Using less antibiotics

Posted on 14 August 2017 by Keith Barrington

Most newborns who receive antibiotics are not infected. This is true of full term babies in normal newborn care, and preterms in the NICU. For most infants antibiotics can be stopped after 36 hours if cultures are negative at that point (for the few which are positive between 36 and 48 hours, antibiotics can be restarted without missing a dose). Duration of treatment of those with positive cultures, or of those who are thought to have culture negative sepsis, is quite arbitrary.

Stocker M, et al. Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). Lancet. 2017.

In this large international RCT of infants who had antibiotics started for suspected early onset sepsis (<72 hours of age) and who were term or late-preterm were randomized. Infants were evaluated with a reasonably objective risk scoring system, and could score 1 point for risk factors, 1 point for clinical findings, and 1 point for lab values.

The 2 randomized groups either had duration of therapy determined by Procalcitonin levels, or by an arbitrary duration, as shown in the figure. Babies who had positive cultures had at least 7 days of antibiotics, regardless of procalcitonin levels.

The group who used procalcitonin levels had shorter duration of antibiotics, a mean of 55 hours versus 65 hours. But of the 1710 babies included in the trial 47% were determined to be “infection possible”, and 41% were “infection unlikely”.  Only 27 babies had proven infections or about 1.5%.

My main problem with this trial is that the duration of antibiotic use in infants who are not infected is much too long. Any infant with a risk factor, even with no clinical signs, no other supportive evidence and with negative cultures at 36 hours receives between 36 and 72 hours of antibiotics. Any infant with a risk factor and one other point on the risk scale (for example for respiratory distress, or an elevated CRP) will receive 5 to 7 days of antibiotics. So any infant born before 37 weeks who has respiratory distress will have got at least 5 days of antibiotics in the non-procalcitonin group.

A baby with a history of chorioamnionitis or 20 hours ruptured membranes, respiratory distress, and an elevated CRP would be considered to be “infection probable” and would get 7 to 21 days of antibiotics, even if they improved rapidly, and had negative cultures. The clinical sign that was the most frequent was indeed respiratory distress.

I think that the authors have not shown that procalcitonin reduces duration of antibiotic use compared to a more reasonable approach, in which they would be stopped in the large majority of infants at 36 hours if cultures are negative.

I think most babies in this study should have had their antibiotics stopped at 36 hours, so the results of 55 and 65 hours of treatment that they found are both too long.

Overuse of antibiotics is a big problem, when less than 2% of treated babies can be proven to have an infection. Under-treating a baby who is truly infected is the concern that drives these numbers; the authors tried to evaluate that by looking also at deaths within the first month of life, and re-infection with 72 hours of stopping antibiotics. However, the numbers of those events was tiny (less than 1%) so there is no significant difference between the groups, the actual numbers are identical between the groups.

Many of the infants enrolled in this study, especially those in the ‘infection unlikely” group would not even have qualified for antibiotics if the evidence-based neonatal sepsis risk calculator, that I discussed previously, had been used. (It obviously wasn’t available when these authors were planning theire trial, but it is easily available now!)

Mukhopadhyay S, Puopolo KM. Clinical and Microbiologic Characteristics of Early-Onset Sepsis Among VLBW Infants: Opportunities for Antibiotic Stewardship. Pediatr Infect Dis J. 2017.

There is clearly room for improvement among preterm babies also. It has long been my practice to not perform cultures or give antibitoics to preterm babies born by Cesarean delivery with intact membranes to mothers who were not in labour.If there isn’t a route for a baby to get infected they aren’t likely to be infected!

This new publication confirms that practice to be safe. They reviewed over 5000 VLBW infants admitted to the Brigham and Women’s hospital, of which 109 had culture positive sepsis. There was only 1 case of a positive culture among an infant delivered with the characteristics that I mentioned, and that was almost certainly a contaminant (1 of 2 bottles grew a coagulase negative staph, which was negative on repeat culture despite the antibiotics not covering the germ).

The study also confirmed that cultures were very often positive before 36 hours, and 98% before 48h, so a 36 duration of initial antibiotic prescription is appropriate.

Being preterm is not an infectious disease. Some babies are at very low risk of actually being septic and we can avoid giving them antibiotics.

Posted in Neonatal Research | Tagged , | 3 Comments

Life, and medicine, with a disability

Posted on 12 August 2017 by Keith Barrington

I met the author of this article at a CPS meeting a few years ago, she immediately impressed me with her unique perspective. Paige is a developmental pediatrician who does long-term follow-up of preterms, and is involved in developmental evaluation and intervention of children with other challenges, including Spina Bifida.

Church P. A personal perspective on disability: Between the words. JAMA Pediatrics. 2017.

As you will see if you read the article, Paige has a form of Spina Bifida herself, a Lipomyelomeningocele, with a neurogenic bladder and neurogenic bowel, requiring life-long interventions. She discusses the poor tolerance many medical people have of disability, and such how things are often discussed as black or white, whereas having a profound personal experience of disability has made her much more nuanced.

She recounts being involved in a discussion regarding a “selective reduction” of a twin pregnancy where the twin being considered for “reduction”, i.e. abortion, had a similar lesion to her own.

That is an experience that I can barely understand: how would I react if a family was considering terminating  a pregnancy because of a condition that I had? Paige recounts the episode with tact and humanity.

I can imagine, as I have heard them many times, the words of the other physicians involved in such a decision, I am sure they talked about handicaps and limitations, poor quality of life, pain, and restrictions on family life. Most of which is said with good intentions but with no real knowledge of the literature, or of the range of experiences of families living with the challenges.

Just as with similar discussions regarding extreme preterm infants, a list of complications, interventions, disabilities, and long-term problems is often presented, but with no similar list of benefits, achievements, abilities, long-term adaptation, and happiness.

Near the end of her moving piece Paige writes:

Like most things in life, and medicine, disability is sharp, painful, humbling, as well as tremendous, giving, awe-inspiring. It is human. It is not easily distilled to an all or none discussion. Medicine sets the tone for this discussion and, to date, has done a miserable job. More is needed to appreciate the incredible opportunities that disability poses. More education is needed to provide the counselling families deserve: balanced, sensitive, thoughtful, and individualized rather than “objective.”

I sincerely hope that this piece by Paige will be part of a new discussion about these issues.

(Of note, even though the article is behind a paywall, JAMA lets you see the first page of the article before buying, in this case there is only one page, so you can read the whole thing for free!)

Posted in Advocating for impaired children, Neonatal Research | 1 Comment

A shiny new test

Posted on 14 July 2017 by Keith Barrington

I have invented a shiny new test, which detects brain injury in preterm infants just before they go home. It can be used at discharge to predict whether a former extremely preterm baby will have developmental delay or neurologic impairment. The test has a threshold of 1 unit for increased risk of poor outcome, and 2 units is a really abnormal test.

When the result is below 2 (that is normal or mildly abnormal) about 5% of babies will have cerebral palsy, and 25 to 35 % will have delay in various domains. When the result is above 2 (moderately or severely abnormal) about 25% will have cerebral palsy, and about 40 to 45% will have developmental delay.

In other words, when the test is severely abnormal, most of the babies will not have delay or movement disorder (even though there is a statistically significant difference in outcomes between groups); I can express the results differently to try and convince you to use my shiny test: there is a highly significant linear correlation between test results and developmental screening test results at 2 years.

What I want to know is; are you buying? It only costs about 600$ (Canadian) per test.

Hopefully in the era of modern neonatology, before doing this test you would discuss it with the parents of each baby, they might well ask “Do you recommend the test, doctor?”

Well?

Extremely preterm infants have increased long term problems, and need to be followed up in focussed programs. Parents are generally aware of the increased risks of their babies by the time they are about to go home. For a pre-discharge test to help families it should reliably inform them of the likely outcome of their infant. In other words it should be both sensitive and specific. Most extremely preterm babies do well, but a test with low sensitivity will have a low positive predictive value for important long term outcomes.

For some outcomes (relatively rare outcomes such as critical congenital heart disease) a screening test with low positive predictive value is acceptable, there are more false positives than real positives (even though many of the positive results of pulse oximetry screening actually have problems that need addressing) and a 0.5% false positive rate, for a condition with an incidence of 1:10,000 does not create huge problems. Especially when the patients who are truly positive need urgent intervention to prevent serious complications.

But when the risk of a particular outcome is moderately common, a test with the same characteristics is much less acceptable, large numbers of families will be identified as being at risk, and most of them will end up OK. Plus, in the case of former preterm infants at discharge, you actually don’t change your intervention based on the test results.

You could actually get almost as good discrimination by sitting in the waiting room of the test station, pointing at all the babies and saying “You will probably be OK”.

Are you takers for my shiny new test?

What I am trying to get at, is just because a test slightly improves prediction of delay or motor issues, does not necessarily mean that all of our patients should have that test. To be useful you need a test that discriminates between babies who will need follow-up and intervention, and those that do not. I think my shiny new test might not be so useful after all.

What is my shiny new test?

It will be obvious to many of my readers that my shiny new test is a term-equivalent cerebral magnetic resonance image.

What I have described is where we are with predischarge MRI (and probably term equivalent head ultrasound also). Most babies with abnormalities on the MRI have good outcomes. The positive predictive value of anything seen on the MRI is less than 50%. MRIs are really good at finding imaging abnormalities, they are relatively useless at finding developmental problems! Which is as it should be… surely, MRIs can be spectacularly succesful at showing brain structure, mapping tracts and developing connections and showing how some brains are different to others, including the brains of former preterm babies.

A new publication from Melbourne of 186 babies under 30 weeks gestation (or under 1250 g) who had pre-discharge MRI illustrates much of this. (Anderson PJ, et al. Associations of Newborn Brain Magnetic Resonance Imaging with Long-Term Neurodevelopmental Impairments in Very Preterm Children. The Journal of pediatrics. 2017).

This group of infants had the usual amazing high quality follow up from Peter Anderson and their team, and it shows a statistically significant association between abnormal MRI and various aspects of their cognitive abilities at 7 years of age.

But because there is a significant association, that does not mean that it is useful to parents, or that everyone should have the MRI.

This new publication doesn’t present the data in a way that you can calculate the PPV or specificity. What it does show is that if you have a semi-objective MRI scoring system, in a group of former very preterm babies who are now 7 years of age, the mean IQ of those with a normal pre-discharge MRI is 100 (SD 15) those with moderate to severe abnormalities on the MRI it is 89 (SD 15). (For those with mild abnormalities the IQ was 97 (SD 15)).

To show it graphically here are the mean plus or minus 2SD, to show the range of results of 95% of the babies in each group (about).

I think these data are amazing, they show, perhaps a bit surprisingly, that pre-discharge MRI findings at 40 weeks PMA have a statistically significant association with standardized testing 8 years later, after 8 more years of growth and development and stimulation and education and love and warmth in a family, there are still measurable impacts of how the brain developed in those first few weeks of life.

But,  I fail to see how this information is of any value for individual parents, although the authors try to use their results to promote routine pre-discharge MRI. What are you supposed to say to parents when you have a moderate to severe abnormality on the term-equivalent pre-discharge MRI?

Here is an evidence based suggestion for what to say to a parent when you get back the MRI with severely abnormal scores.:

“Your babies predicted IQ at 8 years of age is 95% likely to be somewhere between 59 and 119, if the MRI had been normal the predicted IQ at 8 years of age would have been 95% likely to be between 70 and 130.”

Now if the pre-discharge MRI predicted a response to early intervention programs, for example, then maybe they would be of value, but I don’t think there is any evidence of that; what does seem to correlate with an advantage from early intervention is poorer social circumstances. Perhaps if the sensitivity and the negative predictive value were high enough, you could decide not to follow-up some babies, but, although the NPV is high for cerebral palsy in a few studies, it is not very good for developmental delay. Which means, I think, that all very preterm babies should be in focussed follow-up programs regardless of MRI findings.

The authors of the article state the following in the discussion:

This study confirms that newborn MRI identifies brain abnormalities in CWM, DGM, and CBL that have long-term impact on neurodevelopmental outcomes, independent of perinatal and social risk factors. Thus, quantitative evaluation of structural MRI obtained at term equivalent age provides valuable information for clinicians. Because discussion of neurodevelopmental prognosis with families before neonatal intensive care unit discharge is standard of care, and brain abnormality on MRI is the strongest neonatal predictor of long-term outcome, prognostic discussions with families should be informed about MRI findings alongside other clinical indicators.

As should be clear by now, I really disagree with these statements. Doing a screening test with low specificity in a lowish risk population leads to frequent conversations with parents about the fact that, despite these findings, their baby will probably be fine, I still don’t think that we have answered the question of whether this test (alongside many others that we do, such as term equivalent head ultrasound, especially in babies whose US was previously normal) and that conversation, actually helps families.

Posted in Neonatal Research | 5 Comments

Thanks for Canadian Medicare and Tommy Douglas

Posted on 14 July 2017 by Keith Barrington

I recently had an acute medical event, took myself off to a local emergency room, received excellent immediate attention. After about 8 hours of care, an expensive drug that I had never heard of before, multiple disposables and several high tech investigations, I was able to go home. I got back home in the early hours of Canada Day, the 150th anniversary of the convention that created Canada. Two days later I was seen by a specialist, and had further expensive high tech tests.

When I got home from that, I thought I had better figure out my bill to make sure I could afford it all:

Taxi to hospital $14, taxi home from hospital $14, outpatient prescription drugs $1.84 (outpatient drugs are not completely covered for most people), parking for the specialist appointment $12.

Total cost $41.84

That’s it.

Everything else was covered by the provinical healthcare system, paid for by taxes.

Tommy Douglas was a former professional boxer, who was also a baptist minister, and is the father of Canadian Medicare. He was from the Canadian Prairies, has been referred to as the ‘greatest Canadian of all time’ and worked tirelessly to start a Canadian Health Care system which provides care to all, regardless of ability to pay. It is an interesting contrast to me, the attitude of someone like Tommy Douglas, a committed baptist who believed in creating a just and equal society where all are cared for when they are in need, to some of the attitudes of some christian groups in the USA today.

Our system (actually systems, there are significant differences between provinces that are responsible for administering health care) is far from perfect, acute and emergency care tends to be favoured, so neonatal care, for example, is in a privileged position. Central management makes regionalization quite effective, so we have almost no avoidable deliveries of very preterm babies in non-tertiary hospitals. Central management also creates problems, with the size of medical school intakes oscillating as the government tries to decide if we have too many physicians or too few, and keeps changing its mind.

Chronic care, and domiciliary care are the big losers in our system, as it is politically easier to cut budgets when the adverse effects are slowly cumulative rather than acutely visible. Non-urgent surgery is another place where our system does relatively poorly, so a hip replacement might be quite delayed, with consequent avoidable pain and disability. Although, in fact, some type of waiting list is an important way of containing costs, if everyone can get a hip replacement within a few days of qualifying for one, there has to be a great deal of redundancy in the system.

One interesting comparison with the US system was made a few years ago by John Ralston Saul. The cost of US Medicare and Medicaid, divided by the entire US population, (even though they only cover a smallish part of the US population) was substantially greater than the cost  of Canadian Medicare, divided by the entire Canadian Population; but the Canadian system covers everybody. A system with a layer of administration dedicated to making a profit has to be more costly.

I am certainly grateful for the Canadian health care system, both as a patient and as a part of the system, no-one find themselves in debt because of medical costs, those who pay taxes pay for the medical care of those who pay little or no taxes. In a relatively just society, that is how it should be.

Happy belated 150th Canada Day!

Posted in Neonatal Research | 1 Comment

Better Nutrition, Better Brains

Posted on 5 July 2017 by Keith Barrington

I write frequently on this blog about how prejudice regarding developmental and neurologic problems, and prejudice about preterm infants, combine to over-emphasize the difficulties that former preterm babies have, to the extent that professional societies develop guidelines for withholding care to at-risk babies; based on outcomes that would never be considered grounds for withholding or withdrawing care in other areas of medicine.

Nevertheless, I am not blind to the increased problems experienced by preterm infants, from the mildly preterm to the most immature, and the need to do everything we can to mitigate those impacts.

One thing I often explain to my trainees is that during the 3rd trimester, the developing brain produces 250,000 neurones every minute. In addition to the development of the neuroglial substrate, the production and pruning of synapses and the on-going exquisitely fine structural development of the cortex, grey nuclei, and the connections between them that we call white matter.

In order to do all that you need a constant flow of nutrients, enough calories, enough amino acids in a reasonable proportion, fatty acids of the right type in reasonable proportions, minerals and trace elements, growth factors, and probably all sorts of other things that we know little about.

Good neonatal nutrition is not just a matter of calories, or total protein intake, but the best components also, for which we need much more research. At present we try to mimic intra-uterine weight gain (and often fail badly) but have little knowledge of the impact of our practices on the quality of growth, especially cerebral growth. And to be honest, we don’t know if human breast milk as a nutritional source, is the best way to try to mimic in-utero brain development, which normally works with a substrate of trans-placental supply of nutrients. That is probably quite different to the trans-intestinal supply of nutrients derived from fortified breast milk. On the other hand, I really don’t think that bovine milk derived products could possibly be better!

With this long preamble in mind, I wanted to introduce some recent articles that address these issues. The first is an abstract from the 2017 PAS-meeting which compared early neonatal nutrition among extremely preterm babies, and development of cerebral connections on term equivalent MRI. The changed abstract system for the latest PAS-meeting was a disaster, and it seems that the abstracts for all the recent years, since there was no longer a paper issue of Pediatric research with the abstracts in, are no longer available. Abstracts2view/PASALL and /PAS no longer function, which is a disastrous situation, if you ask me. So when I was trying to find this abstract and remembering that Steven Miller was one of the authors, I eventually found an enormous web page https://registration.pas-meeting.org/2017/reports/rptPAS17_Abstracts.asp that exists from the latest PAS-meeting (but not from the previous ones) and using a web page search (ctl-F) I finally found this badly formatted abstract, I’ll put the whole thing here so you don’t have to go searching for it:

Background: Background: Optimizing early nutritional intake in preterm neonates might enhance brain maturation and improve neurodevelopment. The relationship of energy and nutrient intake in the first weeks of life with brain growth during neonatal intensive care needs to be determined. Objective: Objective: To determine the association of early energy and nutrient intake with brain regional and total growth, and white matter maturation assessed by serial magnetic resonance imaging in very preterm (VPT) neonates. Design/Methods: Methods: 49 VPT (21 males, median[IQR] gestational age (GA): 27.6[2.3] weeks) were scanned serially at median postmenstrual weeks (PMA): 29.4, 31.7 and 41. Thalamus, basal ganglia, cerebellum and total brain were semi-automatically segmented in the T1-weighted images. Fractional anisotropy (FA) was extracted from the diffusion-tensor imaging (DTI) data using tract-based spatial statistics (TBSS). Nutritional intake from days of life 1 to 14 was collected. Multivariate linear regression and generalized estimating equations (GEE) for repeated measures were used to assess the association between nutrient intake and volumes, and FA values in separate models.Results: Results: In GEE models, greater energy [kcal/kg/d] and lipids [g/kg/d] intake predicted increased basal ganglia (?=29.7, p=0.002; ?=28.9, p=0.005, respectively) and total brain (?=776.5, p=0.036; ?=12824.9, p=0.019, respectively) volumes [mm3] over the course of neonatal intensive care to term age, adjusting for PMA, birth GA and sex. A similar association was found with carbohydrates intake and basal ganglia volume (?=12.1, p=0.043). Examining volumes at each scan, adjusting for PMA at MRI, the associations of energy and lipid intake with thalamic, basal ganglia, cerebellar and total brain volumes became increasingly robust on the second and third scans. Each 10-kcal/kg/d-energy intake increase in early life predicted a 2% increase in brain volume at term. Similarly, FA values in the posterior corona radiata and posterior thalamic radiations were significantly associated with early calories and lipid intake, both in linear regression and GEE models (all p<0.05).Conclusion(s): Conclusion: In VPT neonates, greater energy and lipid intake during the first two weeks of life predicted more robust brain growth particularly in subcortical structures and cerebellum, and accelerated white matter maturation. Optimizing early nutrition in VPT neonates warrants further attention as a potential avenue to improve brain health outcomes

There are clearly multiple limitations for a small observational study of this type, but it is nevertheless suggestive and consistent with other data. we shouldn’t be complacent about the period of poor nutrient intake, poor growth, and poor head growth that accompany that poor intake. The millions of lost neurones and disturbed cerebral maturation that occur during the first 14 days of life may have permanent impacts.

The second is a study from the CNN comparing head circumference growth (a reasonable indicator of brain growth, at least in terms of size) between birth and discharge and longer term follow-up, with neurodevelopmental outcomes. (Raghuram K, et al. Head Growth Trajectory and Neurodevelopmental Outcomes in Preterm Neonates. Pediatrics. 2017) They analyzed data from nearly 2000 babies of less than 29 weeks gestation, they divided the babies up into groups depending on changes of head circumference z-scores between birth and discharge from NICU, and between birth and follow-up at 16 to 36 months. Babies were born between april 2009 and september 2011. Sadly, 25% of babies dropped their head circumference z-scores by between 1 and 2 between birth and discharge and another 25% by more than 2. I say sadly, because this is avoidable, in our study of enhanced a nutritional protocol the mean head circumference z-score change from birth to discharge was about 0 (-0.1 to be exact). In this new CNN publication there is a clear association between loss of head circumference growth, the infants in the worst group of head growth between birth and discharge had double the Odds of having significant  developmental delay or neurological impairment (Bayley 3 motor, language or composite scores less than 70, or CP with a GMFCS <2).  Catch up growth of the head after discharge did improve things a little, but not back to the original potential (if I over-interpret the results correctly).

The third is a study just examining a change in nutritional practice and growth outcomes. Not dissimilar to our publication of 4 years ago, then demonstrated that post-natal growth can be improved, to be similar to intra-uterine standards with little postnatal growth delay. Genoni G, et al. Non-randomised interventional study showed that early aggressive nutrition was effective in reducing postnatal growth restriction in preterm infants. Acta Paediatr. 2017  However they still overall had a loss of head circumference from a mean of 0.14 at birth to a mean of -0.78 in the group with the improved nutrition. In their ELBW population there were still very many infants who started with a birth weight above the 10th %le, but were discharged below the 10% percentile 70% with their new protocol, compared to 90% with their old protocol.  This is better than some results, but could be substantially better. Early nutritional intakes can be pushed up faster, than this group do, with a quicker increase in glucose, and perhaps starting lipids at much higher doses immediately after birth. To avoid catabolism we need to achieve over 70 kcal/kg/d as soon as possible after birth, to achieve reasonable growth 100 kcal/kg/d intravenously, and 3.5 g/kg/d of good quality protein are needed as quickly as that can be achieved. Enteral needs are of course higher, at 120 kcal/kg/d and 4 g of protein (maybe 4.5). Focusing on nutrition every day, even when the babies are critically ill can avoid much post-natal growth restriction, and it leads to bigger babies with bigger cerebellums.

Paviotti G, et al. Higher growth, fat and fat-free masses correlate with larger cerebellar volumes in preterm infants at term. Acta Paediatr. 2017;106(6):918-25.  42 VLBW babies were assessed with body composition measures and MRI at 40 weeks, and basically they showed what it says in the title, bigger babies had bigger ‘little brains’. As far as I can see from the limited data presented about total cerebral volume, daily weight gain from birth to term age also was correlated with the size of the entire brain.

Adequate quantities of nutrition and appropriate quality can dramatically reduce postnatal growth restriction, and if we pay enough attention to it, can probably eliminate it. The first couple of weeks are vitally important, and I don’t think we can overcome several days of undernutrition by trying to catch up later. Finding ways to improve fat-free growth and brain growth should be priorities for future.

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New insights on intraventricular haemorrhage

Posted on 19 June 2017 by Keith Barrington

A fascinating new study has been published (Tortora D, et al. Differences in subependymal vein anatomy may predispose preterm infants to GMH–IVH. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2017) looking at cerebral venous anatomy as shown by an MRI trick that I didn’t know about, which is something called susceptibility weighted imaging, or SWI, venography. Using this technique they could map out the venous drainage of the germinal matrix region in former VLBW (<1500 g birthweight) preterm infants when they reached term equivalent age.

You can see some of these interesting images below, they show an image A with the veins labelled, and image B with an angle measured which is called the curvature index, and an illustration in image C one of the two main findings of the study, that babies who had an intraventricular or germinal matrix hemorrhage had an increased curvature of the vein draining into the internal cerebral veins, which is either the thalamostriate vein (the classical pattern) or the direct lateral vein (a fairly common variant).

The other finding was that any of the several anatomic variants were associated with an increased risk of hemorrhage* (although they were also quite common among babies without bleeds). Also the variants weren’t necessarily always symmetrical (as in image A above), in the 14 infants with unilateral bleeds, the venous anatomy on the affected side was characterised by presence of anatomical variations in 12/14 cases. In the contralateral normal hemispheres, they found the classic normal pattern in 13/14 cases.

It is fairly obvious that the neuroradiologists evaluating the anatomy and the venous curvature could easily see the hemorrhages, and cold therefore have been biased, but I think the data are fascinating and suggest that minor abnormalities of venous anatomy could lead to venous congestion in the brain of the preterm infant, and predispose to cerebral injury.

I think it’s great that simple basic findings like this (although they require amazing technology and good quality research) can still be discovered, even after we’ve been looking after preterm babies and worrying about IVH for so many years.

I also think it is an appropriate use of pre-discharge MRI in former very preterm babies, research which increases our understanding and helps to give ideas on how we might improve outcomes.

__________________

*As many of you will have noticed my spelling is rather erratic, sometimes American, sometimes UK and sometimes Canadian (which is a mix of the others, but gradually becoming more Americanis(z)ed). Some words always look to me more scientific when you use the older UK, Latin and Greek derived, spellings (which I know isn’t true); like haemorrhage or oesphagus. Often I just forget which is which, like who hospitalises and who hospitalizes with a z (thats a zed, not a zee).

 

 

 

 

 

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Not just neonatology: trip to Buenos Aires

Posted on 5 June 2017 by Keith Barrington

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

Posted on 25 May 2017 by Keith Barrington

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

Posted on 25 May 2017 by Keith Barrington

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

Posted on 25 May 2017 by Keith Barrington

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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