Not neonatology: the antipodes week 3. Tongariro Crossing: Sweet As!

We ended week 2 and had a warm Christmas in Rorotua, then moved on to Tongariro national park. The plan was to cross the Tongariro Alpine Crossing, which we have long time thought would be one of the highlights of our trip. We were not disappointed.

A 20 kilometre, all day, hike with 3 children aged 7, 9 and 11 needed some planning. Fortunately Annie had organized a guide, who was able to time our movements with the weather so we saw great views of the craters and lakes (as well as teaching us some kiwi slang, see the title of this post). Walking across the Southern Crater was like crossing a Martian landscape (or at least what we see from the Martian Rover photos, not having actually visited myself).

martian

Then a climb up to the Red Crater, where we stopped for lunch (#1).

red crater

A further climb to our highest point of the day just above the Emerald Lakes and the Blue Lake, and lunch number 2.

emerald lakes

After which the walk was mostly downhill, from 10 km onwards, which was great for the kids, they were still running by the end of the day. As we passed close to the site of the 2012 eruption, a steam vent started to pour out steam as you can see on the ridge in this next photo. The steaming earth lower down was hot to the touch, which was not something I had ever experienced before.

steam spout

 

There was a big eruption here only 2 years ago, in August 2012. A rock crashed through the roof of one of the huts which used to be available for overnight stays if you were doing one of the multi-day walks in the region. So it is no longer used. The clouds of gas and dust had killed most of the plan-life in this last part of the track, which is starting to regenerate

regenerating plants

The crossing was very busy, it has become known as one of the 10 great walks in the world, so there were hundreds of people doing the walk; probably more than there would have been becauses the next 2 days weather forecast was for rain.

Probably part of the attraction is that Mount Ngauruhoe, the peak with the typical volcano shape, was used as Mout Doom in the Lord of the Rings movies. Apparently the Mountain is sacred to the Maori (as is much of the land, especially the mountains) so the shape was digitally altered for the movie. Here is an un-altered view:

mount doom

I haven’t done any of the other 10 best walks, but the spectacular, varied scenery on this crossing were certainly worth the climb.

 

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Therapeutic Hypothermia: How low can we go?

A report of secondary outcomes from a trial, prior to the report of the primary outcomes should, in general I think, be resisted. Having said that, we reported the secondary outcomes of the CAP trial before we had the primary outcomes, largely because it was suggested by the data safety monitoring committee, and the idea was that the secondary outcomes that we wanted to report were quite positive, and we had identified no safety concerns, so the ongoing widespread usage of caffeine was probably quite appropriate while awaiting the developmental outcomes.

The new NICHD hypothermia trial has just published secondary outcomes (Shankaran S.: Effect of depth and duration of cooling on deaths in the nicu among neonates with hypoxic ischemic encephalopathy: A randomized clinical trial. JAMA 2014, 312(24):2629-2639.) which I think was also a good idea in this case. Most importantly because there is some doubt about safety of longer or deeper hypothermia resulting from their findings.

This was a factorial trial examining both the effects of longer hypothermia (120 compared to 72 hours) and deeper hypothermia (32 compared to 33.5 degrees).

Multiple (pre-planned) interim analyses were performed, and after exactly half of the expected sample was enrolled (364 of 726) the study was stopped for safety concerns and for ‘futility’. For both of the comparisons there were a few more deaths with the longer or deeper groups compared to the standard approach. Neither of the comparisons in terms of death were significant at conventional levels of significance, which means that there is a 14% chance that the difference in deaths found between longer and standard cooling was due to random variation, and a 26% chance that the difference in deaths between the temperature groups was due to random effects.

What that means is that there really isn’t any proof that lower or longer was harmful in terms of death, but the Safety committee determined that the probability of finding an advantage was small (they calculated it as 2%), which was really the point of doing the study. They can certainly be criticized for stopping the study at this point, but they would have been trashed if they had continued and it turned out that there was a true increase in mortality with the new approaches to treatment.

In addition there were other negative effects found, particularly of deeper cooling to 32 degrees, with an increase in pulmonary hypertension, leading to more NO use, and more ECMO use, as well as more bradycardia, which is not surprising, but might affect systemic oxygen delivery if cardiac function is compromised.

The implication of the study is that 72 hours appears to be long enough, and that 33.5 degrees is low enough, which is a bit strange… does that mean that we got it exactly right, by chance, with the very first studies? I think that would be remarkable; the initial temperature and duration chosen were based on the best pre-clinical data that we had, but they were somewhat arbitrary choices. Maybe a slightly less severe hypothermia might be better, and then it could be for a longer time, which might have advantages, but I don’t know now if we will ever do another study like this one. Another large high quality, multicenter trial of different approaches to hypothermia will probably only ever be done if we can change our models of doing clinical research. If we could cheaply randomize infants who are undergoing cooling already, collect data that is easy available and simple to collect centrally, and then get long term outcome data, without the very expensive infrastructure of a trial like this one, (similar to the registry trial in Scandinavia that I already blogged about in the past), then we could answer many other questions that will be difficult, or impossible to answer otherwise.

 

 

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Counselling parents when their infants have CNS injury.

Marcus Brecht and Dominic Wilkinson have just published an interesting study detailing treatment limitation discussions in the NICU which came after diagnosis of major CNS injury, and what happened to the babies after these discussions.

There is a lot which is of interest in this study, but I want to highlight one particular finding.

When we have such discussions with parents, it is usually because we are concerned enough about the long term outcome of the babies to consider redirection of care, from curative to comfort care. When we have these discussions about limiting or withdrawing life-sustaining interventions, sometimes the decision is to continue with active intensive care, and therefore some infants will survive. In this study the authors show what happened to the babies after the discussion, which survived, and how they did in the long term.

They showed, among those preterm babies who survived, that most of them had no impairment or only mild impairment. Now the numbers were small, but this is consistent with what I was writing about in the last post, early head ultrsound findings are very poor for prognosticaiton.

Which all makes you think… or at least it makes me think, about the others; the many babies who have had comfort care instituted because the head ultrasound looked really bad, but who, in the end would probably have been OK, either unimpaired, mildly or moderately impaired, and who would have had a good life.

Which brings me to another study, from the Pediatrix database detailing causes of death in the NICU; many deaths, of course are among very preterm infants.

The first cause of death among the very preterm was extreme prematurity (79 of the 229 deaths), which is too vague I think to be very helpful, I would have preferred it if this had been clarified, some of the most severely preterm babies develop major metabolic abnormalities and just “fall apart” in the first few days, is that what this group had? The most useful data from this study is the frequency of other diagnoses of potentially preventable complications, sepsis and acquired bowel disease, for example. Which are the third and fourth causes of death among the extremely preterm infants.

The one aetiology of neonatal death that I want to focus on for this post is the category of babies who died of Intracranial Hemorrhage. Among those 229 deaths of babies less than 25 weeks, the second most common cause of death, accounting for 33, or 14%, of the deaths, was “intracranial hemorrhage”.

In my experience death as a direct result of the physiologic consequences of IVH is actually rather rare. It certainly happens, but not very often at all.

When an infant with a severe hemorrhage has palliative care instituted, and dies afterwards, that death is often, I think, classified as being due to the hemorrhage.

I wouldn’t be surprised if most of the babies who are stated to have died of “intracranial hemorrhage” actually died after redirection of care, as a result of head ultrasound findings, which isn’t really the same as dying of intracranial hemorrhage. But I don’t think it is entirely clear in this study.

We are very poor at prognosticating in individual cases based on head imaging findings; as I discussed in a previous post the positive predictive value of most findings, especially those that we see in the first week, is less than 50%. Prediction, that is, for outcomes which themselves are not necessarily very important in terms of quality of life (usually standardized developmental testing (almost always the Bayley scales) at between 18 months and 2 years of age).

To give one example, here is figure that I might have used before in this blog (from Merhar SL, et al: Grade and laterality of intraventricular haemorrhage to predict 18-22 month neurodevelopmental outcomes in extremely low birthweight infants. Acta Paediatr 2012, 101(4):414-418.), which shows that the proportion of infants with NDI (that is neurological impairment or a low developmental score at 24 months) was higher among infants with a grade 1 intraventricular hemorrhage who had postnatal steroids and late-onset sepsis (up to 50%), than among infants with bilateral grade 4 hemorrhage who did not have either of those complications (around 35%).

outcomes

This means that in the first few days of life, when the hemorrhage is discovered, the worst finding that we see (bilateral grade 4 IVH) is associated with 65% of infants having no impairment by that definition. (Unless they go on to have sepsis or need postnatal steroids, in which case the chances of not having ‘NDI’ decrease to about 25%.)

I emphasize that this does not mean that those children who do not have ‘NDI’ will have no problems, they might for example have executive function problems, or behavioural difficulties, or serious issues with mathematics at school, but it does mean that we are lousy at predicting even what is called ‘NDI’; which is of only modest association with eventual functional outcomes.

Part of the problem with the poor prediction of head ultrasounds is the way they are interpreted and the way they are classified. Interpretations are somewhat subjective and there is substantial inter-observer variation in diagnosis of various lesions. Even those lesions where there is agreement however, are subject to the problems of the classification system. A small unilateral intracerebral bleed is classified as a grade 4 hemorrhage. Massive bilateral destructive lesions are also classified as grade 4 hemorrhages. The prognostic importance of those 2 extremes must be different, but you would never know from reading our literature, as there are very few articles that have tried to characterize the extent, or the laterality of the lesions. Which is one reason why I often quote the Merhar paper when I lecture about this issue, as they have done just that, and shown, in fact overall, that a unilateral grade 4 hemorrhage has no impact on ‘NDI’ at 18 to 22 months.

outcomes2

As you can see from this graph, unilateral hemorrhages of any grade do not affect the mean MDI or PDI at 18 to 22 months,  only bilateral hemorrhages, are associated with a reduction in those mean scores.

Decision making in the first week of life, based head imaging findings should be avoided.

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Not neonatology : the antipodes, week 2

The rain slowed down towards the end of our week in Auckland, and then we headed north for a stay in Paihia. Paihia is the main town on the Bay of Islands, one of the places where Captain Cook made contact with the Maori people. He is supposed to have counted 144 islands, which remains the official number, one of the larger of these islands is Urupukapuka where we spent a beautiful day walking, and then kayaking in the bay where the ferry arrives.

Bay of islands

Towards the end of the second week we moved again to Rotorua, the centre of the North Island, where there is a lot of geothermal activity. Also the centre of Maori culture.

Champagne pool

This small lake is called the Champagne Pool, the water is a light yellow colour and bubbles constantly, hence the name, but the red-orange deposits round the edge have a high antimony content, so not quite as nutritious as real champagne.

Despite the toxins in the water there is some algal and invertebrate life, enough to provide food for this stilt

stilt

 

The pools vary enormously in colour, depending on the dissolved minerals, ranging from a light green

Arsenic

To sky blueskyblue

 

Many of New Zealand’s birds have been exterminated by introduced mammals, especially Possums, rats and stoats. A few are still thriving like this fantail, also seen close to the geothermal area.

Fantail

Some of the scenery is really other-worldlyotherworldly

 

 

 

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Predicting Outcomes?

A new publication and an editorial address some of the issues around whether we can predict outcomes in preterm infants.

This was a large cohort study from the NICHD network, the usual multi-multi-multi-author paper, 34 authors wrote this paper apparently,  Hintz SR et al: Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants. Pediatrics 2014. There were 480 infants of less than 28 weeks who were enrolled in the SUPPORT trial (from 16 of the 20 SUPPORT centers), they had early head ultrasounds, late head ultrasound near term, and MRIs close to term. Then followed up with standardized neurodevelopmental testing. 10% had major anomalies on early ultrasound, 6% on late ultrasound. 20% had MRI white matter injury defined as moderate or severe, and 16% had cerebellar lesions seen on MRI.

The authors showed that if you have imaging brain abnormalities you are more likely to have adverse outcomes. There are many p-values less than 0.001.

Which is hardly surprising.

They show that early head ultrasounds are of little value when you take into account clinical factors and late findings. They also show that

 a substantial proportion of children with adverse late Cerebral US or MRI findings in our cohort did not have severe adverse outcomes at 18 to 22 months, emphasizing that neuroimaging must not be used in isolation to predict outcomes.

To me this is the most important finding of this study.

But first lets look at early ultrasound findings: of those without a major finding on a 4 to 14 day ultrasound, there were 6% with “neurodevelopmental impairment”; of those with a serious hemorrhage or cystic PVL there were 28%. If we make that a ‘glass half-full’ statement, that means that if you have serious early ultrasound findings there is a 72% probability that you will not have “impairment”.

Late imaging findings were more strongly associated with “impairment”, but only the 18 babies who had severe MRI white matter injury were really any different in terms of outcomes  (the babies with moderate abnormalities don’t seem much different to those with ‘normal MRI’), and among those babies, half had serious cerebral palsy and 22% had Bayley 3 cognitive scores below 70, (in other words, 78% of infants with severe white matter abnormality on late MRI did not have low cognitive scores on Bayley 3 testing).

The positive predictive value of cerbellar lesions was also very poor, 10% of infants with cerebellar lesions had moderate to severe cerebral palsy, and 15% had cognitive scores below 70.

Late head ultrasounds, (scored as abnormal in the presence of a shunt, moderate to severe ventricular enlargement, cystic PVL or a porencephalic cyst), were to my eyes, just about as good (or bad) as an MRI; with PPVs ranging from 23 to 50%.

What does all this mean in clinical practice? I think we should, as the authors of this study state “re-evaluate the practice of early head imaging” in very preterm infants. I think the data also suggest that we should “re-evaluate the practice of late head imaging”! We should continue to examine closely why we are doing such studies, what we want to get out of them, and how we inform parents, both for prior consent and after we have the result.

An editorial accompanying the study asks many of the same questions, as Eric Eichenwald states, “we need to understand the potential impact of of our predictive uncertainty on the parents of these vulnerable infants. …neuroimaging techniques.. cannot yet be used to determine follow-up strategies or target interventions after discharge and thus may be of little or no benefit to many parents.” (and he references the article by Annie and me!)

I think an objective evaluation of the usefulness of these tests for predicting outcomes in individual babies would lead to the inescapable conclusion that they are close to useless. Sometimes worse than useless, as they give false reassurance, or create false anxieties.

Both early and late head imaging fail to satisfy any of the criteria for a useful screening test. We should consider limiting early head ultrsound to use for detection of treatable lesions, and later imaging for research purposes only, with extensive informed consent to ensure that parents are well aware of the limitations of both MRI and near term head ultrasound.

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Not neonatology: le grand tour

We have decided as a family to take a break, a pseudo-sabbatical to visit the down-unders, learn about their culture, present at conferences, and generally focus on de-stressing and self-improvement. The 3 kids are out of school, and will be getting intensively tutored by Annie and me.

People’s reponses have been universally positive, including our colleagues in Sainte Justine, and the children’s teachers. So far no-one has said ‘but what about the kids missing 3 months of school?’

Tuesday, on our trip down here we had an 8 hour break in San Francisco, so we decided to go to the California Academy of Sciences, as recounted in the blogs that the kids have set up to keep in touch with their class mates: Axel’s blog is tentacules and Violette’s is simply Violette’s blog: even Tai is guest posting on Axel’s blog!

Then on to the antipodes for our 3 month break in the sun, or so we thought… so far New Zealand and sun seem to be antonyms. The countryside is beautiful, and the birds are noisy, but the rain has been almost constant.

Since our arrival in Auckland we have been exploring a little, we have seen most of the indoor attractions of Auckland, which fortunately has an interesting Museum and Art Gallery, and even an indoor mini-golf! we have had a couple of days without rain, just cloudy skies, the first we went walking among the tree ferns at Hunua ranges. The tree ferns are beautiful, and many are unique to New Zealand, this specimen was over 10 metres tall, with epiphytic bromeliads growing from the trunk.

treefern

Close to the car park this pool with waterfall

falls

Another day we climbed a volcano, Rangitoto island in Auckland bay is a volcano that erupted about 600 years ago. I don’t fully understand the lush vegetation, I thought it took longer than that to create good soil from new volcanic rock. This is a view of Auckland from Rangitoto, showing a typical cloudy sky, looking over the lava poking out of the water and the mangroves.

Auckland from Rangitoto

The Auckland museum has a reconstructed Maori dwelling, with this couple as the base of one of the door supports.

Maori figures

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Lactoferrin and the bowel

There’s a lot of activity in Lactoferrin research recently, this protein is very promising as prophylaxis against infections and perhaps also against necrotising enterocolitis.

First of all a study giving bovine lactoferrin to newborn piglets which showed a stimulatory effect on crypt cells in the developing intestine. Reznikov EA, Comstock SS, Yi C, Contractor N, Donovan SM: Dietary bovine lactoferrin increases intestinal cell proliferation in neonatal piglets. J Nutr 2014, 144(9):1401-1408. Exactly which cell type isn’t clear to me, but Paneth cells in the crypt have been suggested to be important in the pathophysiology of NEC. (McElroy SJ, Underwood MA, Sherman MP: Paneth Cells and Necrotizing Enterocolitis: A Novel Hypothesis for Disease Pathogenesis. Neonatology 2013, 103(1):10-20).

Another study from the same group, in the same model (in fact I think it is the same piglets) Comstock SS, Reznikov EA, Contractor N, Donovan SM: Dietary Bovine Lactoferrin Alters Mucosal and Systemic Immune Cell Responses in Neonatal Piglets. The Journal of Nutrition 2014, 144(4):525-532. Both spleen cells and mesenteric lymph node cells showed signs of enhanced immune responses with dietary bovine lactoferrin.

Colostrum, and mature breast milk contain significant amounts of lactoferrin. (in fact the piglets in the previous study were deprived of sow colostrum in order to do the study). Breast milk is almost always colonized with bacteria, very often bifidobacteria are present, and often lactobacilli also. In this study, which included both full term (34) and preterm (14) mother infant (human) pairs, the lactoferrin concentrations were similar to previous data, with around 7 mg/mL in colostrum dropping to 2.3 in mature milk, similar in term and preterm subjects. Mastromarino P, Capobianco D, Campagna G, Laforgia N, Drimaco P, Dileone A, Baldassarre ME: Correlation between lactoferrin and beneficial microbiota in breast milk and infant’s feces. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014, 27(5):1077-1086. They also showed bacterial DNA of lactobacilli in all of the breast milk, and bifidobacteria in all but one of the breast milk samples, with a higher concentration of lactobacilli in the preterm milk, and similar bifidobacteria concentrations. They also analyzed stool samples, and were able to find lactoferrin in the stools, and found lactobacilli and bifidobacteria in almost all the stools also.

The next study examined the effects of heat-treatment and ultraviolet light on the lactoferrin concentration of colostrum (also on what they call hospital milk, which is milk supplied by sick cows which cannot be sold, and may be contaminated with many bacteria). The heat treatment was to 63 degrees for 60 minutes, which is similar to many human milk bank standards I believe. Lactoferrin was measured by an ELISA, and I don’t know whether lactoferricin, or other active or potentially active parts of the molecule would react with the assay. Teixeira AGV, Bicalho MLS, Machado VS, Oikonomou G, Kacar C, Foditsch C, Young R, Knauer WA, Nydam DV, Bicalho RC: Heat and ultraviolet light treatment of colostrum and hospital milk: Effects on colostrum and hospital milk characteristics and calf health and growth parameters. The Veterinary Journal 2013, 197(2):175-181. The study shows a number of things : cows’ milk colostrum has much less lactoferrin than human (which was already known), about 0.3 mg/mL falling to around 0.2 in mature milk. Both heat treatment and ultraviolet treatment reduced the lactoferrin concentrations, and also the IgG concentrations. It’s interesting sometimes to read research form other fields in some detail, this study was performed in a farm which has 2800 cows, and they randomized over 280 animals into the 3 groups. They calculate the sample size based on daily weight gain, which is therefore the primary outcome variable, but they don’t use the term, and report that outcome in very little detail, right at the end of the results.

Also interestingly, low birth weight calves are at higher risk of infection than normal birth weight, being LCBW (low calf birth weight) less than 37 kg is associated with much more diarrhoea, and they also had lower serum IgG concentrations.

Part of the efficacy of lactoferrin may be that it sequesters iron, so that it is no longer available for organisms that rely on iron to replicate, such as E Coli (although there are several other mechanisms also). If you then add more iron to the feed, does this overcome the benefits? A number of in vitro studies have had variable results, the latest took colostrum from mothers delivering at term, and tested bacterial growth effects of the milk with and without the addition of a human milk fortifier, used for preterm infants, that contains iron. They found no effect of the iron on Pseudomonas or Staph Aureus, but E Coli grew a little more actively when the fortifier with iron was used. Apparently other studies have had different effects, such as showing a direct bacteriostatic effect of breast milk, and showing more adverse effects of the iron. Campos LF, Repka JCD, Falcão MC: Effects of human milk fortifier with iron on the bacteriostatic properties of breast milk. Jornal de Pediatria 2013, 89(4):394-399.

Of course iron is also important as a catalyst for the production of reactive oxygen species, so another potential benefit of lactoferrin may be to reduce free iron, and therefore to reduce potential oxidative injury of the gut. This is suggested by the results of another study: Jegasothy H, Weerakkody R, Selby-Pham S, Bennett LE: In vitro heme and non-heme iron capture from hemoglobin, myoglobin and ferritin by bovine lactoferrin and implications for suppression of reactive oxygen species in vivo. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014, 27(6):1371-1382.

Finally a review article which discusses the potential benefit of lactoferrin supplementation. Michael Sherman, who has studied lactoferrin, including recombinant human lactoferrin relates the importance of ensuring that preterm babies get colostrum. Which I certainly agree with. The authors also state however that there is no lactoferrin preparation proved by the FDA for use in preterm infants, which is of course true, but they state in the abstract ‘regulatory burdens required to bring lactoferrin to the bedside may limit its availability’. When the list of trials completed and in progress at the end of the article are examined, I hope that is not true. If the data are confirmatory, we should have plenty of good data to be able to obtain approval. Sherman M, Miller M, Sherman J, Niklas V: Lactoferrin and necrotizing enterocolitis. Current Opinion in Pediatrics 2014, 26(2):146-150.

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