Not just neonatology: trip to Buenos Aires

I was in Buenos Aires last week for a tremendous conference. With many excellent speakers (and me!) and the usual amazing hospitality that anyone who has visited Argentina will have received.

I promised the participants that I would put my powerpoint presentations on the blog for their edification and delight. So here they are.

This was my third time in Buenos Aires, but it was the first time I had visited the “Costanero Sur”, this is a nature reserve not 5 minutes from downtown, where I took my camera and was able to photograph Capybara, like this guy below:

I also photographed numerous birds that I had never seen before, in the 2 hours or so we were in the park.

I have put some of the photos on a page, under photos, named “Argentinian birds”, they include a photo which I took within a few minutes of arriving there, with a Wattled Jacana in the middle, and behind, a capybara and several coots (probably Andean Coots) I unfortunately wasn’t able to get closer to the Jacana. Before leaving I was treated to the sight of a flock of noisy Nanday Parakeets being chased across the sky by a Caracara, a common bird of prey here.

There were also  pair of southern screamers, presumably a male (somewhat larger with a slightly longer crest) and a female. You can see all of them here if you wish.

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Feed and grow

How to measure growth? How to describe growth rates? What does it matter?

Several related articles in today’s post, the first two are about how to measure growth in preterm infants:

Ashton JJ, et al. Assessing the growth of preterm infants using detailed anthropometry. Acta Paediatrica. 2017.

It is clear that body weight is not good enough. Although it can be measured easily, reproducibly and precisely, just because body weight is increasing along the wanted percentiles does not mean that growth is optimal: excess fat, and not enough of everything else, is common in preterm infants. We showed in our study that enhanced nutrition can almost completely prevent post-natal growth failure in the preterm infant, when calculated as loss of body weight Z-scores, but that length z-scores still fell between admission and discharge (by a mean of 1.5, compared to 1.7 with the older cohort) . Just looking at our most immature, longest stay, babies you can see that many of them are ‘short and plump’. Head circumference z-scores were maintained, though, and, as a very rough proxy for brain growth, that is re-assuring that the enhanced nutrition allowed good cerebral growth. Also, measuring length is rather inaccurate in usual daily practice, knemometry seems to be more accurate, but I can’t find a source of a device to do it. When I started working at the Royal Victoria Hospital in Montreal they were using a stadiometer, which is more accurate, but requires a lot more disturbance of the babies, so was only done after they were quite stable, and would be difficult to introduce into routine practice elsewhere.

So what else could we do? Body composition measurements would be ideal, but all current methods require either expensive equipment or extensive manipulation of the baby, or both. It would be great if there was some other measure that was shown to correlate with fat-free mass, that you could simply add to weekly weight and head circumference measurement, and that could then be used to evaluate changes in nutritional practice.

In this new publication the use of additional measures, mid-upper arm circumference, and mid-thigh circumference were compared with repeated measures of weight, length, and head circumference. They showed that the measures are simple and reproducible, and seem to have different progression to measures of weight and head circumference. They haven’t yet proven that they are a useful addition to our other measures, but I am hopeful that something this clinical and simple could give new insight into the quality of growth of our babies, rather than just the quantity.

Fenton TR, et al. Preterm Infant Growth Velocity Calculations: A Systematic Review. Pediatrics. 2017;139(3).

Tanis Fenton is the source of the growth charts that we use in our NICU, she has performed several systematic reviews that have led to our adoption of her charts, and now presents a systematic review of measures of growth velocity calculation. You can present such data as grams per kilogram per day, or as gains in z-scores, or in many different ways, the question of this review was whether or not there  is some sort of consensus. After reviewing hundreds of articles they finally state:

The lack of standardization of methods used to calculate preterm infant growth velocity makes comparisons between studies difficult and presents an obstacle to using research results to guide clinical practice.

They also note:

It is important for researchers to identify which growth charts were used to calculate z scores.

Which would seem to be self-evident, but is apparently not. In our article we did refer to  (and use) the growth and percentile charts and on-line z-score calculator of Tanis Fenton. All referees should ensure that the source of the growth data are clearly referenced.

Paviotti G, et al. Higher growth, fat and fat-free masses correlate with larger cerebellar volumes in preterm infants at term. Acta Paediatrica. 2017.

Does it matter if we can get preterm babies to grow faster, and stay closer to their percentile? Although this is a small study with only 42 babies included, they were able to show that when babies increase their weight better, they have better cerebellar volumes, even if they are fatter than they would otherwise be, and have higher fat-mass, they still have better cerebellar volumes.

Bouyssi-Kobar M, et al. Third Trimester Brain Growth in Preterm Infants Compared With In Utero Healthy Fetuses. Pediatrics. 2016.

In this study the authors compared brain growth between preterm infants and fetuses who remained in utero at similar gestational ages.  They selected infants who did not have obvious brain injury and noted that being ex-utero, rather than in-utero had significant effects on growth of the brain in multiple regions. They corrected for several factors, but I can’t see any adjustment for nutritional intakes, which could potentially account for many of the changes that they have seen.

Finally, an abstract from this year’s PAS meeting with Julie Schneider as first author, from the incomparable Steven Miller and the team at the Sick Kids hospital in Toronto; they also looked at cerebral volumes in various areas of the preterm infant’s brain, as well as fractional inosotropy (which I could probably explain to you, but then I would have to kill you). They saw that the nutritional intakes in the first two weeks of life were strongly associated with improved brain growth and more normal fractional inosotropy when the babies then reached term.

When I was learning neonatology we were just starting to take nutrition seriously, fortunately I had a mentor (Neil Finer) who was already taking nutrition seriously, and the groups I have been involved with since then have been interested in, and committed to, providing optimal nutrition to small preterm infants.

We must continue to improve our standards, find ways to ensure growth that reflects in utero standards, and ensure that growth quality, and not just quantity is optimised to improve short and long-term outcomes.


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Cochrane reviews

The NICHD, in case you didn’t know, supports the neonatal Cochrane reviews,  they are all on their website at this address. I don’t really like the way they are formatted on their website, you have to click on links to see the Forest plots, but they are freely available around the world, with only a few weeks delay between publication and availability here.

My new Cochrane reviews about nitric oxide are now freely available on-line.

The review of inhaled nitric oxide for the preterm infant and the review for term and near-term infants with hypoxic respiratory failure are here.

As you will see, we have added new authors to both reviews, younger authors with much energy who will ensure that the reviews are continually updated, for the rest of their lives.

As I previously mentioned, the updated reviews give a little more evidence about use of nitric oxide.

In the preterm there is no clearly defined situation at present where nitric oxide has been proven to be effective in improving clinically important outcomes, such as lung injury or mortality. There remain question about use in infants with clear evidence of pulmonary hypertension, and during acute deteriorations in developing chronic lung injury.

In full-term infants earlier use is now being promoted by some manufacturers, but the evidence does not show that this improves survival, or survival without ECMO. Earlier use does seem to decrease the number of babies that go on to more severe disease, but if you wait until later, you may still respond, and have the same overall benefit. The power for some of these outcomes is low, however.

I hope you find these analyses useful.

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Probiotics for extremely preterm infants

The use of probiotics for Necrotising enterocolitis prophylaxis in the very preterm is increasing across Canada. There are apparently, though, centers that will only give them to larger preterm infants, and not to the most immature.

I think that is based on a mis-interpretation of the literature, perhaps re-inforced by a phrase in some systematic reviews, such as the following:

There is insufficient data with regard to the benefits and potential adverse effects in the most at risk infants weighing less than 1000 grams at birth.

The facts are that the birth weight stratum under 1000g is just not reported in most studies. Many studies however restricted their enrolment either to infants of less than 32 weeks, or less than 1500 grams (or both). As one example the Proprems study randomized only infants under 32 weeks and under 1500 grams, and as in many trials of VLBW infants, about half of the babies were less than 1000g (mean bwt was just over 1kg), and the mean gestational age just under 28 weeks. Very similar mean gestational ages and birth weights are found in all the studies that limited themselves to VLBW (<1500 g) babies.

Probiotics have therefore been tested in thousands of ELBW babies, and the lack of reporting of that specific stratum is not a valid reason for denying those infants the clear benefits.

If we do look at the limited data that have been reported for the subgroup of babies less than 1000g then we find the following for the outcome of NEC grade 2 or worse, with the difference in the incidence of NEC being in the direction of a benefit for probiotics, but not statistically significant.

That analysis is overwhelmed of course by the results from the PIPS trial, which was a very high quality trial, but one of the few to show no impact of probiotics. It used a previously untested strain, which might possibly account for the lack of effect. If we eliminate that trial for a moment from this subgroup, we find a reduction among the other trials which is of very similar magnitude to the overall meta-analysis, with an RR of about 0.66, again not quite significant.

It seems inherently unlikely that probiotics would have a substantial impact on infants between 1kg and 1.5 kg, but no impact below 1 kg. And despite the thousands of randomized babies, there were no reports in the RCTs, and a very small number of case reports, of adverse consequences, i.e. bacteremia, with the probiotic organisms.

So lets look at 2 very recent systematic reviews to see what is new.

The first is from a journal I had never heard of before, but it seems to have been done according to PRISMA standards. Sawh SC, et al. Prevention of necrotizing enterocolitis with probiotics: a systematic review and meta-analysis. PeerJ. 2016;4:e2429. These authors updated the searches and found, compared to recent systematic reviews, another 17 articles including an additional 5,000 babies! This is what the outcome of severe NEC looks like now:

A nearly 50% reduction in severe NEC, with very little heterogeneity, and a total of 10,500 babies studied. They performed the meta-analysis using a random effects model, and as you can tell used the Cochrane group’s software, Revman.

The results for all-cause mortality are here:

When they restricted the NEC analysis to just VLBW babies they found this:

about a 50% reduction among the 6,500 VLBW babies studied, and a 26% reduction in mortality.

Time to full feeds was 2 days shorter, and duration of TPN was 4 days shorter with probiotics compared to control.

The other very recent systematic review Thomas JP, et al. Probiotics for the prevention of necrotizing enterocolitis in very-low-birth-weight infants: A meta-analysis and systematic review. Acta Paediatr. 2017 only included data from VLBW infants, only included English language studies and only included those with a Jadad score of 3 or more (which is an evaluation of quality that is widely used). One thing they did differently was to analyze the different genera of probiotics used,

I am not sure how valuable this is in terms of selecting the bacteria to test against each other for the future, as there are probably differences between strains within genera that are important. Thus the Bifidobacterium breve BBG-001 that was used in the Pips trial, which is here referred to as Costeloe 2016, was ineffective, either because of random variation in outcomes between studies (the 95% CI include a possible RR of NEC of 0.67)  or perhaps because of an ineffective strain, or a dose that was too low, or maybe because of cross-infection of the controls (37% of whom were colonized with the probiotic at 2 weeks and 49% by 36 weeks PMA). For whatever reason I think future studies should not include a BBG-001 group (unless a much higher dose is tested) and we should forget about saccharomyces.

It looks like the best strains to be tested in future comparative trials would be a combination of a lactobacillus and Bifidobacterium longum ssp infantis.

Across Canada right now there are 2 preparations being used, either Florababy, a mixture of a Lactobacillus rhamnosus and 4 bifidobacteria, and Biogaia, which is Lactobacillus reuteri. At a recent meeting of the Canadian Perinatal Research Meeting a poster was presented with Data from the Canadian Neonatal Network, including only infants under 29 weeks gestational age. It included over 3000 infants, about a quarter of  whom received probiotics among the 17 centers that use probiotics at least occasionally. Dr Balpreet Singh from Dalhousie University in Nova Scotia is the first author. He and his c0-authors showed, in this observational study, a reduction in NEC, with an Odds Ratio of 0.7 for NEC, (0.64 after multivariate adjustment) and a reduction in death and the combined outcome of death or NEC also.  I won’t say too much more about it, but will probably re-blog about it when fully published. But it is re-assuring that this retrospective cohort among these extremely preterm babies is consistent with the data with moderately preterm and VLBW infants in the randomized trials.

I hope to see an analysis of the impact of the 2 different preparations, which might help to decide which future trials need to be done. Overall, the impact of probiotics seems to be the same whether your baseline incidence is high or low (the relative impact is the same, even if the absolute benefit will of course be greater if you start from a higher baseline), and seems to be equivalent if you have a higher or lower rate of exclusive breast-feeding.



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The artificial placenta and the end of neonatology

OK, so I guess I had better blog about this article, that it seems almost everyone has been talking about since it was published…

I have heard for some years that someone at CHOP (for those who are not “in the know” that is the Children’s Hospital of Philadelphia) was working on an ECMO+ device, to keep very tiny preterm babies on extracorporeal support, without the need for pulmonary ventilation, and basically replacing placental function. I thought that the device was probably a couple of decades away, and hadn’t given it much thought, until this new publication.

Partridge EA, Davey MG, Hornick MA, McGovern PE, Mejaddam AY, Vrecenak JD, et al. An extra-uterine system to physiologically support the extreme premature lamb. Nat Commun. 2017;8:15112.

It turns out to be far more advanced than I had thought, and, like ECMO, developed and pushed forward by a Pediatric Surgeon. (capitals intended, almost like G*d).

The latest iteration of their system requires cesarean delivery, cannulation of the umbilical vein, and both arteries, and then connection their device. When you deliver a fetus, they usually start to breathe, but for this procedure the mother is anesthetized and the fetus (in this case a fetal lamb) is given an intramsucular dose of an opiate.

The size of the umbilical catheters were 12 Fr or a specially modified catheter between 8 and 12 Fr, which is a 2.7 mm to 4 mm diameter catheter. The lambs, delivered by cesarean during the later part of their canalicular phase of lung development, weigh around 1.0 to 1.5 kg. The umbilical cord is isolated, treated with papaverine to prevent vascular spasm, (as well as maintenance of warmth and oxygenation) and the catheters (coated with an albumin heparin coating) are inserted a couple of centimeters and sutured in place. The lamb is then placed in a sterile plastic bag filled with artificial amniotic fluid and the catheters attached to a pump-less circuit with a very low resistance oxygenator (which is also, of course, a CO2 eliminator). Nutrition is added into this circuit and the lambs could be maintained for a prolonged period.

The lambs were also heparinized to an ACT of 150 to 180 seconds, and all received a prostaglandin infusion to keep the PDA open. They often needed blood transfusion, but fewer as time went on, probably because they started keeping the oxygen levels similar to the normal fetus, with less suppression of fetal erythropoietin.

They have created a model which does a lot of what the placenta does.

Except; the placenta does a lot of other things as well. The placenta supplies micro-nutrients and growth factors. The placenta metabolizes steroids very efficiently. The placenta regulates the movement of many molecules that pass from the mother to the fetus (and some in the other direction).

Which of these are critical to the developing fetus are unclear; whether your fetus is maintained in utero, in a plastic bag connected to an oxygenator, or in the NICU. One thing which is quite clearly critical to the future of this project is the nutritional aspect. The investigators were able to get the fetal lambs to grow with a combination of amino acid and glucose infusions, and by adding insulin were able to get respectable growth of the fetal lambs. Weaning of the lambs after many days of support was feasible, and succesful in transitioning them to more conventional care.

This is a huge technical achievement, which feels different to other potential advances in neonatology.

When Jere Mead and Mary-Ellen Avery showed that RDS was due to surfactant deficiency, the next step, which took many years, was to develop a replacement surfactant; this was a fairly typical medical advance. The “artificial placenta” is going a big leap further, replacing an entire organ system, the placenta and the uterus. I guess it is more analogous to renal dialysis, in a sense, than other neonatal advances. Other organ systems have been much more difficult to replace; hepatic replacement is much less effective, pulmonary replacement with ECMO or oxygenators is limited to how long they can be used. Even ECMO, when it becomes prolonged, is subject to a huge range of possible complications, even though many babies survive and do well.

One of my first thoughts was whether this would be technically feasible with much smaller subjects, but the last of the videos in the article is of a lamb that weighed 480 grams (much more immature also, of course), and was successfully supported using the system.

I don’t actually think this is going to be the end of neonatology, even neonatology of the most extremely immature babies. If this does eventually get translated to human use, then the procedures described need to be performed during a modified cesarean section delivery, which immediately limits the number of eligible babies. If the eventual plan is to take fetuses who have limited chances of ex-utero survival, which will include extremely preterm infants, then the maternal impacts of the delivery method also need to be considered.

Lambs don’t seem to be subject to intraventricular hemorrhage, which would be a concern for preterm babies getting heparinized, the ACT target ranges they aim for a substantially lower than ECMO, but mildly preterm babies on ECMO often have cerebral bleeds. I think they should try this technique on animals at risk of IVH (like the beagle puppy) before thinking of human trials.

During current ECMO treatment circuit changes, because of oxygenator failure or occlusion, are not rare, I can’t see in this manuscript if there is any report of the technical difficulties during the latest phase of their studies, including whether the oxygenator and circuit lasted the entire period without needing to be changed.

I think if this technique can be perfected, and this level of heparinization proven to be safe, then the plastic bag could be as good, or better, than being on a ventilator in the NICU, but will probably only ever apply to a small percentage of our babies. Now it only requires that the nutrition and oxygenation are varied to breed alphas, betas, gammas, deltas and epsilons!

Oh, wonder!
How many goodly creatures are there here!
How beauteous mankind is! O brave new world,
That has such people in ’t!
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Short courses of Steroids are hazardous… even for adults!

There were a number of things that surprised me in this study. the first was how many adults get short courses of oral steroids in the USA (and for all I know in other countries too). Waljee AK, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357. In their cohort of a huge number of US adults (1.5 million) aged 18 to 64 enrolled in a commercial insurance plan, over 1 in 5 (21%) had an outpatient prescription for a short course of oral steroids (less than 30 days) over a 3 year period. Most of the prescriptions were for a 6 day methylprednisolone dosepak, and the median prednisone equivalent dose was 20 mg.

I can’t fathom why 1 in 5 adults would need potent oral steroids: most of the prescriptions were for URIs and back pain, with allergies and bronchitis following.

Which might be OK if they were safe.

None of the adverse events they were monitoring in this study, sepsis, venous thrombo-embolism, and fractures, were very frequent, but all were more frequent in the 90 days after a patient received short course oral steroids (compared to the 90 days before). Sepsis was 5 times more frequent during the first 30 days, and remained 3 times more frequent between 30 and 90 days after the prescription, when no-one was still taking steroids! Similarly for venous thrombo-embolism, and fractures. The risks were increased by steroids and remained higher for at least 90 days.

This study shows that you sometimes need an awful lot of data to find adverse effects. Even if the baseline risks are much higher, such as for sepsis in preterm babies, huge data sets may be needed to show increased adverse outcomes.

Why would you give steroids for a sore throat? There are some very new data from an RCT of a single dose of dexamethasone, showing that a secondary outcome (proportion with complete symptom resolution by 48 hours) was improved by the steroid from 37% to 27%, but there was no difference in the average time it took to achieve complete symptom resolution.  The primary outcome variable, symptom resolution at 24 hours, was not affected. In other words a few more people get better between 24 and 48 hours, but on average it takes just as long to recover.

That doesn’t sound to me like a good risk/benefit balance, a chance of maybe having a shorter duration of discomfort, with an increased (if tiny) risk of septicemia. So I think I’ll just take some non-toxic symptom relief from the pharmacy next time I have a sore throat, and stay well away from short course steroids.

As for our patients? We need to be sure that there are clinically important benefits, important to families, whenever we consider prescribing steroids. Shortening the duration of oxygen therapy (and thus the diagnosis of “BPD”) is not necessarily worth the risk, and quantifying the risks, unless they are frequent, is very difficult.

It is true that not all the trials of steroids have shown an increase in sepsis, for example. But to be sure there is no increased risk of sepsis (especially after the first few weeks of life of a very preterm baby, when the absolute risks of sepsis are falling and when we are more likely to consider post-natal steroids) requires large numbers, very large numbers, of patients.

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The CAP babies are now 11

I was privileged to be part of the CAP trial group, a pivotal neonatal trial that showed improved Bayley scores and improved motor function at 18 to 21 months corrected age, among infants randomized before 10 days of age, with a birthweight under 1251 g, and considered eligible for caffeine therapy.

By 5 years of age there continued to be some advantages of caffeine treatment, compared to placebo, mostly in the motor domain.

Schmidt B, et al. Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial. JAMA Pediatr. 2017. A new publication presents data from 920 of 1200 of the originally enrolled patients. Quite a remarkable achievement. There were actually 2000 in the original trial but for various reasons (mostly language issues for the standardized testing, and centers who decided not to participate in the longer follow-up) there were 1200 of them eligible for this follow-up.

Functional impairment was less frequent with caffeine than with placebo, but the 95% confidence intervals of the adjusted Odds Ratio were 0.59 to 1.02, which means we can ‘only’ have about 93% confidence that the Odds of escaping impairment are improved by caffeine compared to placebo.

That might be “not significant” in some terms, but I think that’s a pretty significant degree of confidence, for a treatment lacking in any serious side effects.

This new publication confirms that there is no sign of adverse impact at this age of caffeine. The academic achievement mean scores are almost identical between caffeine and placebo groups, with slightly more caffeine children being more than 2SD below the mean.

The motor scores (movement ABC) showed more subjects below -2SD for the various subscales, which was described as being “motor impaired”, in the control group compared to the caffeine treated subjects. I don’t know much about the movement ABC, so I am not sure if “motor impairment” by this measure really has an impact on the child’s life. Only one third of the children with “motor impairment” had cerebral palsy, which was more frequent among placebo babies, 6% compared to 4.3% with caffeine.

We can be re-assured that there has never been evidence of adverse effects of caffeine, now up to 11 years of age, when given as in the CAP trial. It would be great to know if longer durations of treatment (up to term, or even after), or higher doses, could further improve these outcomes. I would be a bit reticent to try higher doses, especially following these publications (Vesoulis ZA, et al. Early High-Dose Caffeine Increases Seizure Burden in Extremely Preterm Neonates: A Preliminary Study. Journal of Caffeine Research. 2016;6(3):101-7. McPherson C, et al. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. 2015;78(2):198-204), which showed potential serious harm.

But a trial of prolonging caffeine therapy, at the point when it would normally be considered to be stopped, would really be worthwhile. Caffeine would probably, at least temporarily, reduce hypoxic events. Hypoxic events leading up to discharge, and beyond, have been associated with worse developmental outcomes. I think a large multi-center RCT, randomizing children to caffeine or placebo when they have their clinically indicated caffeine stopped, and continuing to term, with dose adjustments to take into account the accelerating clearance of caffeine at this developmental stage, could have real benefits for future babies in our care.

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