Anti VEGF treatment of retinopathy: and the long term?

There remains some doubt about the impacts on cerebral development, and thus on developmental progress of anti-VEGF treated babies. It is possible that there are cerebral effects of VEGF inhibition (or interception) and it isn’t clear what the exposure of the brain really is. In this new trial (Stahl et al, that I just posted about), most babies had undetectable serum aflibercept concentrations throughout the study, which is reassuring. Data from other observational cohort studies has shown some association between anti-VEGF “-mab” administration, and poorer outcomes. In this study from the NICHD network, which Roger Soll refers to in his editorial accompanying the FIREFLEYE trial publication, their long term primary outcome, “death or severe NDI” was not much different between bevacizumab and surgery treated babies (adjusted Odds Ratio was 1.42; with 95% CI 0.94 to 2.14). However, mortality was somewhat higher (most of the deaths, and the difference in deaths, was prior to hospital discharge; 9% of the treated babies vs 3.5%), and Bayley III cognitive composite scores were shifted lower by a mean of 3 points, so somewhat more babies were under 85 (aOR 1.78 [95% CI 1.09 to 2.91]). The motor scores were slightly lower in the bevacizumab group, and the language scores were almost identical. The babies in the bevacizumab group also had longer assisted ventilation, oxygen therapy, and hospitalisation, so perhaps they had more severe BPD.

Published follow up of the CNN and CNFUN Canadian cohort also shows lower scores among the bevacizumab treated babies compared to laser surgery, but the pattern is different, cognitive scores were identical between groups, but language and motor scores were worse. There were very few deaths between treatment and discharge. The CNN bevacizumab babies also seem to have been a bit sicker in terms of their lung disease than the laser treated infants. The difference in severity of lung disease is understandable, as bevacizumab was emerging as a treatment during these periods, we tended to use it for babies who we were most worried about deteriorating during surgery, so the simplicity of bedside intravitreal injections made us prefer it among the babies with the most unstable pulmonary status.

The real impacts at long term will require follow up of randomized trials, at present the observational data are conflicting and confusing, in addition to the two large multicentre cohorts discussed above, there are several others, and a systematic review in 2020 that found a total of 8 studies, actually showed no overall difference in outcomes. Another systematic review, (Kaushal et al) also published in 2020 included data from 13 studies. There are however, errors in their meta-analysis which I have just noted as I was reviewing it now. They calculated the mean and SD of the data from the CNN, estimating them from the median and IQR which were published. But the SDs they calculated are tiny, and are, I think, incorrect, using the method they claim to have used (I checked with an online calculator which is supposed to be based on the method the authors used, but gives SDs which are larger and more reasonable). As a result the CNN data are given huge weight compared to the other studies, which means that their calculations for the continuous outcomes are in error, I think.

The Cochrane review of this intervention doesn’t include any long term follow-up, but there are now some data available from comparative trials, or at least from the RAINBOW trial. (Marlow N, et al. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. The Lancet Child & Adolescent Health. 2021;5(10):698-707)

A caution about the introduction to the trial, as you can see from the conflicts of interest statement, there was heavy involvement of Novartis in the trial. Novartis markets both bevacizumab (Avastin) and ranibizumab (Lucentis), which are derived from the same antibody. Novartis, however, want everyone to use ranibizumab for eye injection because they charge many times as much for it, they prepare it in the small doses needed for eye injections, and, according to them, it is less likely to cause systemic effects. The molecules are very different in size, with ranibizumab being a much smaller molecule which is probably cleared from the circulation much faster, which might possibly make it safer. Comparative trials in adults, however, haven’t shown much difference in either efficacy or complications. Bevacizumab is in fact “non-inferior” to ranibizumab in adult wet macular degeneration efficacy. (Moreno TA, Kim SJ. Ranibizumab (Lucentis) versus Bevacizumab (Avastin) for the Treatment of Age-Related Macular Degeneration: An Economic Disparity of Eye Health. Semin Ophthalmol. 2016;31(4):378-84).

All that being said, the first author is Neil Marlow, and I am sure he wouldn’t have written this unless he was sure about the data. These long term outcomes show equivalent development in almost all domains, but ranibizumab led to much less high myopia, and less ocular structural abnormalities than laser. There is very little follow up of the bevacizumab, trials, the BEAT-ROP trial only reported follow up from 16 infants from one centre, and therefore no power to show anything. Kennedy KA, et al. Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity. J AAPOS. 2018;22(1):61-5 e1. Even though cognitive scores were 20 points higher among those who received bevacizumab rather than laser there was such a wide range, and small numbers, that this might well have been a chance difference.

The long term, therefore, must be classified as uncertain, with some concerns from observational studies, and some reassurance from the little data available from RCTs. Which is a very unsatisfactory state of affairs when trying to counsel parents.

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Anti-VEGF vs laser therapy for retinopathy, not worse, but not not worse?

A newer anti-VEGF drug has been invented, and evaluated in retinopathy therapy. This new drug aflibercept works differently to the “-mab” drugs we have been using. Those others are monoclonal antibodies (hence mab) directed against VEGF, whereas this new stuff is some sort of protein that mops up VEGF (intercepts it, I guess, to get its generic name). It is used for therapy of colon cancer (and approved for this indication a few years ago) and for wet macula degeneration, much like bevacizumab. I don’t know what the price is for the tiny doses used for newborn retinal disease, but I guess it won’t be cheap!

The newly published article (Stahl A, et al. Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial. JAMA. 2022;328(4):348-59) is a randomized trial with a 2:1 randomization ratio, which enrolled 118 babies with retinopathy needing intervention (zone I stage 1+, zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, zone II stage 3+, or aggressive posterior RoP). The study was designed as a non-inferiority trial, with the primary outcome being treatment failure. If either eye had active RoP at 24 weeks post treatment, or either eye had retinal detachment (or another structural adverse outcome) then the treatment was determined to be a failure. Of course, if only one eye was treated, then only one was evaluated for success/failure.

You can see that there was little difference between the 2 groups, the aflibercept was slightly better in terms of treatment failure, or at least it was not worse. But according to the twisted syntax of the non-inferiority trial, it wasn’t not-worse!

The explanation of that is that they planned the trial such that, if the lower limit of the 95% confidence interval for the difference between groups was above a -5% difference, they would conclude that aflibercept was not inferior. But the difference between groups was 3.4%, with 95% confidence intervals -8% to infinity. Which is bizarre. A 95% CI up to infinity means that there is a 5% chance that aflibercept is more than infinitely better than laser!

The control group was quite small in this trial, and the failure of laser therapy was lower than their sample size calculations expected. Of the 43 randomized to laser, only 38 actually had laser, and for some reason the primary analysis is not by Intention to Treat, but only includes the 38 actually receiving laser. I can’t see anything in the statistical analysis plan to justify not including the 5 who did not receive laser treatment, but, as far as I can see, they at least weren’t analysed as intravitreal injection subjects (I don’t know what treatment they actually received, if any). The largest numbers of patients were from Russia (18) and Japan (17) with smaller numbers from Turkey, Bulgaria and Romania, and then very small numbers from each of a variety of other countries around the world.

One difference between this trial and the other “-mab” trials such as RAINBOW, is that the laser therapy had fewer failures, they thought that around 72% of laser therapy would be successful, whereas they actually had 82% success. The study was, as a result, underpowered. Definitions of failure were not very different between groups, but in RAINBOW there were many more babies in the laser group (18/74) who failed and then received rescue rabinizumab.

The authors try to explain the difference in failures, but I don’t think it needs any, in such a small group of controls 72% and 82% are almost identical proportions, they had approximately the proportion of treatment failures that would be expected.

What that means is, that although aflibercept was not inferior to laser in the primary outcome expressed as a simple percentage, we cannot say with more than 95% confidence that it isn’t worse than laser, the results are compatible with the possibility of aflibercept having a greater failure rate than laser.

If you want to understand a bit more about non-inferiority trials, you could do worse than watch the NEJM youtube video (not words I thought I would ever write) . Or better still, read this article from the NEJM from a few years ago, which includes the following figure for interpretation of different possible results.

You can see the figure doesn’t include an example which matches this trial (called FIREFLEYE), it does have an example which it calls “noninferiority and inferiority” which is a confusing phrase, “the test treatment is worse but at the same time not worse”, which could be restated, ‘the test treatment was worse, but the confidence intervals did not exceed our prespecified margin, so it might be an acceptable alternative”.

The type of findings that this study had, could be represented by the open circle in the imaginary results below, which I guess could be labelled “superiority but not noninferiority”, (smiley ironic emoji), or you could say “the results were numerically better, but not better enough to be sure they are better and, in fact, they are statistically compatible with a chance that they are worse”, or maybe we should just say “inconclusive”.

The study was underpowered to be able to be confident about the relative efficacy of aflibercept. It looks to be probably about as effective as laser, when compared to a group of babies in whom laser worked fairly well. Long term ocular and visual outcomes will, I guess, likely be much better than laser, if they are similar to the longer term ocular and visual outcomes of rabinizumab or bevacizumab, but of course that remains to be proven with longer follow up. Long term outcomes other than ocular/visual outcomes also need to be studied, as we will see in the next post.

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Resuscitation before clamping the cord?

Delayed cord clamping is now standard of care for all deliveries, at term or preterm. In term deliveries it leads to improved iron stores in the baby which difference persists during the first year of life. In very preterm infants mortality is reduced, and there is some reduction in many complications of prematurity; somewhat fewer cases of IVH, NEC, RoP (each of which, individually, are small reductions and potentially chance findings) and fewer transfusions.

Delaying clamping until pulmonary ventilation is established allows the reduction in pulmonary vascular resistance and increase in pulmonary blood flow and left heart preload to occur. It makes much physiologic sense therefore to ensure that the cord is left intact until this occurs, which complicates resuscitation in babies who don’t start breathing during the usual 60 seconds of delay in cord clamping. It is therefore common, for babies who don’t start to breathe spontaneously early, to clamp and cut the cord and take the baby to a resuscitation table to provide positive pressure ventilation.

Procedures for resuscitation with an intact cord have been developed and are being studied in preterm babies. As you might imagine this is a very difficult subject to study, especially among full term babies few of whom need to be ventilated. So bravo once again to the Melbourne group, this time to a collaborative project between the 2 centres at the Royal Women’s Hospital and Monash. (Badurdeen S, et al. Physiologically based cord clamping for infants >/=32+0 weeks gestation: A randomised clinical trial and reference percentiles for heart rate and oxygen saturation for infants >/=35+0 weeks gestation. PLoS Med. 2022;19(6):e1004029).

Even thinking about how to do such a study makes my head hurt, you need to enrol mothers at increased risk of needing neonatal resuscitation, and then randomize the babies who do actually need resuscitation to either have the usual approach (immediate clamping) or to have initial steps of resuscitation, at least attempts to establish pulmonary ventilation, with the cord intact. But very few babies who are at risk actually need positive pressure ventilation, so you have to put in place the resources required in order to screen nearly 1000 babies, enrol about 500, and finally randomize only 120 of them, as they did in this trial. Those enrolled but not randomized are babies who have delayed clamping and don’t need assisted ventilation. So the team had the great idea of collecting saturation and heart rate data from them in order to update the percentiles for normal transition, using data from infants with delayed clamping. The percentiles we all currently use are from babies with immediate clamping.

Those percentiles are here for the babies in the study of at least 35 weeks gestation who started breathing with just drying suction and stimulation who had at least 2 minutes delay before clamping the cord:

Those babies who did not start breathing when the physicians thought they needed positive pressure ventilation, in the first 60 seconds, were then randomized using a smart phone App. The randomization actually occurred at a mean time of 26 seconds after birth, and the cord was subsequently clamped in the Early cord clamping, ECC, group, at a mean of 37 seconds, and after establishing pulmonary ventilation in what they called the Physiologically based cord clamping, PBCC, group at a mean of 136 seconds.

The primary outcome for the trial was the mean heart rate between 60 and 120 seconds after birth. ECG was installed prior to 60 seconds, and the heart rate was recorded every 10 seconds between 60 to 120 s and then averaged. This is the one thing in this trial that I think is questionable, and I am sure was the subject of many discussions. I presume it was based on the findings from the animal studies, of the same group, that heart rate was lower among preterm lambs who had ECC compared to lambs with PBCC. The clinical significance of an average heart rate during this period is questionable, time to resolution of bradycardia might have been a better measure, but of course, not all the babies would be bradycardic, and further restricting the study to those with slow heart rates would have made the study unfeasible. The results show that after 30 s from birth, fewer than a third of the babies ever had a heart rate under 100. They also show that many of the randomized babies didn’t actually need to have respiratory support, 23 of the 63 PBCC babies and 32 of the 60 in the ECC group did not need any respiratory support.

The primary outcome was not different between groups, or between subgroups, and the numerous secondary outcomes were also all similar. A few of the ECC babies started breathing very quickly after randomization, either before the cord was actually clamped, or within a few seconds afterwards, and the actual heart rates were almost identical during the intervention period, and then were slightly higher in the ECC group than the PBCC.

Despite the good physiologic rationale for the practice, this study doesn’t give any support for resuscitation with an intact umbilical circulation.

In contrast a trial from Kathmandu does show a possible benefit. (Kc A, et al. Effect of early versus delayed cord clamping in neonate on heart rate, breathing and oxygen saturation during first 10 minutes of birth – randomized clinical trial. Matern Health Neonatol Perinatol. 2019;5:7) In that trial, which was somewhat larger, and also had some of the same difficulties with design and recruitment, 1560 babies were randomized of nearly 1800 who were screened. There were 780 in each group, with 134 needing resuscitation in the delayed clamping group, and 97 with ECC.

The eligibility criteria were a bit different (>34 wks) as were procedures and outcomes; the teams were following the Helping Babies Breathe algorithms, which are slightly different in the initial steps to NRP. Babies were randomized prior to birth, but not included unless they didn’t respond to the initial steps of suctioning and stimulation and start breathing within 30 s after birth. At which time the intervention started, which was either immediate clamping, moving the baby to a resuscitation area in a room right next to the DR, or starting PPV “close to the mother in her bed” with clamping delayed at least 3 minutes. Unfortunately only half of the delayed clamping group followed the protocol, with variable durations of delayed clamping, median 105 s (IQR 30 -191). Despite this, there were differences in the primary outcome variable, which for this study was the saturation at 10 minutes of age. The mean saturation with ECC was 85%, compared to 90% for the intact cord group. There were also differences in heart rate at 1 and 5 minutes, but they were actually lower in the intact cord group than ECC, a difference of about 10 bpm at each time. The babies also cried sooner and established regular breathing more quickly. Earlier on in the resuscitation, at 1 and 5 minutes, the differences in saturation were greater between groups, 72% vs 62% at 1 minute, and 84% vs 77% at 5 minutes.

Despite the problems with following the protocol to the full 3 minutes duration of delayed clamping, it looks like most of the intact cord resuscitation group did have either positive pressure or spontaneous breathing before the cord was clamped. 66% of the delayed clamping group, and 20% of the ECC group had breathing efforts before the cord was clamped, and it looks like most of the protocol violations occurred after PPV was at least initiated. They did analyse the data only from those who had the full 3 minutes of delay in clamping, and all the heart rate and saturation differences were a bit larger between groups, but there was no real change in the spontaneous breathing outcomes compared to the ITT analysis.

The clinical importance of having saturations 5 points higher at 10 minutes is questionable, but a trial to show improved clinical outcomes would have to be enormous. Is it feasible to do such a trial? It would probably need cluster randomization, or deferred consent if individually randomized. Otherwise we would have to consent many thousands of mothers prior to delivery in order to have an adequate sample size of babies who are at risk of complications.

It is interesting that the physiologic rationale for this approach includes the demonstration in animals that clamping the cord before PPV leads to lower heart rates, whereas in this study the heart rates were higher with ECC. If you look at the animal data such as this figure from a review article

Heart rate and right ventricular output measured in newborn lambs that either had their umbilical cords clamped 1–2 mins before ventilation was commenced (clamp first; closed circles) or were ventilated and pulmonary blood flow allowed to increase before their cords were clamped (vent first; open circles). The broken line (a) indicates either when cord clamping occurred in the clamp first group or ventilation commenced in the vent first group. The broken line (b), indicates when either clamping occurred in the vent first group or when ventilation commenced in the clamp first group

you can see that the delay in PPV after cord clamping among the lambs was over 2 minutes, and the bradycardia was not really evident for the first 30 seconds (even though RV output is very low). As we don’t wait for 2 minutes of apnoea after cord clamping in human babies, we might well not see the bradycardia that is seen in lambs, despite a probably much lower RV output.

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Not neonatology: Adaptive Variation in the Hawaiian Honeycreepers

The break in my posts was partly due to a vacation in Hawaii, where I was fortunate to have some time to go birding, and take some photographs of birds from a group that has a remarkable evolutionary history, but which is much less well known than Darwin’s Finches. The Hawaiian Honeycreepers are now known to have diverged from a common ancestor. They are all now endangered, critically endangered or extinct, but those that I was able to see are beautiful unique birds.

Above is one of the least endangered, the Apapani, shown here in an Ohia tree, with its curved beak adapted to seeking nectar from the flowers of this tree.

The I’iwi is an iconic bird, shown on Hawaiian publicities or posters whenever they want a photo of a bird

It has somehow learnt to puncture the nectaries of invasive plant species, like the poka banana that this individual is perched on.

These birds are threatened by the loss of habitat, especially the loss of the Ohia tree which is being attacked by ROD (Rapid Ohia Death) due to a fungus probably brought in by the nursery tree industry. They also lack immunity to two mosquito transmitted diseases, avian pox and avian malaria. Mosquitoes were absent on these islands until recently, and the birds have no immunity to the disease carried by them. Each year, with climate warming, the mosquitoes are found at higher and higher altitude, and the birds retreat to smaller and smaller regions of Hawaii.

The Akiapola’au is a bird with a remarkable beak, but only about 600 are left, it is dependent on the Koa tree.

The lower bill is used like a woodpecker to tap and make holes in tree bark, and the long curved upper bill then probes to remove beetle larvae. It is an exclusive insectivore, unlike the other Honeycreepers.

The even more endangered Palila is only found in dry Mamane forest on the western slopes of Mauna Kea above 2000 m elevation. The remaining range is about 5% of its recent extent. It has evolved a resistance to the toxic phenols in the seeds of the Mamane, which is a leguminous flowering tree under threat from invasive species. Most other small animals find the Mamane seeds and pods toxic.

Not the best photo, but there are so few of these birds left I find myself fortunate to have seen one perched among the flowers of the Mamane. The are also very smart birds, as they were able to take the Hawaiian Department of Land and Natural Resources to court and win, to force them to provide some protection of their habitat. : Palila v. Hawaii Department of Land and Natural Resources, 852 F.2d 1106 (9th Cir, 1988).

The evolutionary history and relationships of these birds has been clarified in the recent past and correlated with the appearance of the larger Hawaiian Islands, (Heather R.L. Lerner, et al. Multilocus Resolution of Phylogeny and Timescale in the Extant Adaptive Radiation of Hawaiian Honeycreepers, Current Biology, 2011 (21) 1838-1844).

Bayesian Divergence Date Estimates for Hawaiian Honeycreepers from Whole Mitochondrial Genomes Based on Three Island Age Calibration Points
Mean ages are shown above each node, with horizontal bars across nodes representing 95% highest probability density intervals. Shaded vertical bars encompass the estimated subaerial to maximal shield-building dates for the recent Hawaiian Islands, where the gray bars indicate island ages used as calibrations, and asterisks () identify constrained nodes. Lowercase letters identify divergence of a new morphological lineage before formation of Oahu (a), during or after formation of Oahu (b), or before or during formation of Maui Nui (c). Distributions by island are listed to the right of each taxon where closed circles denote historic and/or extant (and sometimes fossil) distributions, and open circles represent fossil distributions with no known historic or extant populations. (1) The extant population occurs on Nihoa Island, but closely related extinct species mainly differing in size occurred on Kauai, Oahu, and Hawaii Islands. (2) The extant population occurs on Laysan Island, but closely related extinct species mainly differing in sizes occurred on Kauai and Hawaii Islands. (3) A closely related species or subspecies occurred on Laysan Island. Photographs are by Jack Jeffrey

They appear to have arrived after Kauai was formed, then cooled, then was colonized by plants, about 5.8 million years ago, with their forefathers being Eurasian Rosefinches. Each successive island has been colonized and then the various ecological niches been filled by adaptive radiation. Visiting the Hakalau Forest Natural Wildlife Reserve on Hawaii, where I photographed the I’iwi and the Akiapola’au was a highlight, special access with an approved guide is required, and we were fortunate to be able to go with Jack Jeffrey, who took the photos included in that figure above.

I put a few more of my photos of birds from Hawaii on a new page of the blog.

Personally I find the birds more impressive than Darwin’s Finches (which are not actually finches but Tanagers), the Honeycreepers in contrast are actually Finches, but have dramatically varying beaks and coloration, despite their common ancestry. Perhaps if they were more famous, and someone wrote a successful book about them, we might be able to stop their decline and prevent their disappearance.

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Erythropoietin does not protect the brain, what next?

The latest trial to fail to find a benefit of erythropoietin (Epo) for neonatal brain protection has just been published (Wu YW, et al. Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. N Engl J Med. 2022;387(2):148-59). The HEAL trial, a multicentre randomized controlled trial in 500 asphyxiated term infants undergoing cooling found a similar incidence of death, of neurologic impairment, and of developmental delay at 2 to 3 years with Epo or placebo. There was also no difference in MRI injury, either as a percentage or when looking at the patterns of injury, or in discharge neurological examination.

Epo was started before 26 hours of age, in fact at a mean of just less than 18 hours, the dose was 1000 u/kg for a total of 5 doses, about 1/4 had severe (Sarnat 3) encephalopathy, the reminder being moderate.

Erythropoietin is effective in many animal models of HIE, so why did it not work in this trial? At first I thought that maybe it was given too late, but the authors suggest that maybe it was given too early! They put it this way “Other possible explanations for our negative findings include toxic effects of erythropoietin administration early in the injury cascade when combined with therapeutic hypothermia; suboptimal dosage or timing of administration, because later doses may be most effective; and differences in injury mechanisms between preclinical models of hypoxic–ischemic encephalopathy and human hypoxic–ischemic encephalopathy” In the first of the 2 animal studies they refer to in support of their statement about timing, in rats with cerebral artery occlusion the Epo was given starting a week after the injury, and improved outcomes, in the other, in mice with an MCA occlusion, Epo was given starting 3 days after injury and improved outcomes. But I haven’t seen anything to suggest that Epo only works if given late, but not if given early (I am by no means an expert in this literature). Indeed the lamb studies of Alistair Gunn show efficacy of Epo given starting 30 minutes after the injury. His studies, however, suggest that there is no additional benefit if given in combination with therapeutic hypothermia (Wassink G, et al. Recombinant erythropoietin does not augment hypothermic white matter protection after global cerebral ischaemia in near-term fetal sheep. Brain Commun. 2021;3(3):fcab172). Indeed there may be adverse effects of the combination (Dhillon SK, et al. Adverse neural effects of delayed, intermittent treatment with rEPO after asphyxia in preterm fetal sheep. J Physiol. 2021;599(14):3593-609).

It remains possible that if you don’t have access to therapeutic hypothermia, that Epo may have a role, and a much smaller RCT from northern India, (n=100) did suggest a benefit among non-cooled infants. (Malla RR, et al. Erythropoietin monotherapy in perinatal asphyxia with moderate to severe encephalopathy: a randomized placebo-controlled trial. J Perinatol. 2017).

The authors report that the overall incidence of serious adverse events was higher in the Epo group than the controls, but the definition of what is an SAE compared to an adverse event is rather subjective, so hypertension, is considered an SAE, whereas convulsions (which were a bit less common with Epo) are considered a non-serious AE, if you exchange those definitions then there is no “significant” increase in SAE. I know you should not redefine things after seeing the results, but lumping all the very different adverse events which they consider serious together seems to be already quite questionable. Individually, there is nothing which looks different to random variation. Which is to say that Epo is probably safe, but also very likely ineffective when used like this for this indication.

There are other trials, or at least 1 other trial in Australia (PAEAN), which seems to have completed enrolment but has not yet reported outcomes, so it is possible that this will change, but it seems unlikely as there isn’t a hint of an advantage of Epo in the HEAL trial. The PAEAN trial also is in babies under hypothermia, and also plans to randomize prior to 24 hours of age.

The outcomes of babies with HIE after hypothermia remain problematic, there are many infants with long term motor or intellectual difficulties, and further research will be essential. What should be the next trials? There are of course a few already being performed, one promising therapy being studied in a multicentre European trial is allopurinol, in the ALBINO trial, with a sample size of over 800 it will be the largest trial yet of HIE; large trials are needed for this condition, as the chance of seeing an impact as great as the impact of hypothermia are small, but moderate improvements in outcomes, needing large sample sizes to show them with certainty, could be very important. There are a couple of small trials of melatonin, which suggest a possible impact, and a current multicentre trial in Italy has a sample size of only 100, which is underpowered for all except dramatic effects.

This figure from a 2015 review article suggested some other possibilities

The most easily investigated of those possibilities are the same ones that I wrote about 10 years ago! I still think that prophylactic high-dose phenobarbitone is worth investigating, with the same rationale, a small RCT pre the cooling era showed benefit, there are theoretical and some pre-clinical data suggesting a role also.

But for now, there is no proven therapy that improves outcomes beyond the benefits, important and real but limited, of therapeutic hypothermia.

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What is happening for the most preterm deliveries.The Completed Week Heuristic.

There are several recent publications about deliveries at 22 to 25 weeks gestation, evaluating the frequency of intensive care support of the babies, factors associated with support, and survival.

The California Perinatal Quality Care Collaborative reports the proportion of “active treatment of infants born at 22-25 weeks of gestation in California, 2011-2018” which also happens to be the title. (Chen X, et al. The Journal of Pediatrics. 2022) it shows that during those years, the frequency of active treatment of babies thought to be 23 completed weeks of gestation increased, a lot.

I was a bit surprised by the lack of change at 22 weeks, but there are only about 120 per year, which is why the intervals are so wide, and if you ignore 2012, it looks like there is probably an upward trend; perhaps more recent years will show a change. The CPQCC data collection hasn’t changed significantly during those years, with over 90% of California NICUs contributing, and over 97% of very preterm births included, so the data are very reliable for regional trends.

Another intriguing graph is this one

It is interesting, and understandable, that the rate of active treatment increases as the week goes on, from 22 weeks 0 days to 22 and 6, and the same during week 23. What makes no sense, however, scientifically, is the fact that this is not a smooth curve, the difference between 22+5 and 22+6, is so much smaller than the jump from 22+6 to 23+0.

With all the inaccuracies in gestational age dating, the big increases in active care at midnight on day 22+6, and again at midnight on day 23+6 make no sense, and are clear evidence of our preconceptions, I think I will call this the “completed week heuristic”: 22 weeks and 6 days sounds much less mature than 23 weeks, and again 23 weeks and 6 days sounds a lot less than 24 weeks! I hypothesized in a previous post that if human beings had decided a few millennia ago to divide our days into blocks of 10 days rather than 7, our resuscitation patterns would be very different.

Also interesting in this study is that the proportions of babies receiving active intensive care was higher in level 2 NICUs than level 3, which were again higher than level 4 NICUs. The data were analyzed by the hospital of birth, and many level 3 NICUs are associated with a perinatal service, and provide all the care that a level 4 provides except for surgery. It is hard for me to explain why the odds of having active treatment are 34% higher at a hospital with a level 3 NICU at 22 and 23 weeks, and are still 43% higher at 24 and 25 weeks, than a hospital with a level 4 NICU.

The even higher odds of receiving active treatment in a hospital with a level 2 NICU (about twice the odds) are discussed by the authors in the publication, they think that many such babies are delivered rapidly after arrival of the mother, when they do not have time to safely transfer her. As such, there is also less time to counsel the parents, so they may default to initiating intensive care and then transferring.

And what about survival? Well a new publication could have been helpful, but unfortunately ends up being very unhelpful. (Doshi H, et al. National Trends in Survival and Short-Term Outcomes of Periviable Births </=24 Weeks Gestation in the United States, 2009 to 2018. Am J Perinatol. 2022). It analyses data from an administrative database, and reports that there were 71,854 live births in the USA during the years noted in the title, but then ignores all the babies who die at less than 24 hours of life (34,251); I calculated, from the data they present, that the deaths at less than 24 hours were 31,850 babies of 22 or 23 weeks gestation, and about 2,400 babies of 24 weeks. The graph below, like all the others, only includes babies who survived the first 24 hours.

As they give no information about the trends of <24 hour deaths, we don’t know the survival trends among live born babies. Even more annoying, all the data about complications are given as “death or…”, the final figure shows the trends in “death or tracheostomy”, “death or VP shunt” etc. Most of the graphs look just about identical, because death is so much more common than the associated complication, and, as there is no graph for death in that figure, it is not at all clear what the results are for “VP shunt among survivors”, or “tracheostomy among survivors”, which would have been useful and helpful. “Death or BPD” is the one graph which is different, with a much higher percentage of adverse outcomes than the other outcomes, but still, without knowing what the overall mortality is by year, the reader cannot tell if the “BPD among survivors” is increasing or decreasing.

The last of these database analyses (Perry MF, et al. Factors Associated with Receiving No Maternal or Neonatal Interventions among Periviable Deliveries. Am J Perinatol. 2022), looked at the use of antenatal steroids, cesarean delivery and transfer to a tertiary hospital, among mothers who delivered at 22 or 23 completed weeks gestation in the USA. They also examined active interventions for the babies (neonatal intensive care unit admission, surfactant administration, antibiotic administration, or assisted ventilation). The results are somewhat concerning, and reflect, I think, some of the problems in the US medical system, but I also think reflect some cultural variations. Non-hispanic black mothers were significantly less likely to have interventions, which is presented, strangely, as the Odds ratio of having no interventions, which was 1.16 at 22 weeks and 1.21 at 23 weeks. Once born, black babies were less likely to receive no interventions, OR 0.75 at 22 and 23 weeks. SGA babies were more likely to have no interventions and families with private health insurance were also more likely to have no interventions.

When I think of our local practice, I think we also see cultural variations in choices made by and with families from different backgrounds. Parents with some cultural histories are more likely to choose active intervention in the “grey zone” than others, and my guess is, that if we did an objective analysis, we would also see a trend that families with more resources are less likely to choose active intervention. We obviously don’t have families with and without health insurance, this is Canada, we aren’t savages! The discrepancy between maternal and neonatal interventions in this new publication does raise major questions. As an analysis of an enormous administrative database, there are many of those questions that cannot be answered from this data, but they do warrant consideration.

The best outcomes for these babies come when obstetrics works closely with neonatology to co-ordinate active interventions, and ensure that babies who will receive active NICU care are born in the best possible condition. The potential for good survival and excellent long term quality of life is now such that I think I will no longer use the term “periviable”, I am not sure any more what that means, or how to define it.

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The list of shame, and the continued shame of the Journal “Pain”

Randomized controlled trials of pain control measures prior to planned painful procedures that have an untreated control group are unethical.

I would have thought in 2022 that statement was about as uncontroversial as a statement about ethics could be, nevertheless such studies continue to be performed and published.

In one of my recent posts I wrote about an article in the journal “Pain” where a group of babies were randomized to experience pain. I wrote to the editor about my concerns and was asked to write a “letter to the editor”, which I did.

The text of the letter is here:

The article, by Gao et al [3], Effect of combined pharmacological, behavioral, and physical interventions for procedural pain on salivary cortisol and neurobehavioral development in preterm infants: a randomized controlled trial,” published in your journal describes a research project which is clearly unethical[1] and should not have been published.

In this study, newborn babies were assigned to a group designed to experience repeated painful interventions. The express purpose of the design was to create a group of newborn infants who had repeated, avoidable pain. The control group had a mean of 35 painful procedures per baby (SD 15), with mean PIPP scores indicating moderate to severe pain. Pain which could easily have been dramatically reduced or completely avoided.

This research is clearly in conflict with the declaration of Helsinki[6], which notes that untreated controls should only be included in a trial “in the absence of existing proven therapy”, whereas there is an abundance of existing proven therapies for the procedures studied in this trial, from randomized controlled trials involving many thousands of newborn infants. Effective methods to prevent pain caused by skin-breaking procedures are well known, easily available, and cheap or free. Those methods include kangaroo care/skin-to-skin contact, oral sucrose or glucose solutions, especially when combined with non-nutritive sucking, and breastfeeding. There is no valid reason for denying such pain reduction methods to research subjects. Publication in a high-quality journal such as Pain gives credibility to the research and suggests that it is acceptable to inflict pain on babies in order to complete a research project.

Research which compares an analgesic intervention for a painful procedure in newborn infants to an untreated control group is useless in improving care. As effective pain measures are already well known, the only research which could possibly improve care is that which compares different analgesic interventions, or examines the addition of measures to those already known to be effective. It is already clear that repeated painful procedures, as studied in this trial, have adverse effects on stress, neurological and developmental outcomes[5]. It is further already known that routine analgesic interventions mitigate these adverse effects; as a result, national[2] and international[4] guidelines require that analgesia is used for all painful procedures in newborn infants.

The most effective way your journal could improve pain control in newborn infants would be to cease publishing research which unethically randomizes babies to have avoidable pain. All future trials in newborn infants undergoing planned painful procedures that the journal publishes should ensure that all the babies receive proven effective methods of pain control.

I urge you to consider withdrawing this article, and to establish editorial guidelines which prevent the publication of research which imposes avoidable pain on the participants. Specifically, studies comparing pain responses in newborn infants which include an untreated control group should never be published.

The letter was sent out to referees, I guess the same ones who refereed the initial publication, I don’t know as it was all anonymous, referee numbers 1 and 2 had similar points in responses to my letter: They both made the point that the procedures were required for clinical care, that was not in dispute, and has no relevance to my arguments. Referee 2 made the following point:

The article by Gao and colleagues state that it is routine in the unit where the study took place for pain-relieving interventions to be administered once a baby starts crying rather than before. If this RCT had not been conducted, then all the babies in this study would have received this form of care.

Similar comments were made by referee 1, in other words, they are saying that the fact that pain is so badly handled, in this NICU and in many others, is sufficient justification for not providing effective analgesia in the trial. Waiting for the baby to demonstrate that they are in pain, and then trying to soothe them afterwards, is, according to these reviewers, acceptable as a method of pain control. There is, of course, a huge literature showing that pre-emptive pain control, prior to painful procedures, is much more effective than after the fact; waiting for the baby to be in pain, then trying to calm them down afterwards, is completely inadequate as an approach to painful interventions. Just because the NICU does not currently follow adequate pain control standards is not a good reason for publishing a trial comparing their inadequate usual approach to something else.

One of the referees of my letter also notes that it has been stated that neonatal providers in China need a high-quality, evidence-based guideline for the treatment and management of neonatal pain. Which may well be true, but that does not justify performing research on Chinese babies which inflicts avoidable pain. There is already enough published data about pain responses without hurting Chinese babies too.

As you might guess from this post, the editor rejected my letter, which I think shows a certain cowardice, they should at least let the readers consider the arguments for themselves.

One of the referees of the letter actually gives references to 2 articles and a registered protocol which come from a single group. In all of those references there are babies receiving planned painful skin breaking procedures without analgesia, which leads me to guess that there is some auto-justification going on here, and that perhaps this referee has been performing similar unethical studies. When I looked at one of those studies, published as correspondence in a non-paediatric journal (Gursul D, et al. Stroking modulates noxious-evoked brain activity in human infants. Curr Biol. 2018 Dec 17;28(24):R1380-R1381), I was appalled to find that the first of 2 studies, briefly reported together, inflicted pain for no valid reason at all. They took 30 full term infants and gave them pain using a pinprick stimulator and measured the EEG responses, showing noxious related EEG changes in the control babies who received no analgesic intervention. The principal investigator of that study has published articles suggesting that behavioural pain responses are not very important, and that we should use EEG noxious changes as the method to detect pain in newborns. I disagree with that contention, but even if you accept that argument, how does one justify creating pain in otherwise healthy normal babies by sticking needles into them, and “proving” that they have pain using an EEG, without any clinical justification for the pain? This is one of the least ethical studies I have seen in recent years in newborn infants. This part of the study was a comparison between pain from pinpricks with either no analgesic intervention or stroking the leg with a brush, in a specific fashion thought to stimulate C-fibres. The heels of the babies were pricked 27 times in 3 blocks, which appears to be in order to average out the EEG background changes so the the noxious related waves can be seen. I have to admit that this seems to be a relatively mild painful stimulus, the babies usually pulled their legs away, but in similar previous studies this group has shown that the pain they administer with this system is not enough to increase PIPP scores, even though they see EEG changes and the baby withdraws their leg.

In the second part of that letter (Gursul et al) they report a study which appears to be not randomized (it is so poorly reported that it is not clear how the babies were divided into intervention and control groups, at one point they say the controls were “age-matched” but the intervention group was 5 days old and the controls were 2.5 days), the babies had a heel poke for some clinically required blood work, and the (either14 or 16) controls had no analgesic intervention, the 20 in the intervention group had the brushing intervention thought to stimulate C-fibres, which, in 16 of them, decreased the EEG changes and shortened the duration of facial grimacing (they did not do formal assessment on a pain scale). The controls were therefore assigned to a group designed to have pain, with no pre-emptive analgesia, and without even any evidence that they had calming procedures after the heel poke when they were crying.

Other new publications to add to the list of shame include Talebi M, et al. The effect of concurrent use of swaddle and sucrose on the intensity of pain during venous blood sampling in neonate: a clinical trial study. BMC Pediatr. 2022;22(1):263, which studied 4 groups, swaddling, sucrose, combined sucrose and swaddling and nothing at all. Not surprisingly, nothing at all was worse than any of the other interventions, and that control group was completely unnecessary and subjected to avoidable pain.

Another study shows that you can do such research without an untreated control group, and have useful results. They compared breastfeeding to 20% glucose to non-nutritive sucking prior to a clinically required heel-poke, and did not have an untreated group. (Napiórkowska-Orkisz M, et al. Evaluation of Methods to Minimize Pain in Newborns during Capillary Blood Sampling for Screening: A Randomized Clinical Trial. Int J Environ Res Public Health. 2022;19(2):870), I would argue that NNS without glucose is already known to have a somewhat limited efficacy, but this smallish study (n=30 per group) did not show much difference between groups; as a very positive note, they mention in the introduction that they did not have an untreated control group for ethical reasons.

A new systematic review has examined the role of NNS in combination with sucrose, and shows that there is a consistently better control of pain with the combination than with either alone. (Li Q, et al. Efficacy and safety of combined oral sucrose and nonnutritive sucking in pain management for infants: A systematic review and meta-analysis. PLoS One. 2022;17(5):e0268033)

Most of these studies used the PIPP score, if you take out the Mandee study, and O’Sullivan, which used different scales, and should not be analyzed together, the results are similar, with better pain control during heel sticks, and slightly better pain scores during RoP screening, but as you can see from the mean scores, RoP screening still leads to high PIPP scores (means of 12 to 17) even with the combined intervention.

This review also compared combined NNS and sucrose to breastmilk or breastfeeding, but found very little data, 1 study of heelstick comparing NNS and sucrose to breast feeding and 1 of venepuncture comparing the combination to expressed breast milk, both showing similar pain control.

This review supports the idea that the optimal analgesia, prior to heel pokes, if the mother is not present, is a combination of sucrose and a soother; breast milk might be as effective, but there is less data. If mum is there, then breastfeeding for babies when that is appropriate, or skin to skin care, may be about as effective, and if dad is present then skin to skin care by him might also work, but I am having difficulty finding data about that.

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Bronchopulmonary Dysplasia; does it matter?

I just published a “different view” article addressing the question in the title, with a group of expert collaborators, Mai Luu who is our follow up doc in Montreal, and helps to run the Canadian Neonatal Follow-Up Network (CNFUN), Paige Church, who organizes the neonatal follow-up in Toronto, and Peter Davis, who needs no introduction.

Barrington KJ, et al. Respiratory outcomes in preterm babies, is bronchopulmonary dysplasia important? Acta Paediatr. 2022.

I was stimulated to write the article when reviewing publications about postnatal steroid use, we were trying to develop a common approach for our NICU, and be as evidence-based as possible. During the process I realised, what I guess I already knew, that there is no evidence from any of the trials that long term pulmonary health is improved by steroid use. Even though there are many trials showing a reduction in BPD. Regardless of how it is defined; all the various definitions of BPD are based on abnormal oxygenation, either at 28 days of life or at 36 weeks PMA, sometimes requiring x-ray changes. Our contention in the article is that such short term changes in gas exchange do not correlate very strongly with long term respiratory morbidity. In addition, it probably isn’t very important to families if a baby is on oxygen at 36 weeks PMA, if they go home with little support and few respiratory signs, and have minor respiratory problems in the first year or so of life.

You may remember that BPD was first described, and named, by Bill Northway (a radiologist) and colleagues in a seminal paper in the NEJM (Northway WH, Jr., et al. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967;276(7):357-68.) which you can find easily on-line, along with the description of stages (which we rarely use now) and pathology specimens. This was entirely a clinical description of a new phenomenon among babies who had been supported with the new innovation, assisted mechanical ventilation! PEEP was not yet in use, so babies were being ventilated as a last resort to prevent death, using high peak pressures and zero PEEP, and oxygen concentrations were kept extremely high for long periods, as it wasn’t possible to measure oxygenation continuously, or even very frequently, because arterial blood gas results took a while.

The various newer definitions of BPD, have usually been developed because it was realized that many babies who satisfy the contemporary definition (initially, persistent oxygen needs up to a completely arbitrary 28 days of life) had little long term respiratory difficulty. Andy Shennan and colleagues in Toronto (including Michael Dunn, who must have been very young at the time) compared long term outcomes to the neonatal evolution of lung disease, and realized that adverse long term outcomes were much better predicted by oxygen need at 36 weeks Post-Menstrual Age. In other words they were acknowledging from the start that it is the long term respiratory morbidity that is important, and that the definition of BPD is important as an interim, surrogate, outcome. What they used as their long term outcome of interest is any one the following up to 2 years of age: death not due to congenital anomaly; O2 at 40 weeks PMA; respiratory surgery; 2 or more respiratory re-hospitalisations; recurrent wheezing requiring medication; or, X-ray changes or persistent wheezing/retractions/tachypnoea with growth failure, hypotonia, neurological impairment or developmental delay. Which, interestingly, includes neurodevelopmental outcomes in the respiratory morbidity definition. Among the group of babies they studied, the prevalence of that outcome was just under 20%, and the PPV for such an outcome, of needing oxygen at 36 weeks, was 63% with a NPV of 90%.

Other proposed definitions of BPD have also used different aspects of long term respiratory morbidity as their standard for evaluating their definition. The NICHD definition, which introduced grades of BPD, looked at re-hospitalisations in one analysis, and chronic respiratory medication use in another. They showed that having moderate or severe BPD was, statistically speaking, a predictor of both re-hospitalisation and chronic respiratory medication use, but if you look at the data, the PPV for either of those outcomes was only about 40%, and the NPV about 70%. In other words, many babies without BPD have chronic respiratory morbidity, and many babies with BPD, even those with severe BPD, do not, at least using these very broad simplistic descriptions of respiratory morbidity.

I think that our reliance on “BPD” as an outcome could well be having serious adverse impacts on our ability to improve long-term respiratory function among preterm infants.

If we take one example, the SUPPORT trial, the primary outcome of “death or BPD” was just about identical between groups (48% vs 51%) and BPD alone was 39% vs 41%. In marked contrast, all the long term respiratory outcomes, mostly things which probably matter to infants and their families, were better in the CPAP group. The CPAP babies had “fewer episodes of wheezing without a cold (28.9% vs 36.5%; P < .05), respiratory illnesses diagnosed by a doctor (47.7% vs 55.2%; P < .05), and physician or emergency room visits for breathing problems (68.0% vs 72.9%; P < .05) by 18-22 months CA”. Respiratory re-hospitalisations were also less frequent, 43% vs 50%.

According to these outcomes, CPAP is clearly preferable to immediate intubation for surfactant, even though BPD is not improved. In contrast, many studies of postnatal steroids (Yeh et al, Kothadia et al, UK dexamethasone trial….) have shown less BPD, but all those that have published long-term respiratory morbidity data show no benefit of postnatal steroids. My explanation of that is that steroids reduce inflammation and, as a result, improve gas exchange for a period, but they also have adverse effects on pulmonary growth and development. Of course, many of the steroid trials are relatively unreliable for long term outcomes because of high rates of treatment of controls with steroids, but that does hold true for the trials with low rates of control steroid administration (Such as Yeh et al and Kothadia et al). If we focus on improving long-term respiratory morbidity, then there is little indication for postnatal steroids, infants at risk of dying from their lung disease may be saved by postnatal steroids, but giving steroids to reduce FiO2 or to assist in extubation might be successful for those outcomes, but probably won’t improve pulmonary outcomes in the long term.

We should think of BPD as a short term, interim, surrogate outcome, a way of classifying infants and evaluating lung injury in the short term, but with poor predictive value for respiratory morbidity in the longer term. Much like brain injury, and neurological and developmental outcomes compared to head ultrasound findings; we know that head ultrasound abnormalities are statistically related to longer term neurodevelopmental outcomes, but in order to decide which therapies are likely to improve outcomes we do not rely on ultrasound findings, or even MRI, objective evaluation of longer term function is far more important. We cannot, of course, decide after the fact for each individual trial what long term outcomes are valuable, that would lead to a major risk of bias, and post hoc selection of features of respiratory morbidity which are consistent with one’s prejudices. What long term respiratory morbidities should we evaluate?

When I looked at what features of long term respiratory morbidity have been reported in various trials, it is extremely variable, in addition to the factors already discussed, as outcomes in the Shennan et al paper, and in the NICHD definition of BPD paper, and in the respiratory outcomes of SUPPORT, other articles have presented chronic use of inhaled respiratory medications, post-discharge use of systemic or inhaled respiratory medications, emergency room visits, more than 2 re-hospitalisations, cough without other signs of Upper Respiratory Infection, still requiring oxygen at 2 years after discharge, tracheostomy, and so on. Feeding difficulties, and many other outcomes which are important to families according to recent publications, were never reported.

In the article we plead for the development of long-term respiratory morbidity measures which reflect morbidity of importance to babies and families, and the use of such outcomes as the primary measure of efficacy of neonatal respiratory interventions. There have been one or two attempts to create a definition; one definition from the prematurity and respiratory outcomes study created the following definition “one of the following, hospitalization for respiratory indication, home respiratory support, respiratory medication administration, or respiratory symptoms, being present on at least two of the four 3-monthly questionnaires completed by families during the first year of life”. As far as I can tell the definition was arbitrarily created by the investigators; it was used as a dichotomous outcome. PROP showed a statistically significant association between a diagnosis of BPD and the presence of their outcome, that they called Post-Prematurity Respiratory Disease, PRD. But the predictive ability of a diagnosis of BPD or of severe BPD was poor. PPV of BPD for PRD was only 50%, and the NPV was only 30%. The PPV of severe BPD for PRD was only 37%, and the NPV was 83%.

Again, in other words, many babies with a diagnosis of BPD did not have PRD, and many babies without a diagnosis of BPD, nevertheless had this degree of post-discharge respiratory morbidity.

A more complete definition, which gives a score on an ordinal scale has been developed in the Netherlands for children aged 4 to 8 years, (Meijer-Schaap L, et al. Development and construct validation of a parent-proxy quality of life instrument in children with bronchopulmonary dysplasia aged 4-8 years old. Qual Life Res. 2019;28(2):523-33) it includes 33 items, in 5 domains, respiratory symptoms, school functioning, growth and nutrition, exercise and locomotion, and emotional functioning and health care concerns. It has the great advantage of being developed from items proposed by a multidisciplinary group including parents.

There is a real need for a respiratory outcomes scale developed for use in the first couple of years of life, it should be an ordinal scale, reflecting the range of respiratory morbidities among former very preterm infants, it should be simple to administer, and, most importantly, include items that parents report having an impact on the family.

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Preventing desaturation during intubation. Shine on, you crazy….

Recommendations for older children and adults during endotracheal intubation frequently include the use of free flow oxygen, indeed when I was a fellow with Neil Finer we routinely provided additional free flow oxygen from a catheter placed near the nose, a practice based on data from older subjects. As practices changed with the introduction of routine premedication I didn’t continue the practice, reasoning that intubation with premeds was a lot faster, and that the babies were not breathing anyway. This was probably a mistake. Apnoeic oxygenation is something that is well described in various situations, and I have used it to prevent desaturation during apnoea tests for brain death in the PICU. At the same time the development of readily available high-flow nasal cannulae makes provision of a free gas flow during intubation easier, and probably more effective than just holding an oxygen tube near the baby’s nose.

Studies in adults and older kids have shown that having high-flow cannulae in place during intubation delays desaturation, which is a very common reason for terminating an intubation attempt, and leads to reduction in the number of attempts prior to successful intubation.

Not surprisingly it is the Melbourne group who have taken this to a clinical trial in newborn infants. (Hodgson KA, et al. Nasal High-Flow Therapy during Neonatal Endotracheal Intubation. N Engl J Med. 2022;386(17):1627-37), the Stabilisation with Highflow for Intubation of NEonates, SHINE trial. They randomized 251 intubations (in 202 infants) to either have high-flow nasal cannulae (HFNC) placed prior to intubation, or not. Babies of all gestational ages were eligible, and intubations in the delivery room or the NICU were included, if the intubation was not an emergency.

HFNC were used at a flow rate of 8 litres for all the infants, and used the same oxygen concentration that the baby was already receiving, with the opportunity to increase to 100% if the SpO2 fell below 90%. The primary outcome variable was success on the first attempt, without instability, which was defined as hypoxia (>20% decrease in SpO2) or bradycardia (<100 bpm). Three quarters of the intubations were in the NICU, and most were pre-medicated, with the same protocol that we use in my centre, and which is recommended in several guidelines, atropine, succinylcholine and fentanyl.

As you can see from the primary outcomes, there was a much higher rate of success on first attempt without desaturation or bradycardia, which appears to be mostly because of less desaturation, and there was not any significant occurrence of hyperoxia. You can also see that the biggest gain was among those with less experience, with a dramatic improvement in success, but there is probably an improvement among those with more experience also.

If you have access to the NEJM you can watch a video of a real-life intubation with HFNC, but it really is quite simple, as the image below shows.

There doesn’t to me seem to be any good reason to not implement this widely. There were unfortunately few intubations with a video laryngoscope (only about 8%), which other data show improve success, especially with inexperienced operators. But the two approaches are not in any way exclusive, using HFNC and a video laryngoscope might be the best possible approach, especially for inexperienced intubators, which is now the majority of paediatric trainees! Now that we intubate very few meconium stained babies, we try to maintain as many babies as possible on non-invasive ventilation, and we have a tiny baby intubation team, there are few opportunities for trainees to intubate real babies. Simulation training is vital in providing initial training, but making intubation safer for real babies when it becomes necessary, and ensuring that paediatricians in training develop the expertise needed are all important.

This new publication, and the technique that it shows is safe, effective, and simple, is a big advance for neonatal intensive care.

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World NEC awareness day, part 2

As well as all the high tech mechanistic studies in NEC, such as those that I just posted about, sometimes we need to take a step back and ask some very basic questions. What is the current natural history of NEC? How good are we at diagnosing NEC?

So much has changed in neonatology since NEC was first described, that this new study from the Pediatrix database is timely, (Mara K, et al. Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Natural History Study. Am J Perinatol. 2022). It includes data from babies born 23 to 29 weeks GA who had a birthweight less than 1500g. The babies were divided into those with suspected, medical or surgical NEC. It shows a peak in confirmed NEC incidence around 2007, with a fairly marked decrease since then, being relatively stable since 2015. There has also been a switch in antibiotics used, with much more Piperacillin/Tazobactam, much less 3rd generation cephalosporins, and a drop in vancomycin use over the last few years. There has also been a switch from clindamycin to metronidazole for anaerobic coverage.

There is a huge amount of data in this publication, so I will just mention a few highlights. Risk factors for development of NEC are confirmed as being lower GA, male sex, small for gestational age and being outborn. Mortality is elevated, and is extremely high for surgical NEC: 6% for suspected NEC, 16% for medical NEC and 43% for surgical NEC. Positive blood cultures within 7 days of diagnosis were positive in 20%, and among surgical NEC were positive in 40%. Postnatal growth restriction was common among these babies, especially the surviving surgical NEC infants.

In addition to the obvious human costs of NEC the calculated additional financial costs are enormous. Length of stay was 26 days longer for confirmed NEC babies, and just on that basis average increased hospital charges are about $200,000 per case. Which can be calculated for the whole of the USA to be nearly half a billion dollars a year. That estimate does not include post-discharge costs, which are also enormously increased for NEC babies. Any intervention which has a reasonable cost and which decreases NEC will save money, as well as lives. Another good reason for funding NEC research!

The study has the advantages and limitations of a large database, meaning that individual diagnoses were not verified (of course) and we have to assume that these were all cases of NEC. That assumption is challenged somewhat by this meticulous individual examination of cases; BErrington J, Embleton ND. Discriminating necrotising enterocolitis and focal intestinal perforation. Arch Dis Child Fetal Neonatal Ed. 2022;107(3):336-9. By examining in detail the case records of babies in their local database, it was clear that differentiating the 2 phenomena is difficult, there is overlap in age of presentation, clinical signs at presentation, complications and outcomes. There is even confusion when the histology is examined. Only by really carefully examining each individual case were they able to come up with a final decision, and I am sure they would agree that other people examining the same cases might sometimes have different conclusions! Spontaneous intestinal perforation, with the typical anti-mesenteric perforation in the absence of skip necrotic lesions, has some aetiologic characteristics in common with NEC, but I think it is unlikely that interventions to prevent NEC will also prevent SIP.

The long term outcome impacts of NEC are well known, the data about SIP outcomes are more inconsistent, but there do appear to be substantial adverse impacts on neurological outcomes and on developmental progress. There are also major impacts of NEC on feeding and nutritional outcomes, and associations with lung injury and retinopathy and behavioural problems.

On this day we need more than just awareness, a co-ordinated effort to reduce the incidence and the impact of NEC, and SIP, will improve the future lives of thousands of babies and their families.

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