Neonatal Updates

It’s a long time since I did one of these, but there were several publications that I thought warranted a quick comment.

Abbey NV, et al. Electrocardiogram for heart rate evaluation during preterm resuscitation at birth: a randomized trial. Pediatr Res. 2021.

In this RCT of babies of 30 weeks or less, 51 babies were randomized to either what has become standard NRP, i.e. trying to put an ECG in place as quickly as possible after the baby arrives on the resuscitation table, or doing the same thing but hiding the monitor. The study was performed 4 years ago, and the time it took to get the babies to the resusc table is said to be “22” in 1 group and “18” in the other. I have to assume that these are seconds, and I have to assume that delayed cord clamping was not being practiced at that time. The heart rate was visible at just over a minute in both groups, and about 10 seconds earlier in the ECG visible group.

There was no difference in any clinical variable, including time to get a pulse over 100, about half of the babies were bradycardic at first evaluation, and PPV was started at about “36” in each group, i.e. before the heart rate was visible on any monitor, presumably because of auscultation or palpation of a slow heart rate.

This is an OK study, but I hope it isn’t interpreted as showing that the ECG is a waste of time. For most babies, even the very preterm, you don’t need anything other suction or a few puffs of positive pressure to get them going, as in this study, so nothing we do to try and improve resuscitation will likely have much impact in a study of 50 babies. In order to demonstrate whether ECG really makes a difference among those babies who really need resuscitation, you would need a sample size of a few thousand probably. Or at least a few hundred. I don’t know whether adding ECG to our resuscitation standards is a significant improvement or not, we certainly need to be aware that it can be misleading, if there is an ECG but no output (Luong D, et al. Cardiac arrest with pulseless electrical activity rhythm in newborn infants: a case series. Arch Dis Child Fetal Neonatal Ed. 2019). On the other hand if you can have an accurate heart rate faster, I think that is self-evidently a good thing, and will probably occasionally change the resuscitation approach to a more appropriate intervention.


Gehle DB, et al. A predictive model for preterm babies born < 30 weeks gestational age who will not attain full oral feedings. J Perinatol. 2021.

Occasionally I read something, and I wonder if I am on the same neonatology planet as another group. At the University of South Carolina they send about 16% of their babies <30 gestation home with gastrostomies and tube feeding. I found this rather bizarre, I know there are pressures in the US to send babies home that I don’t have to deal with, but that doesn’t seem to be the explanation here. The G-tube babies in this study are not going home early, indeed the major risk factor for not establishing oral feeding seems to be when you first offer oral feeds, which averages 40 weeks in their G-tube babies.

This centre seems to choose gastrostomy over home NG tube feeding, which I think is questionable unless you think the tube feeds are going to last at least several weeks. But we send very few preterm babies home with any kind of tube feeding. The G-tube babies in this study had a mean birth weight of just under 700g and lots of complications, but I am still really stunned by this extremely high frequency of needing home tube feeds. We are often too slow to insert a G-tube I think, when we reach around 42 weeks and babies aren’t feeding very well, and don’t have much sign of improvement then a G-tube may be the best option. I guess without actually doing the calculations that occurs in about 4% of our babies under 28 weeks (we have about 100 a year <28 weeks), almost all of whom are 22 to 24 week babies.

I would like to see some multicentre evaluation of this phenomenon, we should aim to determine whether one can reduce the numbers of babies who need home tube feeds by uniformly introducing oral feeding at different criteria. In South Carolina apparently their “criteria for oral feeding attempts were respiratory support of ≤0.5 LPM NC and PMA of at least 31 w”. This may be part of the difference from our centre, we routinely start oral feeds between 32 and 34 weeks regardless of O2 requirements, babies on high-flow cannulae have oral feeding attempts if they are still dependent on high-flow at 35 weeks, and we have tried to orally feed a few babies who were still on CPAP. We have a standardised feeding competence scale that we developed (and which I am supposed to write up, I will get round to it soon, honestly, maybe) and have just started nutrition rounds, which are mostly oral feeding rounds, with a great team of professionals, including an OT and lactation consultant.

This is something that has a huge impact on babies and their families, and it really needs much more attention.

Takahashi T, et al. Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birth weights when administered to pregnant sheep in combination with betamethasone acetate. Am J Obstet Gynecol. 2021.

I had forgotten, until reading this article, that the “Celestone” that we use in Canada for antenatal lung maturation is a mixture of 2 different molecules, betamethasone phosphate and betamethasone acetate. I vaguely remember hearing about this years ago, and assumed it was unimportant. Not so. Alan Jobe has been emphasising how little we know about this treatment for years, the dose we use is the same as was originally investigated by Liggins and Howie, which was an arbitrary extrapolation from animal data. What has been shown is that the kinetics of the two molecules are quite different, with the Phosphate having a rapid distribution from IM injection to the blood stream, while the Acetate absorbs more slowly and lasts longer.

In this study, pregnant sheep were randomized in 3 groups to either get placebo, or “celestone” (a mixture of betamethasone phosphate and acetate) just like our patients in threatened preterm labour, or just betamethasone acetate. They thought the acetate alone would give a good response as they have previously shown that prolonged low serum concentrations of betamethasone were effective. The total betamethasone dose was twice as large in the combination group as in the acetate alone group.

Efficacy was similar in terms of induction of surfactant synthesis, but the clinical response rate (determined by CO2 levels after 30 minutes of ventilation) was better with the acetate alone. Lung compliance was better and the pressure volume loops more normal with the acetate alone, the lambs were also smaller after the combination drug. There were much higher serum concentrations in the sheep and fetal lamb with the combination, and evidence of pituitary suppression with the combination compared to the acetate alone.

I think we are rapidly approaching having enough data to perform a clinical trial comparing celestone to the acetate alone.

Rakshasbhuvankar AA, et al. Vitamin A supplementation in very-preterm or very-low-birth-weight infants to prevent morbidity and mortality: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2021.

I have always been a bit sheepish about not giving vitamin A to my very preterm babies, with the data showing a reduction in BPD with routine intramuscular injections. The evidence-based approach should be, I believed, to routinely offer vitamin A. My reticence was based on not knowing what the background vitamin A status of mothers in my region, and not wanting to give multiple intramuscular injections for what seemed to be about a 10% reduction in BPD. Vitamin A in TPN is degraded, and very little gets to the baby, although you might be able to improve that by protecting it from light and giving it separately, or mixing it in with the lipid, as is often done in Europe.

This new SR and meta-analysis confirms that vitamin A is probably effective, with a relative reduction in BPD of about 17%, but if you divide up the studies according to background vitamin A intake, those who had a higher enteral intake in the controls (>1500 units/kg/d) didn’t seem to have a benefit. Although the studies with the higher background intake were quite small with a total of 500 babies in a total of 5 trials, this makes me think that we should be making certain that enteral vitamin A intakes are adequate, and if that is difficult then consider parenteral supplementation.

Singh N, Gray JE. Antibiotic stewardship in NICU: De-implementing routine CRP to reduce antibiotic usage in neonates at risk for early-onset sepsis. J Perinatol. 2021;41(10):2488-94.

The CRP does not adequately differentiate between infected and non-infected babies. We should stop doing them. If you stop measuring CRP them you no longer have to treat raised CRP with antibiotics. This study showed that was true for early onset sepsis, there was a 30% reduction in antibiotic usage for early onset sepsis without any downside. If you do the same thing for Late-onset sepsis, where the data about the uselessness of CRP are equally strong, I am sure you would find the same thing. Less antibiotic use, no downside.

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Delivering better CPAP in the delivery room, can we avoid intubation in the most immature babies?

Randomized trials have shown that trying to prevent intubation in the DR leads to less severe lung injury. The Cochrane review of prophylactic CPAP compared to immediate intubation included 3 trials (SUPPORT, COIN and DR Management study), that review found less BPD, and less “BPD or death” among very preterm infants who were randomized to CPAP rather than immediate intubation. The control group frequency of BPD was somewhat different between the studies, due to differences in entry criteria (about 25% in DRM, 33% in COIN, and nearly 50% in SUPPORT) but all showed less BPD with a similar relative risk reduction, which overall was 0.89.

Many of us have found it difficult to avoid intubation in the most immature babies, even though there are reports from centres like Koln, who are able to deliver surfactant without intubation to infants as early as 22 and 23 weeks gestation. Our centre hasn’t been able to avoid DR intubation in 23 weeks or less. I assumed this was a problem with the babies not havign sufficient resiratory drive and stability, but maybe a better CPAP system could improve the chances of keeping the extremely preterm baby extubated.

Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks’ Gestational Age

Donaldsson S, et al. Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks’ Gestational Age: The CORSAD Randomized Clinical Trial. JAMA Pediatr. 2021;175(9):911-8. This multicentre trial enrolled babies under 28 weeks gestation (although the figure above notes < or = 28 weeks), with antenatal consent to have assisted ventilation and CPAP using either a new system or a usual care group of T-piece resuscitator with face mask.

The visual abstract above just shows the patient interface, but there was also a difference in the pressure generation circuit, as shown below.

https://fn.bmj.com/content/fetalneonatal/102/3/F203/F1.large.jpg

In this system the inspiratory gas flow arrives in the small tube with the green arrow (with a bias flow in the larger tube) and the baby receives positive pressure and breathes spontaneously exhaling through the outlet A. In order to deliver positive pressure breaths the outlet is occluded.

The idea behind this circuit is to reduce the imposed work of breathing, and in their published bench testing the iWOB was indeed dramatically less than with a standard neonatal T-piece reuscitator; but how much this matters in clinical practice is unclear to me. Does it really matter if the extra work of breathing imposed by the system is 1 mJ/breath rather than 8 mJ/breath? The authors state that it has “been suggested” that a high iWOB might contribute to treatment failure, (they give a reference from 1979), but I’m not sure if it really is of clinical importance.

Just like the T-piece resuscitators this is not really a constant pressure system (bubble CPAP gives a constant pressure equivalent to the height of the water column), it is a constant flow system, which will need flow and/or resistance adjustments to achieve the pressure desired. In the model system, there wasn’t any difference of importance between the iWOB with facemask compared to short binasal prongs.

In the CORSAD trial babies either were assisted at birth with the new circuit and close fitting short binasal prongs, or with a standard T-piece and a round face mask. Respiratory support protocols were otherwise identical in the 2 groups. Randomisation was masked, but the intervention, for obvious reasons, was not.

The intervention group resuscitators chose prongs which were tight fitting, and gently held the mouth shut with a finger. Controls used a standard face mask covering the nose and mouth.

The primary outcome variable was “death or intubation” in the delivery room, mortality was expected to be very low, I suspect, so the study was really designed to see if intubation could be avoided with the new system. “Criteria for DR intubation were no or inadequate response to PPV and CPAP defined by one of the following: (1) bradycardia heart rate less than 100 beats per minute despite 60 seconds of effective PPV, (2) persistent apnea, (3) poor respiratory effort during the intervention, and (4) inadequate oxygenation and respiratory distress”. Of course, the decision to intubate, even if protocolized, will always be a bit subjective, and you can see in this list of criteria, there is some subjectivity. In a non-masked trial that potentially introduces bias, but I think that is unavoidable in a pragmatic trial.

Secondary outcomes included need for assisted ventilation in the first 72 hours in the NICU, airleaks, IVH surfactant use, etc. But not survival to discharge or BPD, which I think should have been reported, even if the authors thought BPD unlikely to have been improved. Fewer babies in the intervention group were intubated within the first 72 hours of life, 56% vs 69%, which I think is a large enough difference, in what is probably a critical period in postnatal pulmonary adaptation, to improve lung injury. Now it may be that the difference in intubation is mostly among more mature babies, of 26 and 27 weeks gestation with a much lower risk of BPD, but I don’t see that information in the publication or in the supplementary data.

Summarizing, this looks promising as a way of improving the success of keeping extremely preterm babies from being intubated in the DR. I don’t know whether the circuit or the interface is more important, however. Other studies (there are 4 references below if you are interested) have suggested that nasal masks are preferable to short binasal prongs for delivery of CPAP in the NICU, they seem to be associated with less nasal trauma, and perhaps less CPAP failure. Nasal masks and face-masks are of course quite different. I would like to see more studies like CORSAD, isolating the effects of nasal prongs vs face mask, the new circuit vs a standard T-piece. For now, the improvement in success rate of avoiding intubation is a good start, but I don’t know if I should think of changing my interfaces, or wait for commercialisation of the new system and then buy new resuscitation machines. Might a nasal mask be even better in the DR than either a face mask or short binasal prongs?

Bashir T, et al. ‘Nasal mask’ in comparison with ‘nasal prongs’ or ‘rotation of nasal mask with nasal prongs’ reduce the incidence of nasal injury in preterm neonates supported on nasal continuous positive airway pressure (nCPAP): A randomized controlled trial. PLoS One. 2019;14(1):e0211476.
Say B, et al. Binasal Prong versus Nasal Mask for Applying CPAP to Preterm Infants: A Randomized Controlled Trial. Neonatology. 2016;109(4):258-64.
Chandrasekaran A, et al. Nasal masks or binasal prongs for delivering continuous positive airway pressure in preterm neonates-a randomised trial. Eur J Pediatr. 2017;176(3):379-86.7.
McCarthy LK, et al. A Randomized Trial of Nasal Prong or Face Mask for Respiratory Support for Preterm Newborns. Pediatrics. 2013;132(2):e389-e95.
Yong S-C, et al. Incidence of nasal trauma associated with nasal prong versus nasal mask during continuous positive airway pressure treatment in very low birthweight infants: a randomised control study. Arch Dis Child Fetal Neonatal Ed. 2005;90(6):F480-3.

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Babies feel pain, and they remember it!

I usually don’t post about studies of painful procedures where there was no analgesic prophylaxis in some of the the subjects, except to criticize them, and if they are recent, to call for their retraction. So when I first saw this study, which recorded pain responses to arterial punctures in newborns, I was going to file it in the recycle bin. However, after reading the methods, I found that they did have a protocol to use 25% glucose and facilitated tucking during the arterial punctures. The article doesn’t say that the protocol was actually followed, which is a problem in many NICUs; despite good intentions, pain is often not adequately prevented. So let’s assume for this article that the protocol was followed, not a bad protocol, but not optimal. Sucrose is probably preferable to glucose as it tastes sweeter, and the initial analgesic effect is probably due to the intensity of the taste, with a sort of distraction effect, later effects, by about 2 minutes are probably related to endorphin release. Also sucrose is more effective if combined with a soother/pacifier/dummy or whatever the local term is. (Alberice RMC, et al. Assessment of newborn pain during arterial puncture: an observational analytical study. Rev Bras Ter Intensiva. 2021).

The article, as I read it, is a translation of an article in Portuguese, I love the translation of what I suppose is cleaning the skin with antiseptic as “degermation”.

No surprise; aterial punctures hurt!

If we give the authors the benefit of the doubt, and assume that all the babies received the glucose/swaddling intervention, pain was between minimal and severe, with nearly 50% reaching a PIPP score of 12 or more, despite a reasonable analgesic approach.

The NICU that this was from seems to do an awful lot of arterial punctures, they were actually performed by their lab techs! The messages of the article are: don’t do blood work unless you need to; if you need to then capillary sampling can be performed with much lower PIPP scores than the scores reported here when using a combination of sucrose, soother, and swaddling, or skin to skin care. If you do need to do an arterial puncture then consider EMLA or liposomal lidocaine in addition.

In a previous study of infants who had previously had multiple blood sampling (infants of diabetic mothers) it was shown that they start to have adverse responses when someone comes the next day to prepare them for another heel prick, Taddio A, et al. Conditioning and Hyperalgesia in Newborns Exposed to Repeated Heel Lances. JAMA. 2002;288(7):857-61, during the degermation phase the infants were able to anticipate that something bad was about to happen.

In this newer study, (Mehler K, et al. Pain response to vaccination in newborn infants of diabetic mothers. Early Hum Dev. 2020;149:105139) in infants of diabetic mothers who were about to have their 2 month vaccination, all the babies received 20% glucose with a soother prior to the 2 IM injections that the German standards required. Control infants were from a previous study that the authors published, which is one weakness of this study. The controls had a median of 1 heel stick as neonates (maximum 3) while the infants of diabetic mothers had suffered between 4 and 19, median 5.

The IDM babies had a greater increase in their heart rate, and took longer to recover than the controls.

https://ars.els-cdn.com/content/image/1-s2.0-S0378378220303418-gr1_lrg.jpg

They also had greater increases in their salivary cortisol after the vaccine.

https://ars.els-cdn.com/content/image/1-s2.0-S0378378220303418-gr2_lrg.jpg

Although there is some overlap in the results, the authors also examined a more direct measure of pain sensistivity, using the Frey filaments, where you poke the baby with progressively stiffer filaments to see at what threshold they have a withdrawal response. This suggested that the IDM babies had hyperalgesia, responding at a lower threshold than the previous control group.

Of course, the difference in responses my not be because of a “memory” of the painful experiences as a neonate, and may be due to other factors, such as epigenetic changes associated with maternal diabetes. But one possible explanation is that repeated painful experiences as a newborn may have long term consequences in pain reactions at 2 months of age.

Yet another reason, as if we needed more, that pre-emptive analgesia, prior to planned painful procedures, is important.

Indeed, it is a moral imperative.

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Intestinal perforation in the very preterm, what causes it, and what to do about it.

There are 2 main causes of intestinal perforation in the very preterm, Necrotising Enterocolitis and Spontaneous Perforation. NEC, as I have previously discussed, may be a convenient name for a few different conditions which present in a similar fashion. In particular NEC in infants with congenital heart disease, in infants with Hirschsprung disease, and in infants with gastroschisis, may all have differing pathophysiology, and methods to prevent and treat them may also differ. For the moment, very preterm infants without those conditions who develop NEC are considered to have a single disease, but it may be that more than one pathophysiologic process can lead to what we call NEC. After we introduced probiotics in our nursery the incidence of NEC fell, but also the average age of the infants who presented with NEC was substantially younger, making me wonder if the balance of different aetiologic factors is different in younger versus older cases.

Most database publications have noted that NEC overall is quite a lot more frequent than Spontaneous Intestinal Perforation (SIP) and even the NEC infants requiring surgery (mostly for perforation, but not all) are a larger group than SIP.

The Canadian Neonatal Network, for example, reported that among 2,019 infants <28 weeks gestation, 39 (1.9%) had spontaneous intestinal perforation, 61 (3%) had perforated necrotizing enterocolitis, and 115 (5.7%) had non-perforated necrotizing enterocolitis.

The German Neonatal Network reported, among 8,022 babies under 1500g birth weight (and <37 weeks gestation), 177 cases of surgical NEC and 123 with SIP.

Which makes the distribution of cases in this newly published trial somewhat surprising, with rather more SIP than surgical NEC. Blakely ML, et al. Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial. Ann Surg. 2021;274(4):e370-e80.

In this trial, babies of <1001 g birth weight, and less than 8 weeks postnatal age with either NEC or SIP, for whom a decision to perform surgery had been made, were randomized. They either were directed towards initial laparotomy or initial peritoneal drainage in the NICU under local anaesthesia. Planned sample size was 150 per group in order to have an 80% power of detecting a 15% absolute improvement in the primary outcome, which unfortunately was “death or NDI”. For this trial “NDI” was cerebral palsy with a GMFCS of 2 or more, a Bayley III cognitive composite score of <85, or blindness or deafness, at 18 to 22 months corrected age.

This trial is a perfect example of why we should abandon this outcome. Death is common in this group of babies, neurodevelopmental problems are also common among survivors. But this definition of NDI, which is given the same weight in the outcome as being dead, includes infants who will mostly be ambulant but walk with some difficulty, i.e. they will limp. A Bayley cognitive score of <85 has very little correlation with functional capacities or outcomes. Ask a parent of a deaf or blind child if that outcome is equivalent to them being dead; or ask them themselves when they are old enough! There is also no good reason for supposing that mortality and neurological impairment or developmental delay will change in the same direction with these interventions. This would have been a perfect trial for a “win-ratio” approach, with a substantial risk of death, and a major risk of long term difficulties among survivors. What I want to know, in order to make the best decision for my patients, is whether mortality will be affected, and if not then is the long term outcome better or worse? If mortality is better with one approach rather than another, are all the extra survivors profoundly impaired? (That would be a unique result in neonatology if it happened, but I guess it is possible). Becaue if not, then mortlaity trumps all the other outcomes.

The authors achieved a very high follow up of 96%, but the difficulties on doing such a trial are illustrated by the fact that enrollment took 10 years!

They did indeed finally enrol 300 babies, but as mentioned, somewhat surprisingly, there were 95 with NEC and 213 with SIP. This immediately makes me concerned about some sort of selection bias in the enrolment process. It may be that infants with what was thought to be definite NEC were less likely to be approached for consent, I would guess that for many of those babies the care team thought that going straight to laparotomy was appropriate, but potential randomisation to bedside drainage was not. Among the NEC babies enrolled nearly half were on vasopressors at enrollment, suggesting that babies who were more unstable, and therefore thought potentially worth consideration of peritoneal drainage, were more likely to be enrolled.

With those provisos, lets look at the results. In a strictly trial design sense, there was a nul result. No difference between the 2 approaches for the primary outcome, 69% death or NDI with laparotomy, and 70% with peritoneal drainage. About half of the drainage babies went on to have a later laparotomy, about 1 in 5 of the laparotomy babies needed another laparotomy later on. Mortality for the 2 randomized groups was similar, 29% vs 30%.

Mortality, however, was quite different among those babies who the Surgeon thought, pre-op, were NEC rather than SIP, (there were 7% of the laparotomy babies who actually had neither NEC nor SIP, but another diagnosis including volvulus and gastric perforation). Among the “thought to be NEC” babies, mortality was 40% with laparotomy and 51% with initial drainage, the “thought to be SIP” babies mortalities were 23% (laparotomy) vs 19% (drainage).

Although neither of these differences is “statistically significant”, the authors performed a Bayesian analysis of the results (Jon Tyson is the second author!), which showed that initial laparotomy is much more likely to lead to a reduction in “death or NDI” in the NEC babies with a probability of 97%, and is somewhat less likely to be beneficial in the SIP babies, only 18% chance of being better, compared to 82% chance of being worse.

I think these Bayesian analyses are a reasonable attempt to explain the implications of the data, when, despite the enormous efforts involved in a trial lasting 10 years, final sample sizes are modest. Obviously not as good as having a trial with 1000 babies per group, but it does suggest that such a large trial would be very unlikely to show a benefit of intial drainage among bbies with surgical NEC.

Among babies with a pre-op diagnosis of NEC, there were 25 long-term survivors after laparotomy (of 42 infants), and 26 survivors of the 52 who had initial drainage, of whom 25 were followed up. Of the laparotomy babies, 13 of the 25 survivors had no “NDI”; among the drainage babies 9 of the 25 had no “NDI”. The fairly small numbers lead to low confidence in the results, but all the differences in long term outcomes in these babies favour intial laparotomy. Among the SIP babies there are fewer babies with CP (GMFCS 2 or more) after initial laparotomy, but somewhat more babies with lowish Bayley scores. Here are the details of the “NDI” outcome, from the supplemental materials:

As an article I just published with Elliott Weiss and Stephanie Kukora (Weiss EM, et al. Use of composite NICU research outcomes for goals of care counselling creates ethical challenges. Acta Paediatr. 2021) discusses, not only are such composite outcomes a problem for clinical trial design and interpretation, they make counselling of families more difficult, what are we to say to families when trying to decide which approach to take for an infant with NEC who needs surgery? This trial shows, strictly, no difference between the two approaches. But I think it is much more helpful to parents to be able to say, for a baby with a diagnosis of NEC and an indication for surgery, that mortality is lower with immediate laparotomy, and in the long term, despite significant risks with either approach, outcomes seem to better with immediate surgery (48% “NDI” among survivors with laparotomy and 68% “NDI” among survivors after initial drainage, in this trial).

There are 2 previous trials with similarities to this one. A European trial of 69 babies with perforation, including NEC and SIP babies (Rees CM, et al. Peritoneal drainage or laparotomy for neonatal bowel perforation? A randomized controlled trial. Ann Surg. 2008;248(1):44-51) showed somewhat lower mortality with laparotomy, 33% vs 40%. In that trial over 60% of the babies had NEC confirmed if they had surgery. A previous North American trial of 117 infants (Moss RL, et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. NEJM 2006;354(21):2225-34), was supposedly limited to infants with NEC, but the entry criteria as described in the article would have included SIP “preterm infants (birth weight, <1500 g; gestational age, <34 weeks) with evidence of intestinal perforation, including free intraperitoneal air on an abdominal radiograph (96 infants); stool, bile, or pus found at paracentesis; or clinical evidence of perforation in the joint opinion of the attending surgeon and the neonatologist. This definition included both infants with extensive disease and others with focal perforation”. 60% of their subjects did not have pneumatosis on abdominal x-ray. In that study mortality was 35% in each group.

If I try and put all of this together, it looks to me that infants with perforated NEC should probably be directed, if possible, to immediate laparotomy. There is no advantage to initial drainage, and some evidence of lower mortality, and perhaps better long term neurologic and developmental outcomes, with immediate laparotomy. Also, 7% of the infants may turn out to have another diagnosis, which probably mostly require surgery also.

In infants with probable SIP the question is more difficult, but there doesn’t appear to be a clear advantage to delaying laparotomy, there may be a slightly higher survival with initial drainage, but in the long term outcomes seem rather balanced; with the highly problematic outcome, of uncertain real importance, that a cognitive Bayley composite <85 was a little more frequent after laparotomy than after drainage.

Makes me wonder, yet again, how we got to the point where a Bayley cognitive composite of 86 is fine, but a Bayley cognitive composite score of 84 is a disaster, an impairment, equivalent to death! Dichotomizing human development into normal and subnormal is an affront to me, and I think to most of those who actually do follow up.

This review points out a number of problems with NEC research, one is the lack of good definitions. A recent publication by Janet Berrington and Nick Embleton (Berrington J, Embleton ND. Discriminating necrotising enterocolitis and focal intestinal perforation. Arch Dis Child Fetal Neonatal Ed. 2021) has illustrated some of the difficulties: reviewing a large cohort, many cases that had been classified as NEC were found after extensive review to more likely be SIP. Some of the babies satisfied published diagnostic criteria for one disease, but after review, including surgical histopathology, they had the other. I am rather sceptical in general about the usefulness of many published biomarkers, which often seem to be a way of increasing numbers of publications rather than helping clinical practice, but here is one situation where a good discriminating biomarker might really help to differentiate these conditions, and also point, perhaps to other diagnoses. This study shows clearly, yet again, that CRP is of no use (not always being elevated with either diagnosis), and most of the articles that I have looked at don’t seem to have tried to differentiate NEC and SIP using their biomarker.

Surgical NEC has a very high mortality in all of these studies, and the mortality of SIP is not negligible. Neurological impairments and developmental delay are frequent with surgical NEC, medical NEC, and probably following SIP also. The fight to reduce these diseases has to intensify, we have made relatively little progress in recent years. Mother’s milk, and donated human milk when mother’s milk is not available are interventions that reduce NEC compared to formula feeding, but we have known that for years. Finding ways to normalise the intestinal microbiome are are potential part of the solution, but administration of current probiotics is only partly successful, both in normalising the microbiome and in reducing NEC. Avoiding antibiotics whenever you can, and having a feeding protocol are both helpful, but neither can eliminate NEC, and probably have no impact on SIP.

I have seen too many babies die of NEC in my career, I sincerely hope that, during the careers of my trainees, we will be able to stop these scourges.

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Extreme preterm survival and outcomes

There are frequently publications about the outcomes of extreme preterm infants; as a community I think we should be proud of our investment in outcome research. Indeed, neonatologists invented the entire field of outcomes research (Barrington KJ, Saigal S. Long-term caring for neonates. Paediatr Child Health. 2006;11(5):265-6). When very preterm babies started surviving, the obvious question was: how will they do in the long term? With the survival of extremely preterm (24-28 weeks) and now profoundly preterm (<24 weeks) infants the questions continue.

Multiple cohorts have been extremely informative, and give an opportunity to perform comparisons between those cohorts. A new publication comparing babies from France, Canada, and New Zealand has just been published. (Chevallier M, et al. Mortality and significant neurosensory impairment in preterm infants: an international comparison. Arch Dis Child Fetal Neonatal Ed. 2021). As a disclosure, the first author, Marie Chevallier, was one of the excellent fellows in our programme, and has gone on to be a neonatologist and researcher in Grenoble; the last author, Thuy Mai Luu, is a colleague and friend from my hospital.

They and an international groupd of researchers compared outcomes from 3 cohorts born in 2011. The Canadian cohort have their data collected in CNN, with standardized examinations and data collection in the Canadian Neonatal Follow-Up Network (CNFUN) at 18 – 21 months corrected age. The Australian and New Zealand Network is a similar prospective database with outcome data also being collected at 2 to 3 years, but without the same structured follow-up and data collection. The data from France are derived from EPIPAGE-2, with outcomes at 2 years corrected age derived from questionnaires.

The authors have focussed survival and on long term neurosensory impairments, which I think was wise, given the differences in ages and methodologies. Disabling cerebral palsy, blindness and deafness and relatively stable outcomes, and probably less affected by methods of data collection than, for example, developmental delay.

There are 3 findings of note, I think. One of which is not discussed in the article, that being the proportion of babies by completed week of gestational age, which was much lower at 24 weeks in France than the other 2 cohorts.

Birth and antenatal characteristicsANZNNCNNEPIPAGE-2P value
n=960n=1019n=1076
Gestational age, mean (SD), weeks25.7 (1.1)25.8 (1.1)25.9 (1.0)<0.01
 24 weeks, n (%)182 (19.0)159 (15.6)102 (9.5)<0.01
 25 weeks, n (%)218 (22.7)235 (23.1)258 (24.0)0.78
 26 weeks, n (%)254 (26.5)314 (30.8)361 (33.6)<0.01
 27 weeks, n (%)306 (31.8)311 (30.5)355 (33.0)0.48
Birth weight, mean (SD), g856 (201)864 (216)843 (172)0.05
Male sex, n (%)519 (54.1)537 (52.8)557 (51.8)0.58
Maternal age, mean (SD), years29.3 (6.5)30.7 (5.8)29.4 (5.9)<0.01
Complete course of antenatal steroids, n (%)601 (63.1)692 (70.0)622 (60.2)<0.01

I don’t think there is any biological reason why French women would have fewer deliveries at 24 weeks, this difference is probably because of a relatively lower willingness to provide active obstetrical and neonatal care to babies born at this gestation.

Keeping in mind that there are somewhat fewer of the highest risk babies in France, the outcomes, the primary and the various parts of the primary are here:

OutcomesANZNN, n/N (%)CNN/CNFUN, n/N (%)EPIPAGE-2, n/N (%)P value
Mortality or sNSI204/960 (21.3)210/1019 (20.6)305/1076 (28.4)<0.01
Mortality179/960 (18.7)177/1019 (17.4)283/1076 (26.3)<0.01
Any sNSI among survivors25/578 (4.3)33/621 (5.3)22/659 (3.3)0.22
Cerebral palsy with GMFCS >214/565 (2.5)14/610 (2.3)15/659 (2.3)0.97
Disabling hearing loss12/568 (2.1)14/607 (2.3)7/641 (1.1)0.23
Visual impairment4/570 (0.7)12/562 (2.1)2/623 (0.3)0.01

Mortality is substantially higher in France, but impairments are very similar; apart from more visual impairment in Canada. (But remember that the CNN/CNFUN have formal visual testing, which was not the case in France or in the ANZNN, so this may not be directly comparable).

One general implication of these results is that having a less “aggressive” intervention policy does not select babies who are more likely to have unimpaired outcomes. It just leads to fewer survivors.

These data are, of course, from babies born 10 years ago. Even though neonatal clinical science has not changed that much, attitudes can change much more quickly! In Canada in 2012 about 9% of babies delivering alive at 24weeks gestation had palliative care instituted at birth, in 2019 that was 6%. The CNN doesn’t detail why such babies did not receive active intensive care, but many would have been because of serious congential anomalies or severe growth restriction. It has become quite unusual in Canada for an infant born at 24 weeks gestation to not be admitted for active NICU care in the absence of such additional complications. (CNN annual reports available here, and the CNFUN annual reports here)

From what I have seen, the attitudes in France have also changed, and many more babies born at 24 weeks or profoundly preterm (using the Barrington classification above) now receive active intensive care. These data suggest that such “interventionism” should lead to more survivors, with a similar proportion of survivors having neurosensory impairments.

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Opioid infusions for ventilated preterm babies

Many practices in neonatology are variable between NICUs, and many vary from year to year; without any good scientific data practices become fashionable or routine or ingrained without necessarily having an evidence base to support them.

One such practice is that mentioned in the title, a few years ago it was rare for me to see babies with opioid infusions, but it seems to have become more common, despite the lack of a good rationale.

Infants who are unquestionably in pain, such as in the post-operative period, are excluded from this discussion; pain control after surgery is unquestionably necessary,(although there are serious questions about agents, route, and dosage, etc). I am referring to the use of opioid infusions (most commonly either morphine or fentanyl) for infants who are receiving routine care during assisted ventilation, which includes some potentially painful interventions, blood sampling and endotracheal suctining being the most common.

I think one of the first considerations is that the procedure of being intubated is very painful and should always be premedicated with analgesics, potent opioids with a rapid onset of action are needed (fentanyl or analogues; not morphine).

But I question whether being ventilated is painful. Earlier in my career I worked in the PICU, where it was not unusual to have chldren who were intubated (usually nasotracheally) and on assisted ventilation who needed no analgesia or sedation, I have played with intubated children and seen them reading and listening to music with no need for opiates!

Many babies can spend days or weeks ventilated, during which they can sleep for over 20 hours a day, without routine sedation or analgesia.

There are several considerations that should enter into our decision of whether to use opioids for a ventilated preterm baby. One of which is the lack of evidence from randomized trials of benefit. Indeed the latest version of the Cochrane review was recently published, Bellù R, et al. Opioids for newborn infants receiving mechanical ventilation. Cochrane Database Syst Rev. 2021 Mar 17;3(3):CD013732. doi: 10.1002/14651858.CD013732.pub2. As always you can access for free via the VON website, https://public.vtoxford.org/cochrane-at-von/. That review found 23 relevant trials, 15 of which compared routine opioid use to control (although, in all of them where I can see the information, opioids were permitted in the controls). They found no evidence of benefit, in the short or the long term. Of particular importance, there was little evidence of a reduction in pain scores, the best and easily the largest trial (NEOPAIN) showed, after the first few hours of infusion, a trivially lower PIPP score among the opioid group than the controls; 8 vs 8.7. For each of the long term outcome measures, only a single small study was available, therefore showing little difference, and with very little confidence.

We can learn, I think, from the recent evolution of practice in adult ICUs where light or no sedation has become routine. Trials have shown that routine heavy sedation prolongs assisted ventilation in adults. There are, as a result, a number of studies of patient experiences of being ventilated, many of which have addressed pain, as well as other parts of the patient experience of awake assisted ventilation. (Baumgarten M, Poulsen I. Patients’ experiences of being mechanically ventilated in an ICU: a qualitative metasynthesis. Scand J Caring Sci. 2015;29(2):205-14). In general, pain is not a major part of the reported experience of ventilated adults. They do, however, concur that being suctioned is very painful and unpleasant, although they often report feeling better after the suctioning, as the airway secretions are cleared.

Volume Controlled Ventilation in Adults works differently to volume “guarantee” ventilation in babies, with the presence of a background bias flow babies can take larger breaths if they wish, one of the complaints reported by adults during awake assisted ventilatoin was that they could not take a larger breath when they wanted, which should be less of a problem with our systems.

Also of note, many of these neonatal studies were performed in order to get babies to be better synchronised with the ventilator, at a time when non-synchronized assisted ventilation was the norm in the NICU. With the development of synchronous modes, which are now universal, that is no longer an issue, in general as long as the ventilator is set correctly.

With these considerations in mind, these are the major issues for deciding whether to give analgesia or sedation to a ventilated preterm baby, in particular morphine infusions:

  1. Being ventilated is not, by itself, usually painful. It is stressful for adults, but it doesn’t hurt. Non-pharmacological calming procedures help adults (in particular communication, less relevant for the newborn but calming sounds, voice, touch, swaddling, and gentle interventions are likely to be helpful).
  2. Opiod infusions are ineffective for preventing pain from blood sampling procedures;
    1. sucrose, skin to skin care, in combination and with the addition of non-nutritive sucking, can dramatically decrease pain from blood sampling.
    2. These interventions are still required even in a baby on an opioid infusion!
  3. More invasive skin-breaking procedures, such as lumbar puncture or chest drain insertion, benefit from local anaesthesia as well as sucrose etc. Lidocaine should always be administered for lumbar punctures and chest drain insertion.
  4. Endotracheal suctioning is unpleasant and painful but pain responses are not improved by any currently investigated modality. In particular opioids are ineffective.
  5. Retrospective and observational studies have shown more IVH, more death, and more NEC among preterm infants who receive opioid infusions.
  6. The prospective trials, in particular NEOPAIN, showed a very small increase in mortality and IVH (with 95% confidence intervals which included no difference), but did not report NEC.
  7. Morphine infusions often cause hypotension.
  8. Morphine infusions do not improve short or long term outcomes, additional doses are associated with worse pulmonary outcomes.
  9. Fentanyl is an unreliable sedative, but an excellent analgesic, as a relatively selective mu-opioid receptor agonist it is a poor choice when sedation is the goal.

There are some recent PK studies that I think are very relevant. The most immature babies risk major accumulation of morphine and its metabolites. There is a dramatic accumulation of morphine-3-glucuronide during morphine infusions in the very immature infant. It is a metabolite which is an opioid antagonist. In other words it prevents the analgesic effects of morphine, and interferes with the sedative effects also. This may be why morphine is not a very effective sedative in the most immature infants. Very immature babies accumulate M3G and have enormously high concentrations after a few hours of infusion.

There is a meta-model of neonatal morphine pharmacokinetics published a couple of years ago (Knosgaard KR, et al. Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model. Eur J Pharm Sci. 2016;92:117-30) which paper has a link to this app https://unicph.shinyapps.io/MorphineNeonates/ . Play around with it for a while and you will see that the most immature babies risk having extremely high morphine and M-3-G concentrations after standard doses of morphine.

This is an example of predicted morphine and morphine metabolite concentrations for a 24 week 600g 1-day old baby who receives a 100 mcg/kg bolus and a 10 mcg/kg/h infusion, with the 95% confidence limits.

And here for clarity without the confidence limits

There are also huge variations in kinetics, one study showing a 40-fold variation in clearance! That variability can be reduced by taking into account gestational and postnatal age.

How about the long term? Well as mentioned there is very little information from randomized trials, so little confidence in the impact. However, there are observational studies, in particular a worrying series from Vancouver (Zwicker JG, et al. Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine. J Pediatr. 2016;172:81-7 e2. Ranger M, et al. Internalizing behaviours in school-age children born very preterm are predicted by neonatal pain and morphine exposure. Eur J Pain. 2014;18(6):844-52) which show that the more morphine the babies received, the smaller were their cerebella (cerebellums?), and the more behaviour problems they had at long term.

They have recently followed this up to show that differences in morphine kinetics, or at least differences in the genes which metabolized morphine, were correlated with those behaviour problems. (Chau CMY, et al. Morphine biotransformation genes and neonatal clinical factors predicted behaviour problems in very preterm children at 18months. EBioMedicine. 2019;40:655-62), the exact meaning of which isn’t clear yet, but continues to make me anxious about the use of morphine for babies who are not clearly in pain.

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Drug use and abuse in the NICU

The title does not refer to”drugs of abuse” but rather to how we use and choose medications for use in newborns, particularly the very immature. A new publication has just appeared on-line which focuses of medication use in the NICU, and the changes over an 8 year period. (Stark A, et al. Medication Use in the Neonatal Intensive Care Unit and Changes from 2010-2018. The Journal of Pediatrics. 2021).

The enormous database of the Pediatrix medical group has been trawled to find medication exposure data for nearly 800,000 newborns.

There are a number of striking findings, in particular the amazing relative growth of the use of dexmedetomidine. Practically speaking use was 0 in 2010, now 5 per 1000 NICU patients are exposed to it, and 23 per 1000 extremely low birth weight infants.

Dexmedetomidine is routinely touted as being “neuro-protective”, but that assertion is based on questionably relevant animal models, some of which show reduced neuronal apoptosis. I don’t believe there is any long term human outcome data with which to make the assertion that dexmedetomidine is neuro-protective in humans. But of course we don’t have much similar data for any of the sedative/analgesic medications that we use. Morphine probably being the only exception, but the data for morphine are not very robust or very reassuring.

One recent animal study showed that adding dexmedetomidine to a reduced concentration of sevoflurane reduced apoptosis, but if enough dexmedetomidine was given to achieve the same level of anaesthesia as the higher concentration of sevoflurane, then the neuronal apoptosis was identical. (Lee JR, et al. Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats. Br J Anaesth. 2021;126(5):1009-21). So, in this model at least, dexmedetomidine was not neuro-protective. In contrast, this review article found several animal studies that did seem to show neuro-protection (van Hoorn CE, et al. A systematic review and narrative synthesis on the histological and neurobehavioral long-term effects of dexmedetomidine. Paediatr Anaesth. 2019;29(2):125-36) but it was not universal, the details of the animal models and experimental procedures vary greatly. How relevant each one is to the sick newborn is very uncertain.

Multiple use, prolonged infusions, and use in the most fragile babies are all things which need to be better investigated for dexmedetomidine, and for our other sedative/analgesia drugs.

In contrast the same article showed the reduction in use of other medications. Three of them because they are no longer available, (at least in the USA) THAM, chloral hydrate, and ranitidine. No great loss to neonatology, I think. I was pleased to see a dramatic reduction in metoclopramide use, for which I think there is no indication in neonatology. Also, and a little more surprising to me, a marked reduction in lansoprazole use. Again I don’t think that there is much role for the medication; treatment for babies with reflux by prescibing lansoproazole ignores the fact that 50% of reflux in the preterm is non-acid, and the clinical signs attributed to reflux are both non-specific for reflux, and not necessarily caused by acid. Also gastric acid is an important barrier to GI colonisation, helps to prevent respiratory infections, and is probably important for absorption of iron and calcium.

Although it hasn’t changed much over this period, there is still a lot of midazolam being used, being the 9th most frequently prescribed medication overall, and the 13th most frequent in the ELBW. I can’t remember the last time I prescibed midazolam, other than a case of status epilepticus unresponsive to 3 other anticonvulsants in a baby at term. 21% of ELBW babies were exposed to this drug, with a total of 3,700 days of use per 1,000 patients. My comments about sedative/analgeisc medications apply here. What little data we have for long term effects of midazolam are worrying.

The study points out how much we still need to know about the common medications that we use, the majority of which are not specifically licensed for the newborn.

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Pain studies with untreated control groups in babies are unethical.

If you are performing a study of pain control in the newborn and you assign babies to untreated controls, you are creating unnecessary avoidable pain in the control patients. That is true for any patient who is incompetent, obviously including newborns, but also older children and adults unable to give consent for themselves. I guess you could allow competent adults to consent to be randomised to control and have painful procedures without analgesia, but good luck enrolling subjects!

There is no way this is ethical, and it should never be done, and should never be allowed by ethics review boards. (Bellieni CV, et al. Should an IRB approve a placebo-controlled randomized trial of analgesia for procedural pain in neonates? Pediatrics. 2012;130(3):550-3). There is no benefit to anyone, especially not the babies, but not to medical knowledge either. We already know that sticking needles into babies causes pain, and that there are many ways to reduce that pain. Why on earth would you perform a study comparing different methods of reducing pain for blood sampling, and include an untreated control group?

Unfortunately, it still goes on. (Bellieni CV, Johnston CC. Analgesia, nil or placebo to babies, in trials that test new analgesic treatments for procedural pain. Acta Paediatr. 2016;105(2):129-36). I was stimulated to write this post after my weekly trawl through the literature found 2 such studies. I hesitate to give them any credence by referencing them, but maybe naming and shaming is the way to go.

The first is from Stanford, of all places, by a group of people that should know better (Chang J, Filoteo L, Nasr AS. Comparing the Analgesic Effects of 4 Nonpharmacologic Interventions on Term Newborns Undergoing Heel Lance: A Randomized Controlled Trial. J Perinat Neonatal Nurs. 2020 Oct/Dec;34(4):338-345). The study design is also poor, it seems that the control group was enrolled and assigned to have pain without being randomized, but the other 4 interventions were randomized. At first the authors (and apparently the IRB) didn’t think this was research, even though they were prospectively randomizing babies to different interventions and recording responses! The study clearly satisfies every possible definition of clinical research, and, if the researchers and the IRB can’t recognize that, it bodes poorly indeed. The study was therefore started without IRB approval, which means it should never have been performed and clearly should never have been published. They recruited newborns from the postpartum wards, who they say were identified by “medical record review”, which makes no sense, presumably there were individuals screening admitted babies at some point.

It was also retrospectively registered, which means that the authors don’t understand the basics of doing clinical research.

Not surprisingly, the group of 50 babies assigned to having more pain had more pain.

I think the researchers, and the IRB, and Stanford Lucile Packard Children’s Hospital owe an apology to these infants and to their parents.

The second study (Cakirli M, Acikgoz A. A Randomized Controlled Trial: The Effect of Own Mother’s Breast Milk Odor and Another Mother’s Breast Milk Odor on Pain Level of Newborn Infants. Breastfeed Med. 2021 Jan;16(1):75-81) randomized babies into 3 groups, one of which was an untreated control group. The study is behind a paywall, and I am certainly not going to pay to get it, so I don’t know the numerical results, but the abstract notes that the group randomized to having more pain had more pain.

As I performed a quick recent literature search, what is clear is that many of recent articles of painful procedures in the newborn with untreated control groups appear in specialist pain journals, where surely the reviewers should know how unethical it is to deny analgesia to babies having planned painful procedures. Other articles I have seen recently compared skin to skin contact with control (it is already clear that skin to skin contact is effective) another using a vibrating device compared to control (why not give both groups sucrose and see if the device has additional benefit?) and another with combined sucrose, music, non-nutritive sucking and massage compared to untreated controls, (completely useless as an addition to the literature, no idea whether any of the interventions was a useful addition to the others).

Other recent articles have shown how you can do such studies without assigning babies to have more pain, for example this one (Benoit B, et al. The influence of breastfeeding on cortical and bio-behavioural indicators of procedural pain in newborns: Findings of a randomized controlled trial. Early Hum Dev. 2021;154:105308) which randomized babies to either breastfeeding or oral sucrose prior to blood sampling, so all received an effective intervention, they showed no susbtantial difference in pain scores between the gorups. Or this one (Hoarau K, et al. “Holding-Cuddling” and Sucrose for Pain Relief During Venepuncture in Newborn Infants: A Randomized, Controlled Trial (CASA). Front Pediatr. 2020;8:607900.) in which all received sucrose and non-nutritive suckling, but one group also were cuddled during the procedure. Adding a new or additional intervention to previously proven analgesic intervention is ethically acceptable, if it is not already known that the combination of interventions is substantially superior; this study showed no difference in mean pain scores, but fewer babies exceeded a pain score threshold with the combined intervention compared to sucrose alone.

These two studies are a useful addition to the literature, showing that breast-feeding or sucrose are both reasonable alternatives for blood sampling analgesia, and that cuddling a baby in addition to sucrose and NNS has some benefit at the higher end of the pain scores.

Researchers want to perform studies showing differences between groups, it is easier to get them published, which helps to advance your career. But no study with an untreated control group has any scientific value, we already know effective ways of reducing pain. Subjecting babies to painful procdures to improve your CV is unconscionable.

My plea is that if you are asked to be a reviewer for an article for publication which includes babies prospectively assigned to be untreated during a painful procedure, you reject the article with a clear note to the editor that the study was unethical.

If you sit on an IRB, please reject any study which assigns newborn infants, or any incompetent participant, to have avoidable pain.

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Plug the Lung Until it Grows: the FETO RCTs of antenatal diaphragmatic hernia intervention.

What was at one time called PLUG, and, with the change from open to endoscopic intervention, is now called FETO (fetal endoscopic tracheal occlusion) is a way to harness the normal physiology of the lung in congential diaphragmatic hernia (CDH) to improve lung growth and architecture in order to improve outcomes. Lung growth is partially dependent on the rhythmic increases in fetal intrapulmonary pressures which occur because of the active production of fetal lung liquid and intermittent breathing movements of the fetus associated with partial adduction of the vocal cords. Numerous fetal animal studies showed that interrupting this process (with phrenic nerve section or tracheotomy, for example) leads to pulmonary hypoplasia, while increasing the intrapulmonary pressures, by ligating the trachea, caused pulmonary hyperplasia. Finally animal models of diaphragmatic hernia followed by tracheal obstruction showed at least partial normalisation of lung growth. Interventional obstetricians and paediatric surgeons have attempted to temporarily obstruct the fetal trachea in some fetuses with CDH and very high predicted mortality. Initial attempts were apparently successful, but with a risk of preterm labour and delivery.

The improvements in technique and change to purely endoscopic approaches have led to lower complication rates (importantly prematurity), but it remained unclear whether, overall, survival was improved.

The recent publication of the results of 2 parallel trials in high-risk and moderate-risk patients has largely answered that question.

Deprest JA, et al. Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia. N Engl J Med. 2021.
Deprest JA, et al. Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia. N Engl J Med. 2021.

This was a remarkable undertaking, a truly international collboration in a group of mothers carrying a fetus at extremely high risk of dying. And here, as an aside, I always feel a little uncomfortable with the way we talk about these interventions. Although it was indeed “fetal” surgery, there happens to be a woman in the way! Perhaps we should rather talk about “maternal-fetal” interventions. Even the pretty pictures below represent the mother just as an abdominal and uterine wall to be pierced…

As you can see from this summary, there was a dramatic improvement in survival. I do think it is important to emphasize that there is still a very high mortality of 60% in the treatment group; this is a terribly high risk group of babies. The eligibility criteria included a ratio of observed to expected lung-head ratio (O:E LHR) of less than 25%, predicting a mortality of about 82%, very close to the 85% actually seen in ther controls. The median age of delivery for the FETO babies was 34.6 weeks compared to 38.4 for the controls; this doesn’t sound like a huge difference, but 16 FETO babies delivered before 34 weeks compared to 0 controls, and 10 of them delivered before 32 weeks. Managing moderately preterm babies with CDH is very difficult. It seems likely that if we can find ways to prevent the rupture of membranes and preterm labour impacts of FETO, the benefits would be even greater.

The other trial was run in parallel, it enrolled mothers carrying a fetus with an observed lung to head ratio that was 25.0 to 34.9% of the expected, irrespective of liver position, or 35.0 to 44.9% with intrathoracic liver herniation. This was calculated to lead to a survival of 55% and sample size calculated for a 20% improvement.

The primary outcome was actually changed early on by the DSMC of the trial, which was initially designed with a primary outcome of BPD, or oxygen dependence at 28 days, with survival to discharge as a secondary outcome. I think the DSMC did exactly the right thing here, I don’t know who thought that 28 day oxygen requirement was important for infants with CDH, but to have given that priority over survival would have been a major problem. Perhaps that was initially chosen as the investigators are Obstetricians, not Neonatologists (he typed with tongue in cheek)?

Survival to discharge was higher in the FETO group, 62 of 98 treated compared to 49 of 98 controls, RR 1.27 (95%CI 0.99-1.63), as the confidence intervals for the RR just includes 1.0 the intervention was deemed not to show a significant benefit.

The impact on prematurity was very similar to the high-risk group trial, with the median gestational age at delivery being 2 weeks earlier with FETO than control, but both groups being about 2 weeks later than the other trial, that is 36 weeks for the FETO and 38 weeks for the controls. The relative risk and risk difference of being born before 37 weeks was very similar in the 2 studies.

Although this was a “moderate” risk trial, there was still a huge mortality of 50% in the controls (showing again that the O:E LHR is a reliable predictor of mortality), 20% of both groups required ECMO, and they had between 1 and 3 months of hospitalisation (average about 48 days in each group).

The division into “severe” and “moderate” risk groups (perhaps better termed “extreme” and “severe”) was completely arbitrary. A threshold of 25% O:E LHR could easily have been set to 30, or 31.5%. Such a threshold would have included more infants in the extreme trial, and I can guess would not have changed the result to a “non-significant” result.

In fact I don’t have to guess, because if these trials had been run as a single trial and included all the babies eligible for the two trials, with subgroups of extreme and severe risk, then the total survival to hospital discharge would have been 78 of 138 FETO babies and 55 of 138 controls; p=0.0081 (chi-square with Yates correction). In that case the conclusion would have been that FETO is beneficial for babies with an O:E LHR of < 35%, and for babies with intrathoracic liver with an O:E LHR of <45%, perhaps with a subgroup analysis showing a greater effect in the most severely affected fetuses.

It is evident that, at some point, the increased relative risk of prematurity (which was similar between the trials) will outweigh the benefit of the procedure, but we cannot from these data conclude that below a threshold of 25% O:E LHR, FETO is overall a beneficial intervention, but that above 25% it is not beneficial. Unfortunately, I think that is how the data will be interpreted. A secondary analysis of the overall survival benefits of FETO according to baseline O:E LHR needs to be performed, otherwise mothers carrying fetuses who would benefit will not be offered the intervention.

There are not many conditions in medicine for which a trial of 80 patients will show a dramatic and reliable difference in outcome between groups. The substantial benefits of this intervention for a profoundly serious condition mandate that all centres that have potential links to an experienced FETO centre should find a way to offer the intervention to mothers carrying an eligible fetus.

Currently, mothers who have had the procedue need to stay within reach of the FETO centre until the balloon is removed, for very good reasons. This creates limitations for many families, which may be insuperable, our FETO centre for example is 550 km away, for some mothers for other parts of the province it will be 2000 km away! Moving to live in Toronto for 8 weeks is not necessarily feasible for some mothers, especially as health care costs are all covered by our provinicial systems, but not daily living expenses. I wonder if we could create satellite centres who would develop the expertise required to remove or puncture the balloon in case of preterm labour, or routinely at 34 weeks, including the team, the equipment, and the protocols. Then a mother could travel to the FETO centre for the procedure, stay a couple of weeks in the region, and then return to be close to a satellite centre for the rest of the pregnancy. I have no relevant expertise in the interventions, but it seems to me that ultrasound guided balloon puncture is not that different to many of the interventions performed by our MFM specialists, at least compared to fetal bronchoscopy which seems to me to be a greater level of complexity.

Thank you to the mothers who were prepared to be randomised in this trial, which will have a major impact for many future babies. Your willingness to help others is enormously appreciated.

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What is critical in a “critical sample”?

It is common practice in the evaluation of neonatal hypoglycaemic episodes, especially if unusual or prolonged, to perform a “critical sample”. This is performed to rule out underlying metabolic or endocrine disorders. But what should the critical sample consist of?

I have looked at several recommednations, and there is great variability in what is included in such samples; it is near universal that a lab glucose, a serum cortisol, insulin and growth hormone are included, but after that there is little consensus.

One exception to those inclusions is the American Pediatric Endocrine Society, who are quite minimalist, recommending that the critical sample includes a glucose, bicarbonate, Beta-hydroxy-butyrate and a lactate. They further recommend that plasma be kept in reserve for further tests (and give the following as examples: plasma insulin, FFA, and C-peptide : total and free carnitine and acyl-carnitine), they don’t even overtly mention cortisol and growth hormone as part of the critical sample. Their recommendation is meant for screening for neonates but is also meant for older children, and it therefore ignores the relative incidence of the various causes of hypoglycaemia in the neonatal period. With substrate deficiency (transitional hypoglycaemia) and hyperinsulinaemia being much more common than other causes, and endocrine causes being next and relatively speaking fairly uncommon.

Beta-hydroxy-butyrate is recommended by many to be included in initial screen, it is the most commonly measured of the ketone bodies, and is depressed in hyperinsulinaemic infants, but is low also in infants with transitional hypoglycaemia, so is really only helpful as a flag for endocrine deficiencies and for the rarer glycogen storage diseases, where it is raised during hypoglycaemia.

Ketones, such as beta-hydroxy-butyrate, are increased during hypoglycaemia due to growth hormone or cortisol deficiency. The diagnosis of those entities is sometimes tricky, growth hormone secretion being pulsatile and the range of normal serum cortisol being wide. Often, also, when an infant has a critical sample performed because the bedside glucose is low, the lab glucose will be taken a few minutes later and often ends up being low normal, either because of the delay, and/or because bedside glucose is inaccurate and usually lower than the lab glucose. So, a serum cortisol which is on the low side of normal on a critical sample with a lab glucose of 2.8 (for example) what does that mean? Knowing that the ketones were high would be a good clue that further endocrine evaluation is required.

Ketones are also elevated in ketotic hypoglycaemia, which is one justification for measuring them in some guidelines, but it is not on the differential of neonatal hypoglycaemia, becoming important in older children.

Free Fatty Acids are also in many recommendations, and mainly serve to distinguish fatty acid oxidation defects, where they are elevated during hypoglycaemia despite low ketone bodies, the total incidence of all those disorders is probably about 1:10,000 births, but they are treatable, and picking them up when an infant is hypoglycaemic in the first few days of life is probably beneficial, and may well improve outcomes. I think we should keep them in our critical sample, but I don’t know the proportion of babies with fatty acid oxidationn defects who present with hypoglycaemia in the first few days of life, so diagnosing them from a critical sample is likely to be very uncommon.

Some recommend including a C-peptide measurement, with the idea that a high insulin with a low C-peptide is evidence of exogenous insulin administration. As that is an extremely unlikely scenario in the neonatal ward or NICU I think we can drop the C-peptide, (especially as some varieties of commercial insulin do not even register with some insulin assays). It is mostly paediatric endocrinologists who seem to want a C-peptide, and as part of the work-up of an older child it might be more relevant.

Many recommendations suggest growth hormone and cortisol estimation in the critical sample, and these seem to be the next most likely to lead to a diagnosis, after high insulin concentrations. Inappropriately low concentrations have led to a diagnosis in several babies I have seen over the last few years.

The Canadian Paediatric Society recommends obtaining a critical sample, but does not mention what should be measured in the sample. Others have suggested IGF binding protein-1 levels, without a good explanation why, and then several suggest other tests in later work up depending on the initial findings, including ammonia, urine organic acids and serum amino acids, triglycerides, carnitine and acylcarnitine profiles.

The volume of blood required is an issue for most blood sampling in the newborn, so I think the tests required for specific diagnosis of other rare conditions that rarely present with neonatal hypoglycaemia can be left out of the initial “critical sample”.

The other consideration is that you can get an idea whether a hypoglycaemic infant is hyper-insulinaemic from the amount of glucose that they are requiring. Those that require very high glucose intakes to remain normoglycaemic (more than 8 to 10 mg/kg/min) are likely to be hyper-insulinaemic. That includes a proportion of those who are Small for Gestational Age, or with birth asphyxia as well as infants of diabetic mothers or LGA infants. Of course the uncommon babies with congenital hyperinsulinism syndromes will fit this picture.

Putting all this together, I think the most appropriate critical sample when it is required; that is, unexplained, prolonged, or recurrent hypoglycaemia, should measure the following, and if blood volume is a problem, start with the first 2 items on the list and work down:

Glucose

Insulin

Serum Cortisol

Growth Hormone

Ketones (either Beta-Hydroxy-Butyrate or ketone bodies depending on your lab)

Free Fatty Acids

If you can get enough blood, then do a blood gas with bicarbonate and lactate concentrations.

After that, if you still don’t have an answer and hypoglycaemia is recurrent, a call to your helpful local paediatric endocrinologist would be a good idea!

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