD (even though many infants “without BPD” have respiratory problems in the first 18 months after discharge). So one could propose its use as a proxy for clinically important lung injury. But, importantly, an intervention which improves short term gas exchange and lung mechanics, but does not improve lung repair, could easily lead to a reduction in the proportion of babies with a research diagnosis of BPD, without any benefit on pulmonary outcomes in the longer term.

Systemic steroids reduce inflammation in the short term, improving lung mechanics and gas exchange, leading to fewer babies being diagnosed with BPD in many trials. But they also impair lung growth and development in animal models, and have never been shown to enhance repair in relevant models. It is possible, at least, that they could decrease the proportion of babies with “BPD”, but worsen longer term pulmonary health.

What are the impacts of postnatal steroids during evolving chronic lung disease of prematurity, on long term pulmonary health? The very depressing answer is that we have no clear idea. Despite more than 20 trials, including over a thousand very preterm infants, there is very limited data to determine whether giving a course of hydrocortisone or dexamethasone actually improves long term pulmonary health outcomes.

The Cochrane reviews of postnatal steroids in preterm infants don’t even have long term pulmonary health as an outcome. The longest term outcome they analyse is home oxygen, which is an important outcome for its impact on families, but misses a lot of respiratory morbidity.

Is there any evidence at all that postnatal systemic steroids improve long term respiratory health?

There is a small amount of information from some of the trials of dexamethasone (DEXA). The UK led dexamethasone trial published 3 year outcome data (Jones R, et al. Controlled trial of dexamethasone in neonatal chronic lung disease: a 3-year follow-up. Pediatrics. 1995;96(5 Pt 1):897-906), and found small differences in the outcomes they measured, but no clear advantage of DEXA. You also have to remember that over 40% of the placebo babies received DEXA at some point.

There are two publications of very tiny studies with some longer term respiratory follow up, which show either no difference, or an advantage of DEXA in terms of shorter home oxygen.

The Taiwan early dexamethasone trial was performed in the pre-surfactant era, dexamethasone was started within 12 hours and tapered off over 4 weeks in 262 ventilated preterm infants <2kg. The relevance to this discussion is that there was very little treatment of controls with DEXA (7 controls and 5 DEXA babies), and it was one of the first studies to confirm the neurotoxicity of DEXA, with lower BSID2 scores (both MDI and particularly the PDI) and much more cerebral palsy. Even though the results showed less oxygen requirement at 36 weeks, and thus less BPD (21% vs 36%), on 2 year follow up of 116 of the survivors, there were no differences at all in clinical respiratory outcomes : “There was no difference in the incidence of lower respiratory infections between the two groups (control group 13/59 vs dexamethasone-treated group 11/57). There was also no significant difference in rehospitalization for respiratory reasons during the first 2 y of life between the two groups (control group 18/59 vs dexamethasone-treated group 15/57)” and more extensive lung function testing also showed no differences of any note:

The DART trial enrolled infants much later in their hospital course, and did show acute impacts leading to reduced ventilatory dependency. However, almost all the babies satisfied BPD definition in both groups, at around 90%, and nearly half in each group went home on oxygen. Hospital readmissions and duration of home oxygen were very similar in the two groups.

One of the few trials in which controls were not allowed to receive open-label DEXA was the trial of O’Shea et al, in which a 42 day tapering course of DEXA was started at 15 to 25 days of age for VLBW infants who were ventilator dependent in more than 30% O2. 120 babies were randomized, and those who received DEXA were weaned faster from the ventilator, mortality was 7/57 with DEXA compared to 16/61, which was not “statistically significant” but is quite a big reduction in a small study, O2 dependency at 36 weeks was much lower in the DEXA group, 59% vs 82% in controls. The one year outcome of the study showed no difference in re-hospitalisation, which is the only longer term respiratory outcome reported (most re-hospitalisations are for respiratory reasons, but that was not specified in the publication). To recall, this was the trial that, more than any other because of the prohibition of DEXA use in controls, showed that DEX causes cerebral palsy. Definite CP in the controls was 7%, with DEXA that increased to 25%. Let us also remember that you don’t need a 42 day course of DEXA to increase the risk of CP, the 3 day course of 0.5 mg/kg/day studied by Shinwell et al, in 248 preterm infants with HMD started within 12 hours of life, increased CP from 14% in the controls to 46% with DEXA (25% of controls received open label steroids in this study). No data on respiratory long term outcomes was presented.

The very limited evidence that is available, therefore, shows no improvement in long term pulmonary health with DEXA, either early or late, despite a reduction in the diagnosis of BPD.

What about moderately early intervention with hydrocortisone? Use of this molecule between 1 and 4 weeks of age, has really only been studied in these two recent trials I have been discussing, STOP-BPD and the NICHD hydrocortisone study. Although there are clearly differences, there are enough similarities, I think to draw some conclusions. Together, they suggest that starting hydrocortisone will improve short term respiratory status, allowing extubation. There is a suggestion of a reduction in mortality, but as physicians have difficulty in avoiding systemic steroids in the sickest babies, this is not entirely clear. You would expect, however, that improving lung mechanics and gas exchange in the acute phase will prevent some respiratory deaths. Because of clinicians appropriate unwillingness to let babies die without a trial of steroids, it is impossible to prove from the current literature that hydrocortisone (or indeed DEXA) given moderately early do indeed decrease mortality.

The implications for practice, I think, are that steroids should be used to prevent mortality. For an infant who is at increased risk of respiratory death, use of steroids is justifiable, but which steroid and which dose are still uncertain. Initial treatment with hydrocortisone may be effective, and, if there is inadequate response, dexamethasone might be a more effective alternative but with known neurotoxicity issues.

There is currently little reliable evidence about the neurotoxicity of hydrocortisone in the developing preterm human brain. I can’t find a huge amount of animal data either, but there are certainly some studies which suggest that hydrocortisone may also have negative impacts on brain development, this one for example 😦Aden P, et al. Low-potency glucocorticoid hydrocortisone has similar neurotoxic effects as high-potency glucocorticoid dexamethasone on neurons in the immature chicken cerebellum. Brain Res. 2008;1236:39-48). It seems likely that DEXA has more negative effects on brain development that does hydrocortisone. Observational studies have shown more negative impact on MRI of DEXA compared to hydrocortisone, but with all the usual limitations of that type of evidence.

I think we should really question the use of steroids, DEXA or hydrocortisone, as a tool for getting babies extubated. Which is worse in the long term, a few more days of assisted ventilation, or a course of systemic steroids? In an intubated baby at low risk of dying, but high risk of developing BPD, hydrocortisone (or DEXA) will lead to earlier extubation, and may reduce the probability of having a BPD diagnosis, with no evidence that any important aspect of long term pulmonary health is improved.

Is there enough equipoise to perform another study? (And the willpower!) If we eliminate babies for whom steroids are already probably indicated (say a predicted mortality over 25% using the NICHD calculator, which remember was produced from a population where steroids were being used for the sickest babies) we could randomize intubated babies at 14 days of age to a course of hydrocortisone between the STOP-BPD and NICHD trial schedules, and have restricted criteria for open-label steroid use, criteria which would be developed in order to predict mortality, rather than just remaining intubated. The primary outcome could be long-term pulmonary health, a hierarchical composite of in-hospital mortality, post-discharge respiratory mortality, readmission to hospital or ER visits for respiratory disease, and frequent respiratory symptoms. Construction of the long term health outcome should be a process involving all stake-holders, especially parents. I would be willing to ask parents to have their infants randomized in a study like that, would anyone be willing to fund it?

Without such data we we always be left prescribing these potentially toxic medications for short term gains but with unknown long term risks and benefits.

More generally, Bronchopulmonary Dysplasia should be considered to be an intermediate, surrogate outcome in trials, as an indicator of probable increased risk for long term respiratory morbidity, but not a firm end point in itself.

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Hydrocortisone, with backup dexamethasone, to prevent Bronchopulmonary Dysplasia

A trial that has been awaited for a while has just been published (Watterberg KL, et al. Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. N Engl J Med. 2022;386(12):1121-31). It was a multi-centre RCT of hydrocortisone in 800 very preterm babies at elevated risk of developing chronic lung disease. Eligibility criteria were a GA at birth of <30 weeks, being intubated for more than 7 days, and still receiving invasive assisted ventilation at 14 to 28 days postnatal age. They had not previously received steroids for lung disease (it seems that a short prior course of steroids for other indications was acceptable according to the protocol, but many exclusions were of babies who had previous short course steroids). The study was performed with 2 primary outcomes, a short term outcome of “BPD or death”, BPD being defined as “moderate or severe BPD”, that is, needing oxygen or positive pressure ventilatory assistance at 36 weeks PostMenstrual Age.

The long term primary outcome was “NDI or death” NDI being a BayleyIII cognitive or motor composite <85, cerebral palsy with a GMFCS of >1, blindness or deafness.

The intervention was hydrocortisone at a starting dose of 4 mg/kg/day (iv or enterally) and weaned over a total of 10 days or placebo. The intervention also included the possible use of open-label dexamethasone (DEXA), in either group, at least 4 days after the hydrocortisone was stopped.

The relevant section of the protocol reads as follows : Infants who remain successfully extubated are not to be treated with open-label glucocorticoids as therapy for BPD. This will be a protocol violation. (ii) Infants who are not extubated during the study treatment period or who are subsequently re-intubated may be treated with open-label dexamethasone after ≥ 4 days following the last dose of study drug. Open-label dexamethasone will be encouraged to be prescribed as described by Doyle.

Forty per cent in each group received DEXA. Those who received DEXA got a median of 10 days treatment. There were another 15% of babies who received non-study systemic steroids (presumably mostly DEXA) during the “14 day study period”, that is, the 10 days of hydrocortisone and the 4 days delay before DEXA was allowed by protocol, therefore they were protocol violations; the proportion was similar in the 2 groups, 14% of the hydrocortisone group, 16% placebo. Its not clear how many of the protocol violation babies also received open-label DEXA by protocol, and there is likely to be some overlap, but probably around 50% or more of each group received a course of DEXA.

At 36 weeks there was a small survival advantage to the hydrocortisone group (mortality 4.8% compared to 7% in controls) but this difference was even smaller by discharge (8.8% vs 10%).

The babies in the hydrocortisone group were more likely to be extubated during that 14 day study period, but, as you can see from the overall results above, this did not lead to a lower proportion of babies with “moderate to severe” BPD.

I put the “moderate to severe” in quotations as, of course, this is what in the past was just referred to BPD. Is this the outcome we should be focusing on, in large important trials like this?

There is little correlation between having a 36 week diagnosis of BPD and longer term respiratory problems, in one study from the CNN and CNFUN (Isayama T, et al. Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. JAMA Pediatr. 2017;171(3):271-9), only 10% of babies with this as a diagnosis had “serious respiratory morbidity” after discharge, which was defined as “either (1) 3 or more rehospitalizations after NICU discharge owing to respiratory problems (infectious or noninfectious); (2) having a tracheostomy; (3) using respiratory monitoring or support devices at home such as an apnea monitor or pulse oximeter; and (4) being on home oxygen or continuous positive airway pressure at the time of assessment between 18 and 21 months corrected age.” That does seem like fairly serious respiratory morbidity, and having oxygen or respiratory support at 40 weeks led to 16% of the babies having this outcome, rather than 10% at 36 weeks. The 3 or more hospitalisations was used in this definition based on it being the 95th percentile, which I think is not the best way to define “adverse respiratory outcome”, wouldn’t it be better to ask parents what they think is an adverse respiratory outcome, and use that to determine how much impact postdischarge respiratory morbidity has on a family?

To return to the new trial publication, the neurological and developmental outcomes at 2 years corrected age were very similar between the groups, the supplementary data file has this table:

In other words, slightly better cognitive outcomes with hydrocortisone, slightly better motor outcomes with placebo, but no convincing difference in either, and all compatible with random variability.

The average GA of the babies was just under 25 weeks, and the stratum of babies 22 to 26 weeks GA had a similar primary outcome (i.e. no real difference) to the more mature babies. The mean oxygen requirement at enrolment was 50%, even though there was no minimum FiO2 requirement for eligibility. The high mean FiO2 at enrolment suggests to me that those babies who were considered close to extubation, perhaps on low settings and close to 21% oxygen, may not have been enrolled.

The study is therefore a comparison of hydrocortisone with backup dexamethasone, to placebo with backup dexamethasone, in a very high risk group of babies. It would be interesting to see the long term outcomes of babies who did not receive dexamethasone in the two groups, such a comparison might help to reassure that hydrocortisone used like this is safe. As it is, the very frequent treatment with DEXA in both groups may have diminished the ability to find a long term negative (or positive) impact of hydrocortisone, as well as dramatically diluting any potential advantage of hydrocortisone on lung injury.

Comparing this trial to the previous trial which is the most similar, STOP-BPD, in that trial the steroid dose was slightly higher to start with (5 mg/kg) and continued for twice as long (22 days total),was started earlier (7 to 14 days), and had more restrictive entry criteria (respiratory index by the end of the study (MAP x FiO2) >2.5). You will remember that the entry criteria were modified during the performance of that trial, as many babies who had a respiratory index which was not high enough to satisfy the initial entry criterion (>4.5) were being treated with hydrocortisone outside of the trial. 2.5 means 25% oxygen with a mean airway pressure of 10, for example. But in fact the babies were not as sick as those in the new trial, the average respiratory index at enrolment was around 4, in the new NICHD trial it was over 5.5. (The methods of calculation are slightly different, either using FiO2 as a fraction or as a percentage, so just multiply or divide by a hundred).

In STOP-BPD, rescue steroid use was with open-label hydrocortisone, rather than with DEXA, and was also very frequent, but, in contrast to the new trial, there was a big difference in rescue steroid use between groups, 28% in the active treatment group, 57% in the placebo group.

That study also had neurodevelopmental follow up at 2 years corrected age. The trends all were in favour of the hydrocortisone group, with both BayleyIII cognitive and motor scores slightly favouring the hydrocortisone group. Unfortunately this was only published as a research letter in JAMA (Halbmeijer NM, et al. Effect of Systemic Hydrocortisone Initiated 7 to 14 Days After Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 Years’ Corrected Age: Follow-up of a Randomized Clinical Trial. JAMA. 2021;326(4):355-7), so it is a short publication, without much detail, and there is no additional analysis of the babies according to treatment actually received.

These results were obtained with over 100 of the placebo babies having received hydrocortisone, so again, it is not clear if the hydrocortisone was harmful to long term outcomes or not. With so much cross over, it would be very difficult to ascertain in any case, as the sickest babies will have received non protocol steroids, so they are likely to have poorer long term outcomes. But at least in this trial the additional, non protocol steroids appear to have been mostly hydrocortisone, so it might be possible to determine, for example, whether there was a dose-response for developmental outcomes.

What does this all mean for steroid use in preterm babies with evolving BPD?…. part 2 coming soon!

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Dexmedetomidine: new wonder drug or next neonatal disaster?

In many units, including my own, dexmedetomidine (DXM) has been creeping into use. Initially, we noticed in some full term babies who returned from the operating room, the medication appeared in the anaesthesia record, then when infants returned occasionally with an infusion still in place. Eventually we have started using it ourselves for some infants where the short term profile seems to have some advantages. It is a medication that seems very interesting, with sedative, anxiolytic, sympatholytic and analgesic effects, which also seems well tolerated, with the most frequent clinically evident problem being bradycardia, usually responding to a reduction in dose. It appears that the bradycardia is usually a reflex bradycardia, baroceptor mediated, due to vasoconstriction.

One supposed advantage of DXM is that it reduces apoptosis, or at least the apoptosis induced by other anaesthetic agents. A review from 2018 (Andropoulos DB. Effect of Anesthesia on the Developing Brain: Infant and Fetus. Fetal Diagn Ther. 2018;43(1):1-11) described all the then available animal data, and showed that the apoptosis caused by isoflurane, ketamine, and propofol, seemed to be reduced by DXM.

However, one of those studies (Pancaro C, et al. Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain. J Matern Fetal Neonatal Med. 2016;29(23):3827-33) showed, in contrast, increased apoptosis with DXM, and since then other studies, especially those using prolonged infusion or higher doses, have also shown increased apoptosis, although some continue to suggest protection against apoptosis caused by other agents (such as propofol).

Amazing changes in Brain connectivity between 24 weeks (W24) and term (W40), in these postmortem specimens (Takahashi E, et al. Emerging cerebral connectivity in the human fetal brain: an MR tractography study. Cerebral cortex 2012;22(2):455-64) Normal brain development and maturation requires apoptosis.

Apoptosis is of course a vital part of normal cerebral development, so decreasing apoptosis is not necessarily a better effect than increasing it! It would be better to have a drug which had no impact on normal apoptosis or any other aspect of brain development. It is unlikely, however, that a medication that is sedative and analgesic will have no impact on the brain! Thus, I found the title of this recent article a little humorous, (Cortes-Ledesma C, et al. Dexmedetomidine affects cerebral activity in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2022:fetalneonatal-2021-323411), my first response being, well of course it does, that is why it is used. But the article does have an important message, which is that we know hardly anything about this drug in the newborn, and zero in the preterm newborn. So their findings that amplitude integrated EEG activity was decreased by DXM was not too surprising, but the description of how it is impacted, with an increase in interburst intervals and a reduction in cycling, is really helpful.

More concerning, however, is the reduction in cerebral regional O2 saturation measured by NIRS, that they found, from a mean of 75% to 68%. If DXM was only affecting neuronal activity, then cerebral oxygen consumption should fall, and regional cerebral saturation should increase. This decrease implies a significant reduction in brain O2 delivery, and, as peripheral saturations stayed at 93% and haemoglobin did not change, this means that brain perfusion probably fell, most likely as a result of vasoconstriction. I mentioned at the start of the post that systemic vasoconstriction occurs with DXM, leading to reflex bradycardia, but the doses used in this study did not cause measurable systemic haemodynamic changes, non-invasively measured blood pressure and heart rate were unaffected. This implies that there is local cerebral vasoconstriction with DXM.

This drug, which is creeping into use in the NICU, without any good data regarding safety, either in full term babies or in the preterm, reminds me of several previous neonatal disasters, benzoic acid, chloramphenicol and hexachlorophene, where it took years to discover the very serious harms that they were causing.

As far as I am aware, DXM is not licensed for use in the newborn anywhere in the world, in North America at least, it is not licensed for use in children at all. The current FDA labelling states:

8.4 Pediatric Use
Safety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of Precedex for this patient population. The use of Precedex for procedural sedation in pediatric patients has not been evaluated.

One of our current problems in sedation, and one where DXM has become frequently used, is babies with milder forms of HIE under therapeutic hypothermia. They often seem quite uncomfortable, and review articles have suggested that DXM might be a useful agent, in part because of supposed neuro-protective effects. (McPherson C, et al. Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia. Semin Fetal Neonatal Med. 2021;26(4):101264) But, let’s be careful out there, one recent neonatal piglet study showed that DXM combined with therapeutic hypothermia was neurotoxic. (Ezzati M, et al. Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia. Dev Neurosci. 2017;39(1-4):156-70).

We desperately need good clinical studies of DXM use in newborns, term and preterm. So I was initially excited to see a study with my new favourite acronym T-REX. The published article was, however, an uncontrolled pilot to try and determine efficacy of a particular anaesthetic approach, and only in infants over 1 month. The full T-REX trial (NCT03089905) is underway, with a sample size of 450 and eligibility criteria which include term neonates and infants, with a primary outcome of IQ at 3 years. I can’t see any registered trial on clinicaltrials.gov that really addresses the concerns that I have about potential toxicity in the newborn, the DICE trial (NCT04772222) is a controlled trial in babies being cooled for encephalopathy, with a sample size of only 50, which may be enough for their short term safety outcomes, and even though there is long term follow up planned, not enough power for anything other than enormous effects on development.

A big question for designing a study in, initially full-term babies, is what the comparison group should be. A placebo controlled trial would be tricky to do, unless you studied routine sedation in intubated newborn. A comparison with another agent might be more practicable. Is there any current alternative agent which is known to be safe in the short and long term? I think, pragmatically we would have to compare to morphine infusions, which are sedative, and widely used, and a study would only include babies for whom a decision that they require sedation has already been made. There is no evidence that supports routine use of sedation (morphine or anything else) for ventilated newborns, so a study of those for whom it is thought to be necessary would be an ethical way of studying DXM. It is possible that DXM is a big advance in neonatal care, allowing sedation and analgesia without adverse impacts, but we really need to find out, otherwise there remains a risk that in a few years we will find out that we have, yet again, been doing the wrong thing.

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Common interventions for common conditions; what do they have in common? A lack of evidence.

There are a number of problems in neonatal care for which good evidence is lacking, and an evidence based approach is therefore not really possible. Two recent reviews highlight this problem.

The first is a systematic review of tactile stimulation for newborn infants with inadequate respiratory drive in the delivery room (Guinsburg R, et al. Tactile Stimulation in Newborn Infants With Inadequate Respiration at Birth: A Systematic Review. Pediatrics. 2022:e2021055067). I think, from years of experience, that it is likely that tactile stimulation does increase respiratory drive in some infants who are apnoeic of have poor respiratory effort in the delivery room. Indeed even many mammals do this, they vigorously lick their newborn offspring after birth, which might be to remove the membranes, at least in some animals, but may also stimulate respiration. I did a quick search to see if there is any data about this in mammals, but I found mostly just opinion.

We should be careful here, though, just because some apnoeic babies start breathing after being stimulated doesn’t mean that it was the stimulation that caused it. I am led to the idea of placebo buttons in elevators. Many elevators have a “door close” button, which often has no real function. In some places the regulations even state that door close buttons are not allowed to have any function, and they are only present because the universal design of the elevator cages has that space. Nevertheless, people press these buttons when they are in a rush, and often bash the button multiple times if the doors don’t close after the first push. Many people are convinced that the button closes the doors faster, even in places where they are not attached! I’ve done this myself; I actually, because I am a nerd, timed how long it takes the elevator doors of my usual elevator at the hospital to close without pressing the button, and it is exactly the same as when the button is pressed. It is still difficult to refrain from pushing the button when I am in a hurry, and usually the doors will then close!

Tactile stimulation could be the same, perhaps it has no actual effect, but, as most babies respiratory drive improves with time (or a decreasing pH in the respiratory centres), the apparent effect could be an illusion. Worse, it might distract resuscitators from intervening with effective manoeuvres when a baby actually needs more help.

Surely, it wouldn’t be too hard to determine if tactile stimulation actually works (i.e. leads to shorter time to adequate spontaneous respiration) and what the indications should be, and what method to use, and when to stop and proceed to more invasive techniques.

Ruth Guinsburg and colleagues new review winnowed the reliable evidence down to 2 observational studies, “the prespecified 3 primary outcomes were the establishment of spontaneous breathing without positive pressure ventilation (yes or no), time to the first spontaneous breath or crying from birth, and time to heart rate >100 beats per minute from birth”. I think those are entirely reasonable, and would be adequate justification for performing tactile stimulation if it was effective for any of those outcomes. Of the two trials they found that had some value, they could only extract somewhat reliable data from one of them, which only included preterm babies. The results suggested that perhaps endotracheal intubation was less frequent among infants who received stimulation, compared to the controls without stimulation; of course as an observational study there are biases which are impossible to eliminate.

Performing a randomized controlled trial of stimulation compared to no stimulation whatever would be difficult. I think it would be ethically acceptable if the no-stimulation group had a control intervention that was of low invasiveness and very safe, such as perhaps mask CPAP or low pressure PPV, but it would be essential to have buy-in from all the delivery room staff. In the days before we put babies in plastic bags after delivery, I used to teach that drying the baby with a towel was adequate stimulation, and if the baby was still not breathing after that, then the next steps should be performed. It was still difficult to stop other team members from flicking feet or rubbing the back yet again, and of course, it seems to be relatively harmless, as long as other procedures are also being performed.

It would probably be easier to perform an RCT comparing different methods of stimulation, foot flicking and back rubbing being the most commonly performed where I have worked. It would also be of enormous clinical significance if one was more effective than the other.

Another problem where there is a distinct lack of good evidence is the treatment of TTN (transient tachypnoea of the newborn) also sometimes known as RFLF (retained fetal lung fluid) which I prefer as being more euphonious, however, unfortunately “riflif” doesn’t work in Québec, where we treat TTNN (tachypnée transitoire du nouveau-né).

Probable TTN, image from Guglani L, et al. Transient tachypnea of the newborn. Pediatr Rev. 2008;29(11):e59-65.

An overview of the systematic reviews of therapies for TTN has recently been published (Bruschettini M, et al. Interventions for the management of transient tachypnoea of the newborn – an overview of systematic reviews. Cochrane Database Syst Rev. 2022;2(2):CD013563). There are numerous problems in studying TTN, in part because of a lack of widely accepted diagnostic criteria, but this is an area wide open for research, for which large amounts of resources are currently used. The image above, I would suggest, is classic for TTN, but there is a great deal of inter-rater variability in the diagnosis even among radiologists.

The overview summarizes six Cochrane reviews of therapy for TTN, and the findings are disappointing. Despite the prevalence of this condition there are few studies, they all tend to be small, and the trials were mostly at high risk of bias. The largest amount of data existed for salbutamol inhalations, with 7 trials. The rationale for salbutamol is the known physiologic effect of beta adrenoreceptor stimulation on increasing lung fluid clearance, but, as endogenous circulating catecholamines are already very elevated after delivery, it is questionable whether further betamimetic stimulation would be effective or safe, the trials show low-quality evidence that tachypnoea may be shortened. For the other interventions there were between 0 and 3 trials, and no convincing evidence for the efficacy or safety of any of them.

The findings were as follows:

Salbutamol may reduce the duration of tachypnoea slightly. We are uncertain as to whether salbutamol reduces the need for mechanical ventilation. We are uncertain whether epinephrine, corticosteroids, diuretics, fluid restriction, or non‐invasive respiratory support reduce the duration of tachypnoea and the need for mechanical ventilation, due to the extremely limited evidence available. Data on harms were lacking.

I have long been sceptical of the value of CPAP and non-invasive ventilation in TTN, CPAP is great for low volume lung diseases, but lung volumes on chest x-ray of TTN are often increased (as in the radiograph above), and whether external positive pressure actually improves lung liquid clearance and clinical resolution is uncertain. This should be a research priority, shortening the duration of intensive care for these babies would benefit many thousands of families, and could save significant resources.

Currently, for apnoeic babies in the delivery room, there is no clear answer to the questions of whether we should use tactile stimulation, how, and for how long. For babies with TTN, we have no evidence-based therapy to improve the resolution of their clinical condition. Research on either of those areas has the potential to have a major impact on neonatal care.

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Composite outcomes for research; this is how to do it!

As regular readers of the blog will know, I have been very critical of some very important, otherwise excellent, trials over one vital part of their design, that is, the use of composite outcomes such as “death or BPD”, “death or RoP”, or, the worst of all, “death or NDI” which is a composite of composites. The use of these outcomes is, however, understandable for two reasons. Firstly the outcomes are often competing, that is if you die before 36 weeks you can’t have a research diagnosis of BPD, even if you die of lung injury, so a study investigating a method to reduce lung injury has to take into account the babies who die, otherwise the result might be misleading. Secondly composite outcomes may (although this is not always the case, they may do the opposite) reduce the required sample size.

The problems with this approach are numerous, if the components of the primary outcome change in opposite directions then the result may be null, despite a clinically important difference between the treatments. For example the STOP-BPD trial showed no difference in the composite outcome of death or BPD, despite having fewer deaths at discharge. But, surely surviving with BPD is a preferable outcome to dying. In the most famous example of SUPPORT, the result was again null, no difference in the primary outcome of death or severe retinopathy, but there were more deaths in the low saturation group, and less severe RoP. Again, surely being alive and having laser retinal surgery is to be preferred over being dead.

These composite outcomes imply that the parts of the outcomes are equivalent in importance, which those two examples illustrate, is often not true. However, there are alternatives. Several have been proposed, including the win-ratio that I have discussed several times. A few studies have been published using these techniques, although none as yet in neonatology. One that just caught my eye is this new trial in adults with heart failure and preserved ejection fraction. (Shah SJ, et al. Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial. The Lancet. 2022;399(10330):1130-40).

The intervention was the installation of an inter-atrial shunt by catheterisation to decompress the left atrium, an intervention previously shown to have haemodynamic advantages, and potential clinical benefit. It is basically like creating a permanent secundum ASD of 8 mm diameter. There are a number of potentially competing outcomes of clinical importance for patients with this condition, including death, stroke, progression of heart failure and so on. Just as in neonatology, if you die you can’t get worsening heart failure, so the primary outcome was a hierarchical composite and the primary analysis was a form of the win ratio

The primary efficacy endpoint was a hierarchical composite of cardiovascular death or non-fatal ischaemic stroke up to 12 months post-randomisation; rate of total (first plus recurrent) heart failure events (defined as admissions to hospital or urgent visits to a health-care facility for intravenous diuresis, or intensification of oral diuretics) up to 24 months post-randomisation, analysed when the last randomised patient completed 12 months of follow-up; and change in KCCQ overall summary score between baseline and 12 months.

The KCCQ is the Kansas City Cardiomyopathy Questionnaire, and the score is a continuous variable of clinical status. The statistic that was used to compare the intervention and sham procedure groups was the win ratio, and the p-value was calculated using a method that can integrate dichotomous, recurrent, and continuous outcomes, something called the Finkelstein-Schoenfeld approach.

The authors describe the win ratio calculation in the supplementary materials clearly: “The first patient is compared to every patient, one at a time, and this first patient is assigned a score of 1/0/-1 for each comparison if this first patient has a better (did not experience CV death/ischemic stroke and the comparator patient did), same, or worse (experienced CV death/ischemic stroke and the comparator patient did not) outcome, respectively. For every pairwise comparison where the score is 0, the first patient is assigned a score of 1/0/-1 depending on whether he/she has a better (less HF events than the comparator patient), same (same number of HF events as the comparator patient), or worse outcome (more HF events than the comparator patient), respectively. Finally, for every pairwise comparison where the score is still 0, the first patient is assigned a score of 1/0/-1 depending on whether he/she has a better (change in 12-month KCCQ score at least 5 points larger than the comparator), same (change in 12-month KCCQ score within +/-5 points of comparator) or worse (change in 12-month KCCQ 5 at least 5 points lower than the comparator). This algorithm is then repeated for every patient in the study”.

The results showed a win-ratio was 1.0, which means that overall there was no advantage or disadvantage of the procedure compared to a sham procedure on the components of the primary outcome, when considered in this hierarchical fashion. There were very few deaths or strokes in either group, and in both groups the KCCQ score tended to increase (which means an improvement in symptoms).

One of the interesting things about this trial is that the calculated sample size was a manageable 300, despite outcomes which are somewhat uncommon, and relatively small changes in the continuous score, which suggests that this might be easily applicable for neonatal multi-centre RCTs.

One disappointment I do have for this trial is that there is no mention of whether patients or families were involved in developing the outcomes. It has become essential that there is at least some consultation with those impacted by the conditions we are investigating during development of trial designs, especially when it comes to designing the primary outcomes. In addition to assuring that trials collect data on a group of core outcomes, ensuring that the primary outcomes are what matter most to patients (or, in our case, former patients, and families of neonatal patients), and ensuring that any hierarchy in an analysis of a composite outcome follows what they believe to be most important.

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