Weekly updates #26

Posted on 14 March 2013 by Keith Barrington

Richburg DA, Kim JH: Real-time bowel ultrasound to characterize intestinal motility in the preterm neonate. J Perinatol 2013. You can quantify intestinal motility with bed-side ultrasound. Neat. Now we need to know what to do with the information, sounds like Jae Kim is already looking into that.

Boss RD, Urban A, Barnett MD, Arnold RM: Neonatal critical care communication (nc3): Training nicu physicians and nurse practitioners. J Perinatol 2013. This is addressing a real need, how to teach neonatal health care providers to talk to parents. It sounds like they have a good system, the trainees felt more comfortable, and used the skills taught frequently. What we don’t know is whether the parents were better informed, felt more comfortable etc.

Cremer M, Weimann A, Szekessy D, Hammer H, Buhrer C, Dame C: Low immature platelet fraction suggests decreased megakaryopoiesis in neonates with sepsis or necrotizing enterocolitis. J Perinatol 2013. So where do the platelets go to? It happens quite often that the platelet count gets very low during sepsis or NEC, this study suggests that they aren’t being consumed, rather, usually they are not being produced. I don’t know if my lab can measure this feature of the platelets, it sounds a bit complex, but then most of what they do in the lab sounds complex to me.

Slaughter JL, Stenger MR, Reagan PB: Variation in the use of diuretic therapy for infants with bronchopulmonary dysplasia. Pediatrics 2013. This database study looks at diuretic use in infants with BPD. There are enormous differences, ranging from a hospital that gives about 62% of the babies occasional short courses of less than 5 days, but rarely gives more than 5 days, to one hospital where over 80% of the babies get both long and short courses. I guess as usual that means we need some good data.

Posted in Neonatal Research | Leave a comment

Losing a twin

Posted on 13 March 2013 by Keith Barrington

Vasilescu C, Garel M, Caeymaex L: [experience of parents after the loss of a newborn twin in the nicu: A qualitative study 3 years after the death.]. Archives de pediatrie. 2013(0). This is a nice qualitative study, with a reasonable sample size of 26 parents, (15 mothers and 11 fathers) who lost a twin in the NICU, while the other survived. How do they live that experience? The article is in French, and I think it is probably unique in the literature. I am sometimes a bit cynical about qualitative studies, but this is the type of thing that you can’t do any other way, and which can be really important.

I reproduce the final conclusions below, with a translation beneath that if you don’t parler.

Entre la perte d’un singleton et d’un enfant jumeau, la question n’est pas la différence d’intensité de la tristesse des parents, mais plutôt la coexistence de sentiments très
forts : joie et tristesse, espoir et désespoir, investissement et détachement. Pendant l’hospitalisation et au cours d’un suivi ultérieur, les soignants doivent pouvoir entendre les
parents évoquer ces sentiments contradictoires qui les assaillent. On peut alors espérer que les parents se sentent soutenus dans le processus qui leur permet d’intégrer la
perte, d’investir l’enfant en vie, de faire en sorte que les représentations des enfants s’emmêlent le moins possible et que dans l’histoire familiale, la place de chaque enfant
soit préservéeé.

”Between the loss of a singleton and of a twin, the question is not the difference in intensity of the parents grief, but rather the co-existence of very strong emotions: joy and sadness, hope and despair, investment and detachment. During the hospitalization and subsequent follow up, carers must be able to listen to the parents expressing these contradictory feelings. It is to be hoped that the parents feel supported in a process which allows them to come to terms with their loss, to invest in the living child, to find a way that the images of the two infants become confused as little as possible, and that in the story of the family the place of each child is preserved.”

There aren’t many studies of what happens to parents after a neonatal death, but Dr Caeymaex has been publishing in this area. It is understandably a little tricky to do this kind of research, but it can really help us to find out how to give the best care to families. One of the groups previous publications was in PLoS one, which is nice because it is free access, but unfortunately, probably didn’t get the attention it deserved, as not many people I know read PLos one (I don’t either!). This is one of the very few times that parents have been followed after an end-of life decision was made. That one is in English, Caeymaex L, Speranza M, Vasilescu C, Danan C, Bourrat MM, Garel M, Jousselme C: Living with a crucial decision: A qualitative study of parental narratives three years after the loss of their newborn in the nicu. PLoS One 2011, 6(12):e28633. It gives some guidance based on the parent interviews:

‘The physicians’ attitudes that were perceived as helpful in the long term were explicit sharing of responsibility, clear expression of staff preferences, and respectful care and language toward the child.’

I am against a one size fits all approach, but I think those sort of general guidelines are indeed generally applicable. The clear expression of staff preferences I think needs some modulation, to avoid being coercive, once you say that ‘everybody here thinks that we should do A’, then that leaves little room for the parents values to be expressed.

The interpretation section of the abstract is nicely put: ‘Parents find it valuable to express their opinion in the end-of-life decision making process of their child. Nonetheless, they do need continuous emotional support and an explicit share of the responsibility for the decision. As involvement preferences and associated feelings can vary, parents should be able to decide what role they want to play. However, our study suggests that fully autonomous decisions should be misadvised in these types of tragic choices’

Posted in Neonatal Research | Tagged , , | Leave a comment

Oh No; not renal dose dopamine again!

Posted on 13 March 2013 by Keith Barrington

This is the sort of thing that really irritates me: If you report ‘we did X, and Y happened’ the obvious question should be, ‘what would have happened if you didn’t do X?’

That is called having controls! It is the basis of all science! I am using too many exclamation marks!

So if you take normotensive preterm infants with a low urine output, and give them low dose dopamine, the urine output increases. SO WHAT! (exclamation marks and all capitals, not good scientific blogging technique, but I am a bit irritated by this publication)

(Crouchley JL, Smith PB, Cotten CM, Hornik CD, Goldberg RN, Foreman JW, et al. Effects of low-dose dopamine on urine output in normotensive very low birth weight neonates. J Perinatol. 2013)

I can tell you from simple first principles of common sense, that if you take normotensive preterm infants with  low urine output and DON’T give them dopamine, then their urine output increases! If you further analyze the data, then the lower the urine output before not giving dopamine, the greater the increase when you don’t give them dopamine.  That is called regression to the mean.

I think there are many good reasons to report case series, and there are many things we can learn from them, but to report something that we already know is done without good supporting evidence, that has been proven ineffective in older patients in randomized trials, that has no good physiological evidence to support it, helps no one.

To recap those points, there are systematic reviews in pediatrics and in adult intensive care that show no evidence of renal protection from low dose dopamine infusion. There are multiple studies in neonatal mammals which show that the renal vascular dopamine receptors are present, but stimulating them has no effect in the perinatal period. Dopamine receptors (and there are many) are G-Protein linked receptors, and it appears that the renal vasodilatation that you can get from dopamine stimulation of these receptors is absent in the neonatal period, even though the receptors are present (at term at least, probably) and the G proteins are present, the link between them appears to be inactive. Even when it is present, as in healthy older patients and adults, there is no evidence that stimulating the dopamine receptor produces clinical benefit in the critically ill.

On the other hand we know that low-dose dopamine suppresses the pituitary, and specifically the production of TSH, so the longer you give dopamine, the lower the activity of the thyroid. Prolactin, in addition (even though I don’t know how important it is in a newborn infant), is completely suppressed by dopamine administration.

Dopamine also depresses respiratory drive. Dopamine receptors in the carotid body, when stimulated by dopamine, decrease their output which projects on respiratory control centers. So you can induce apnea in newborn lambs when you give them dopamine. (Don’t try and find that in the literature, I did the study in the lab of Jim Fewell in Calgary when I was a new staff in Edmonton, but I never published it, to my shame. It was quite dramatic, when I started the dopamine the lambs immediately stopped breathing, and then after a long pause started breathing periodically, within a few seconds of stopping the dopamine infusion they started breathing regularly again). Other data which is actually published also shows the respiratory depression with dopamine.

If someone wants to show whether there is an effect of low dose dopamine on urine output, you have to have controls! And in fact is has been done… Cuevas et al published in 1991 one of the very few studies of a catecholamine compared to no treatment. In a small study with 3 groups, they showed that with no dopamine urine output increased  to 4.8 mL/kg/h. With either of the 2 doses of dopamine that they used the urine output increased less! (to 3.8 mL/kg/h with 1 mcg/kg/min, and to 3.2 with 2.5 mcg/kg/min).

The only thing which they report as being significant was that the lower dose group, but not the higher dose, had higher fractional excretion of sodium, but as they used uncorrected t-tests to compare the data in the 3 groups, and they compared 7 different renal variables at 3 time points, it is hardly surprising that something was ‘significant’.

To re-iterate there is no evidence that low dose dopamine has any beneficial effects, neither on the kidney nor on other organs, and this new publication does not change that.

Posted in Neonatal Research | Tagged , , | 3 Comments

Weekly Updates #25

Posted on 28 February 2013 by Keith Barrington

The postings have been light the last 3 weeks. With 2 periods of service and between them a trip to San Francisco for an NIH workshop, for which I have to author a review article, (and co-author 2 others) as well as 3 or 4 other things I have to finish writing, there has been little time left for my ‘hobby’. But fear not! I continue to survey the literature for whatever I think is interesting, and will catch up with some new ideas and new scribblings over the next few weeks.

O’Hare FM, Watson RWG, Molloy EJ: Toll-like receptors in Neonatal Sepsis. Acta Paediatrica 2013. If you are like me, you have heard about these things, but don’t know much about them. Maybe its because they hadn’t been discovered 35 years ago when I was in Med School, but then neither had surfactant and I know a lot about that. In fact I think they had only just figured out oxygen… anyway this is a clearly written and understandable introduction to these receptors that we may be trying to manipulate directly in the future.

Shen CM, Lin SC, Niu DM, Ru Kou Y: Development of monocyte toll-like receptor 2 and toll-like receptor 4 in preterm newborns during the first few months of life. Pediatr Res 2013. At the same time this article points out how little we know about the development of the TLRs and provides new data about 1 cell type.

Rautava S, Collado MC, Salminen S, Isolauri E: Probiotics modulate host-microbe interaction in the placenta and fetal gut: A randomized, double-blind, placebo-controlled trial. Neonatology 2012, 102(3):178-184. 43 pregnant women were randomized to receive probiotics or placebo before they had a cesarean section at term. Probiotics were either bifidobacteria in 1 group, or B lactis plus a lactobacillus in another group. They found lactobacillus in all the placentas, including the controls! They also found bifidobacteria in some, and they found differences in toll like receptor modulation between the groups. Don’t know exactly what this means, but it seemed like a theme was developing for this weeks updates!

And now for something completely different…

Gandhi B, Rich W, Finer N: Achieving targeted pulse oximetry values in preterm infants in the delivery room. The Journal of pediatrics 2013(0). Neil Finer and his group (especially Wade Rich) have been instrumental in helping us figure out what happens to oxygen saturation in the first few minutes of life, and in trying to study how to resuscitate small babies better. This study studied the use of a system they have developed to track saturations, a system which gives a graphic display of whether you are in the right range. They found that using the system enables you to keep the baby in that range more of the time.

Posted in Neonatal Research | 1 Comment

A life of quality

Posted on 28 February 2013 by Keith Barrington

Saroj Saigal has just published a very important review of long term quality of life of former preterm infants. As you can imagine, as she originated this area of study for the preterm, it is clearly written and thoughtful. (Saigal S: Quality of life of former premature infants during adolescence and beyond. Early Human Development 2013). She describes how QoL is conceptualized, how it is measured and the differing constructs behind the different scales.

Some of you will know that the CPS has released a new position statement on counseling mothers before threatened preterm delivery. I am writing a series of posts about that statement, but as a “taster”… the position statement says next to nothing about quality of life, which is strange for a statement which is supposed to be about ethical principles.  What it does say is the following “A few small studies have followed infants < 1000 grams birthweight through to adolescence and adulthood, but these may not be representative of the wider population. … no differences in self-esteem or self-perceived health-related quality of life were found.”

In fact the “few small studies” that this position statement refers to have been the biggest advance in describing the outcomes of very preterm infants. When a systematic review was published in 2008 Zwicker and Harris found 15 studies. Since then there are at least another 20 studies that have been published. Some of them are regional or population based studies some of them are hospital based cohorts, most have had remarkably good retention rates for the very long term follow up that they report.

I don’t see how all that can be dismissed as “may not be representative”

These studies all note similar findings, that quality of life as reported by the children/adolescents/adults themselves is either indistinguishable from controls, or slightly worse than controls. When children who are too impaired to answer for themselves are included, and usually it is the parents who are the proxy respondents in those studies, then the QoL scores are slightly lower than controls. When medical staff describe the QoL of the infants, in contrast, what has been referred to, I think inaccurately, as “objective QoL”, the scores of the former preterm infants are lower, especially those with impairments.

Dr Saigal ends the review with 3 major teaching points:

Research has shown that it is possible for children and adolescents to provide unique and reliable information about their own QoL. This information can only be obtained from the individual concerned.

It is important for the medical community to accept, that even if the stated QoL is at odds with the objective assessment by a clinician, it is the perception of the affected individual that should take priority.

Self-reported QoL provides important complementary information to the traditional medical outcomes, and despite their subjective nature, they can be extremely useful in tailoring the care of patients based on their perceived needs.

and she makes 3 recommendations, one of which I reproduce here

QoL measures should be integrated in clinical trials, in long-term outcome of children with disabilities and chronic health conditions, and in treatment decisions on whether to offer intensive care

I agree.

Posted in Advocating for impaired children | Tagged , , | 1 Comment

Bloody Stools

Posted on 27 February 2013 by Keith Barrington

It is not infrequent in the neonatal unit to be faced with an infant who has rectal bleeding. In some places the tendency has been to assume that the infant has cows milk protein intolerance (even among those who are breast fed!) and place the infants on a hydrolysed protein diet or even on an amino acid based diet. What is the evidence for the diagnosis and treatment of cows milk protein intolerance in the preterm, or term newborn?

There are very few reports of cow’s milk protein intolerance in the preterm infant. Even those that have reported have not usually confirmed the diagnosis, but how to do that? There are two methods which have been reported as being reliable, although their reliability is uncertain as we do not have a gold-standard. The most commonly used is response to exclusion of cow’s milk protein, but this must be followed by a challenge; the re-introduction of cow’s milk to see if the signs return and, if they do, the re-exclusion to make sure they go away again. If you don’t do the challenge then any case of transient clinical signs will be mis-diagnosed as cow’s milk protein intolerance.

One study in older infants found 2 things, (Xanthakos SA, Schwimmer JB, Melin-Aldana H, Rothenberg ME, Witte DP, Cohen MB: Prevalence and Outcome of Allergic Colitis in Healthy Infants with Rectal Bleeding: A Prospective Cohort Study. Journal of Pediatric Gastroenterology & Nutrition 2005, 41(1):16-22) firstly, most pediatric gastroenterologists don’t follow their own societies guidelines, and don’t do a challenge if a child presents with rectal bleeding that improves after exclusion. Which means that many infants end up with a diagnosis that has not been confirmed. Secondly, they also showed that using the other method of diagnosis, that is doing a rectal biopsy, less than half of the infants with rectal bleeding actually had evidence of allergic colitis.  Another study, (Arvola T, Ruuska T, Keränen J, Hyöty H, Salminen S, Isolauri E: Rectal Bleeding in Infancy: Clinical, Allergological, and Microbiological Examination. Pediatrics 2006, 117(4):e760-e768) also in infants, noted that rectal bleeding was benign and self-limited, and despite rectal biopsies etc, were able to confirm the diagnosis in only 7 of 40 consecutive cases of rectal bleeding. Interestingly they noted a low number of bifidobacteria in the stools of the infants, suggesting that an imbalance in the microbiota may play a rôle.

Even a test as invasive as a biopsy is not certain, the findings of patchy eosinophilic colitis is supposed to be diagnostic, but the cause of the allergic colitis cannot be determined from the biopsy. As it may be found in infants who are exclusively breast-fed, even among those whose mother is on a cows milk free diet, the diagnosis of human milk protein allergy has been created. Which I find very doubtful! What is the evidence that human milk may contain cows milk proteins if the mother consumes them? Well the most common protein implicated is bovine beta lactoglobulin, in one older study one third of mothers consuming cows milk based products had detectable traces of bovine BLG in their breast milk. So it is possible that these trace amounts might trigger symptoms. That study also found that breast fed babies with signs of cows milk protein intolerance had all received supplements with a cows milk based formula in the neonatal period.

For full term infants does it matter if they have a diagnosis of cows milk protein intolerance which is not correct? It is actually pretty straight forward to find nutritionally adequate hydrolyzed protein formulae for the full term infant. (Not soy protein based formulae; a lot of infants proven to be intolerant of bovine proteins are also intolerant of soy proteins). On the other hand they are more expensive, and not all kids will tolerate even them; but amino acid based mixtures are much more expensive. Also bovine protein exclusion diets are a real pain for mothers who are breast feeding, and some of them are inappropriately discouraged from breast feeding. Having a diagnostic label that is incorrect is not the best situation, but some parents are happy to buy hydrolysed protein formulae, accept that the diagnosis is not certain, and live with that uncertainty for a few months, (more than half of proven cows milk protein intolerance disappears in the first year).

For preterm infants the situation is different, there are no artificial milk formulae which are nutritionally adequate for the preterm and yet are free of bovine proteins. So a diagnosis in the preterm has other implications for their nutrition. In addition all approved and appropriate fortifiers which are required to add protein, calories and minerals to  human milk are based on cow’s milk.

So going back to the diagnosis of bloody stools, and now looking at the neonatal period, a recent study using new microarray methods found that newborn infants with rectal bleeding did not have findings consistent with allergy. (Ohtsuka Y, Jimbo K, Inage E, Mori M, Yamakawa Y, Aoyagi Y, Suzuki M, Kudo T, Suzuki R, Shimizu T: Microarray analysis of mucosal biopsy specimens in neonates with rectal bleeding: Is it really an allergic disease? Journal of Allergy and Clinical Immunology 2012, 129(6):1676-1678.) Other studies have found weird viruses in the stools of such babies (Chappé C, Minjolle S, Dabadie A, Morel L, Colimon R, Pladys P: Astrovirus and digestive disorders in neonatal units. Acta Paediatrica 2012, 101(5):e208-e212). I have certainly seen rectal bleeding associated with rotavirus in more than one preterm infant.

Rectal bleeding may also occur in the setting of strictures, either congenital strictures or post enterocolitis. This is probably the most common cause of rectal bleeding in the preterm after NEC, and is often misdiagnosed, often as cows milk protein intolerance. 

In fact there is evidence that the pre-term period is a time when exposure to foreign proteins is more likely to lead to tolerance than to allergy. There is certainly no evidence of an increase in allergic diseases among preterm infants. There are a couple of large cohort studies showing a similar, and relatively low rate of allergic diseases, and specifically cows milk protein intolerance, among preterm infants to term infants. (Zachariassen G, Faerk J, Esberg BH, Fenger-Gron J, Mortensen S, Christesen HT, Halken S: Allergic diseases among very preterm infants according to nutrition after hospital discharge. Pediatric allergy and immunology 2011, 22(5):515-520.)

In general then a baby in the NICU who has rectal bleeding is more likely to have something other than cows milk protein intolerance, and it becomes even less likely to be that diagnosis if the infant is preterm, and very much less likely if they are breast fed.

Posted in Neonatal Research | Tagged | 5 Comments

Weekly Updates #24

Posted on 24 February 2013 by Keith Barrington

Stutchfield PR, Whitaker R, Gliddon AE, Hobson L, Kotecha S, Doull IJM: Behavioural, educational and respiratory outcomes of antenatal betamethasone for term caesarean section (ASTECS trial). Archives of Disease in Childhood – Fetal and Neonatal Edition 2013. Caesarean delivery, even at term, leads to more respiratory problems than vaginal delivery. This is particularly the case when slightly early, at 37 and 38 weeks gestation. Transient tachypnea of the newborn, hyaline membrane disease and pulmonary hypertension are all more frequent. The ASTECS trial published in 2005 showed in a multicenter RCT that respiratory morbidity was reduced by 50% when antenatal betamethasone was given for 48 hours before elective caesarean delivery at term. There were 1000 mothers in the original trial, unfortunately they were only able to collect childhood follow up data on 407 of the babies. But they found no evidence of any adverse effect of the steroids. I think the better solution is not to do elective caesareans before 39 weeks. But if for some reason you have to, then it looks like betamethasone might be worth discussing with the mother.

Ohlsson A, Jacobs SE: NIDCAP: A Systematic Review and Meta-analyses of Randomized Controlled Trials. Pediatrics 2013. There are several varieties of “developmental care” the original, NIDCAP, has been the most studied, but as noted in the discussion of this systematic review includes many untested features, and is “resource-consuming, labor intensive and expensive”. This systematic review was unable to find reliable evidence that long term neuro-developmental outcomes are improved, or short term medical outcomes. Hospital stay is shorter, by an estimated 6 days in overall. There are not a large number of babies studied, in the 2 largest trials, which were of good quality, there are a total of only about 200 infants. I think that a greater sensitivity to the preterm infants behavior and trying to disturb them less, recognizing signs of stress, are good things to do. The overall NIDCAP program though has not been shown to have clinically important benefits.

El-Khuffash AF, Jain A, McNamara PJ: Ligation of the Patent Ductus Arteriosus in Preterm Infants: Understanding the Physiology. The Journal of pediatrics 2013(0) Very well written review article about the effects of PDA ligation in the preterm infant. I do have some issues with the suggested algorithm at the end, which proposes using drugs that are not known to have any beneficial effects in the preterm infant (such as milrinone, which is stated to be a vasodilator that improves contractility, there is no evidence that it increases contractility in the preterm infant, it may well not do so). I think the hemodynamic complications that he describes are ripe for investigation. The algorithm he described could well be prospectively studied.

Posted in Neonatal Research | Leave a comment

Post hemorrhagic hydrocephalus: when to drain the ventricles

Posted on 22 February 2013 by Keith Barrington

A new editorial from Linda de Vries, (de Vries LS, Brouwer AJ, Groenendaal F: Posthaemorrhagic ventricular dilatation: When should we intervene? Archives of Disease in Childhood – Fetal and Neonatal Edition 2013.) comments on an article which has been available on-line for a couple of months. The title poses a question that many of us have struggled with. I have reviewed the data from the CNN, (and am trying to find time to write the article) which shows huge variation in the proportion of babies in different NICUs with hydrocephalus who get shunted. The article that triggered the new editorial was a study of neurophysiological recordings (flash evoked visual potentials and amplitude integrated EEG), in infants who were developing PHVD (Klebermass-Schrehof K, Rona Z, Waldhor T, Czaba C, Beke A, Weninger M, Olischar M: Can neurophysiological assessment improve timing of intervention in posthaemorrhagic ventricular dilatation? Archives of Disease in Childhood – Fetal and Neonatal Edition 2012.)

That article showed, in 17 cases of very preterm infants who had PVHD which had reached the 97th percentile, that wave latencies on the evoked potentials and aEEG suppression were both increased. When the infants had shunts inserted these features returned to normal.

The standard indication (as I noted above there is no real standardization here) is to intervene when the ventricular width is more than 4 mm above the 97th percentile, this threshold arose somewhat arbitrarily in the 1980’s, and provides a benchmark against which to compare other approaches. Ten of the patients in this new study were below that cut off, yet still showed the neurophysiologic changes, with the evoked potential changes being more reliably affected.

Dr de Vries editorial was written to address the specific issues in the Klebermass article, she notes that they have not consistently found the same aEEG changes in her unit, but that they have noted prolongation of the visual evoked potential wave latencies.

A recent more complete review article by Andy Whitelaw (Whitelaw A, Aquilina K: Management of posthaemorrhagic ventricular dilatation. Archives of Disease in Childhood – Fetal and Neonatal Edition 2012, 97(3):F229-F223.) addressed many other issues. One of which was to note that clinical signs of intracranial hypertension may be absent even when the intraventricular pressure is raised, and that other measures such as doppler resistance index calculation may be preferable.

We will hopefully soon have better information on which to base our interventions, the European study called ELVIS (early versus late ventricular intervention study) is an RCT comparing intervention at the standard threshold that I have described (which is the ‘late arm) to intervention once the ventricles are over the 97th percentile. Until those results are in it looks like visual evoked potentials may give us some idea of which babies have cerebral dysfunction from their PVHD.

Posted in Neonatal Research | Tagged , | Leave a comment

Weekly Updates #23

Posted on 19 February 2013 by Keith Barrington

Arboleya S, Binetti A, Salazar N, Fernández N, Solís G, Hernández-Barranco A, Margolles A, de los Reyes-Gavilán CG, Gueimonde M: Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiology Ecology 2012, 79(3):763-772.
These Spanish investigators surveyed the intestinal microbiome of 10 full term breast fed, vaginally delivered newborns sequentially over 3 months of life, and compared this to 21 preterm infants many of whom had antibiotics, and who were born between 30 and 34 weeks. The patterns were different, particularly there were fewer bifidobacteria in the preterms, this work is more quantitative and over a more prolonged period than previous similar studies.

Collado MC, Delgado S, Maldonado A, Rodríguez JM: Assessment of the bacterial diversity of breast milk of healthy women by quantitative real-time pcr. Letters in Applied Microbiology 2009, 48(5):523-528. This is a slightly older study that I just saw. The breast milk of healthy women was studied, they found a lot of stuff by PCR, including in 100% of the samples, bifidobacteria and lactobacilli!

Keski-Nisula L, Kyynäräinen H-R, Kärkkäinen U, Karhukorpi J, Heinonen S, Pekkanen J: Maternal intrapartum antibiotics and decreased vertical transmission of lactobacillus to neonates during birth. Acta Paediatrica 2013. When mothers get antibiotics, it kills their lactobacilli. So the babies don’t get them. Lactobacilli are good bugs, we should try not to kill them.

All of which makes me think of the Oracle II trial; a large multicenter trial of antibiotics for preventing premature delivery in mothers presenting with preterm labor without PROM and without signs of infection. Most of the mothers eventually delivered after 37 weeks, so there wasn’t a big group of preterm infants at risk for NEC. William Tarnow-Mordi reminded me recently that there were twice as many cases of NEC per 100 babies when the mother received antibiotics as when she received placebo. This wasn’t statistically significant, but is suggestive, giving antibiotics to the mother messes up her flora, changes what she can pass on to the baby and so increases the chance of developing NEC.

Christmann V, Visser R, Engelkes M, de Grauw AM, van Goudoever JB, van Heijst AFJ: The enigma to achieve normal postnatal growth in preterm infants – using parenteral or enteral nutrition? Acta Paediatrica 2013. This I don’t understand. The group in Nijmegen in the Netherlands, including Jan van Goudoever and others have shown repeatedly that preterm babies can tolerate intravenous amino acids at 2.4 or even 3.5 g/kg/d right from birth, and are in an anabolic state if they receive that. They now present a comparison of 2 cohorts from their own NICU where they changed the nutritional protocols. In the new enhanced protocol, the babies start on ….0.75 g/kg/d of amino acids, and increase over the next 3 days to a maximum of 3. Cohort 1 (from 2004) started at 0.5 and reached a maximum intake of 2.5 g/kg/d, and they took a week to get to nearly adequate calories of 92 kcal/kg/d. Not surprisingly the infants overall grew poorly, progressively falling off their growth curves. As I said I don’t understand, why the nutrition protocol is this limited in a center who have been world leaders in research in this area.It is possible to do better than this.

Sanders RC, Jr., Giuliano JS, Jr., Sullivan JE, Brown CA, 3rd, Walls RM, Nadkarni V, Nishisaki A, for the National Emergency Airway Registry for Children I, Pediatric Acute Lung I, Sepsis Investigators N: Level of trainee and tracheal intubation outcomes. Pediatrics 2013. intubation success in the PICU is no better than in the NICU for junior trainess. Critically ill patients are not the place for trainees to learn techniques, not now that we have alternatives.

Posted in Neonatal Research | Leave a comment

How long is a piece of string? When is a PDA hemodynamically significant?

Posted on 16 February 2013 by Keith Barrington

The answer to the first question is traditionally ‘twice as long as half a piece of string’ which is supposed to be funny.

Equally difficult is the second question, when is a patent ductus arteriosus (PDA)  hemodynamically significant? We could answer ‘when there is too big a shunt’ but that also begs the question, how big is too big, and how do we measure it accurately. But is that what is really important about a PDA, is the size of the shunt the most important factor? So what is a clinically significant PDA? In the past we have treated the ductus if we thought by doing so we could reduce the risk of adverse outcomes, in particular BPD. The problem with that is that although there is a correlation between the development of BPD and having had a PDA, there is no good evidence that any treatment of the PDA reduces the risk of BPD.

A systematic review of definitions of what is a hemodynamically significant PDA was published in 2011. Those authors found that was no consistency in definitions of hemodynamic significance, sometimes it was based on clinical findings, sometimes on echocardiographic features and those echo features were very variable. Even when the same index was used (most commonly the LA:Ao ratio) the threshold for significance was inconsistent. This means of course that you cannot compare the results of the various trials. Most often in fact, no definition was given in the articles they reviewed.

A new study from Monash in Melbourne has tried to answer some of these questions. The authors compared the echocardiographic data they have recorded, from an extensive standardised evaluation of the PDA performed within the 48 hours prior to the first treatment with ibuprofen, between infants who did and did not develop BPD.  (Sehgal A, Paul E, Menahem S: Functional echocardiography in staging for ductal disease severity : Role in predicting outcomes. Eur J Pediatr 2013, 172(2):179-184). Their scoring system includes items for size of the duct, size of the shunt, and impact on left ventricular function.

All of the  individual items in the scoring system were significantly different between those infants who developed BPD and those who did not, except for left ventricle to Aortic root ratio.

The authors showed a progressively increasing risk of developing BPD with increasing scores, and a pretty good predictive function of the score. I think this is really useful information; if you have a bigger PDA with more shunt, and the left ventricular function is more affected by it, then you are more likely to develop BPD. It has never been clear whether the statistical association between PDA and BPD was causative in any way, this new data suggests that it might be, and perhaps only among those with the PDAs that have larger shunts.

We could use this sort of assessment as the basis for clinical trials of PDA treatment.

Posted in Neonatal Research | Tagged , , | 1 Comment