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.

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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.

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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.

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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.

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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.

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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.

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The acid test

Posted on 7 February 2013 by Keith Barrington

As well as avoiding putting anything untested in the intestinal tracts of preterm babies, we should also leave alone their intestinal function. My good friend Sanjay Patole has published, with his group of systematic reviewers in Perth, a review of the effects of gastric acid secretion blockers on the incidence of NEC. There were only 2 informative studies found, both focusing on histamine receptor blockers, and the analysis showed a substantial association between the use of this class of agent in the preterm and the occurrence of necrotising enterocolitis. Both the studies were observational, one case control, one  a prospective cohort. The size of the effect differed greatly between the 2 studies, which is not surprising for 2 observational studies especially with a different structure, but the effect size was substantial in each of the studies. More K, Athalye-Jape G, Rao S, Patole S: Association of inhibitors of gastric acid secretion and higher incidence of necrotizing enterocolitis in preterm very low-birth-weight infants. American journal of perinatology 2013(EFirst).

Gastric acid is there for a reason, as well as aiding in digestion it kills a lot of ingested organisms, so blocking it increases infection risk, and, as for NEC, presumably permits colonization with more pathogenic bacteria involved in the pathophysiology of NEC, but it is possible that other adverse effects of histamine receptor blockade are involved also.

A reminder that other adverse effects of acid blockade are systemic infections, (also see here) and increased mortality. They also seem to interfere with absorption of calcium, iron and vitamin B12. In older infants histamine blockers cause agitation and headache, PPI agents increase chest infections in asthmatic children, and they do not improve apnea or bradycardia in preterm infants, nor improve symptoms of GER in older infants.

So before blocking acid production we should really think of what clinical benefits we expect to counterbalance these known adverse effects… which sounds a lot like just good basic medical principles to me.

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Weekly Updates #22

Posted on 6 February 2013 by Keith Barrington

Milstone AM, Elward A, Song X, Zerr DM, Orscheln R, Speck K, Obeng D, Reich NG, Coffin SE, Perl TM et al: Daily chlorhexidine bathing to reduce bacteraemia in critically ill children: A multicentre, cluster-randomised, crossover trial. Lancet 2013(0). Nearly 5000 Children more than 2 months old who were admitted to the PICU for more than 2 days were randomized to either get a bath with chlorhexidine every day (or being wiped all over with a chlorhexidine cloth) or control. Actually it was the ICUs that were randomized and had periods with and without chlorhexidine. There was an almost significant reduction in sepsis with the ITT analysis, and a just significant reduction with the ‘actually treated as they were supposed to be according to the way they were randomized’ analysis. An accompanying editorial (Toltzis P, Goldmann D: Rethinking infection prevention research. Lancet 2013(0). Suggests that such trial should be done only when all the quality control initiatives have reduced central line infection rates to minimal levels. I am not so sure; despite the best efforts using evidence based interventions currently there are still substantial variations between hospitals. We need further evidence based interventions and good trials to show us what to do next.

Chong E, Reynolds J, Shaw J, Forur L, Delmore P, Uner H, Bloom BT, Gordon P: Results of a two-center, before and after study of piperacillin-tazobactam versus ampicillin and gentamicin as empiric therapy for suspected sepsis at birth in neonates <1500g. J Perinatol 2013. I think this is a Very Bad Idea. Giving broad spectrum antibiotics that are not indicated to infants with negative cultures for reasons that are questionable (one of the reasons given for changing empiric therapy of early onset sepsis was an increase in resistant organisms causing late onset sepsis). They didn’t show an adverse effects, but just wait a while! We should be focussing on giving fewer antibiotics, with narrower, appropriate, spectra, for shorter periods. And not giving them at all unless there is an indication.

Berardi A, Rossi C, Lugli L, Creti R, Bacchi Reggiani ML, Lanari M, Memo L, Pedna MF, Venturelli C, Perrone E et al: Group b streptococcus late-onset disease: 2003-2010. Pediatrics 2013, 131(2):e361-e368. An epidemiologic study from Italy of late onset GBS. Being preterm increased the risk, as we already know, there is a high incidence of serious brain lesions associated with late onset disease. If the mother had intrapartum antibiotics, the disease tended to be milder, and to present later.

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Leave my gut alone!

Posted on 5 February 2013 by Keith Barrington

Many things that we put in the intestines of preterm infants increase the risk of necrotising enterocolitis, including xanthan gum, kayexalate, and now, it seems, gastrografin.

A group from Vienna performed a masked RCT in 96 very low birth weight, preterm infants who were administered either 3 mL/kg of a hypertonic contrast agent (gastrografin) diluted 1:3 via the NG tube in the first 24 hours of life which they say gave 9 mL/kg of liquid, or the controls who got 9mL/kg of water. (Now I am not a mathematician, but I would have thought that 3 mL of gastrografin diluted 1:3 should give you 12 mL of liquid, not 9; I guess the authors and the reviewers aren’t mathematicians either!) Haiden N, Norooz F, Klebermass-Schrehof K, Horak AS, Jilma B, Berger A, Repa A: The effect of an osmotic contrast agent on complete meconium evacuation in preterm infants. Pediatrics 2012, 130(6):e1600-1606.

The idea behind this is that delayed meconium passage is associated with bad outcomes (delayed feeding intolerance, and in at least 1 study with NEC) and that therefore if you can speed up meconium clearance, maybe you can reduce those bad outcomes. The primary outcome of the study was time to clearance of meconium, which is rather questionable as an outcome of clinical significance. They also recorded other secondary outcomes, feeding tolerance, duration of hospital stay and NEC. The first thing to note is that they enrolled 96 babies out of 789 eligible infants, this immediately makes you wonder how representative the babies in the study were. The second thing to note is that the ‘intention to treat’ analysis showed no difference in anything. The only differences were in the ‘per protocol’ analysis (when they re-analyzed the data after excluding 18 infants with protocol violations) which showed a much shorter NICU stay in the gastrografin group, and some evidence of achieving full feeds faster. Here again there are some weird findings, the duration of hospital stay was as low as 4 days. So some babies in Vienna who weigh less than 1500 g at birth and are less than 32 weeks can go home in 4 days!! I don’t know how they do that. They are also clearly very fixated on stools, many of the babies in both groups also got glycerine suppositories, and in addition the babies averaged more than 1 enema each before discharge.

But most importantly, there were 8 cases of NEC in the gastrografin group vs 3 in the controls, and there were 5 NEC deaths in the gastrografin group. I would suggest that this is not a good thing to do!

Also just because slow clearance of stools might be associated with other signs of poor intestinal function and maybe with NEC, does not mean that enhancing meconium passage will improve feeding tolerance or NEC. The same authors have already investigated giving dilute glycerine enemas to their babies (Haiden N, Jilma B, Gerhold B, Klebermass K, Prusa AR, Kuhle S, Rohrmeister K, Kohlhauser-Vollmuth C, Pollak A: Small volume enemas do not accelerate meconium evacuation in very low birth weight infants. Journal of Pediatric Gastroenterology & Nutrition 2007, 44(2):270-273.), they gave the enemas every day until all the meconium was gone, and in the controls they left them alone. They showed no benefit of the intervention, even when they analyzed as ‘per protocol’ rather than intention to treat.

Which brings me back to the new study, why were the authors allowed to emphasize the non-ITT analysis in the abstract and to present this as a study showing decreased length of stay? In a small pilot study with a lot of exclusions, I am not averse to presenting a ‘per protocol’ analysis as a secondary suggestive analysis that might warrant a future study with more strict enforcement of a protocol. But the deviations from the protocol might well be a result of the intervention (indeed in this trial the exclusion was commonly because of vomiting after the large volume of fluid) so it is essential that the primary analysis which is presented is the intention to treat, only that way can a true estimate of the use of an intervention in the real world be estimated.

Finally a word about NEC prevention. I was surprised recently by an editorial in the Journal of Perinatology (Swanson JR: Necrotizing enterocolitis: Is it time for zero tolerance? J Perinatol 2013, 33(1):1-2) which made the following statement : ‘Experts have suggested that we could cut the incidence of NEC in half if neonatologists would just do four things: (1) practice as a group (instead of individuals), (2) promote breast-milk feeding and start it as trophic feeds early in life, (3) have a standardized feeding advance that is gestational age-based and (4) minimize the feeding intolerance episodes with liberal use of glycerin.’

A number of things bug me about this, first of all the ‘call to authority’ is not what we should be doing as scientists, secondly even if experts suggest this it had better be based on some evidence, which it clearly isn’t, and finally the reference given doesn’t even say these things! It NEVER mentions glycerin. (or indeed mentions working as a group rather than individuals, nor does it mention trophic feeds) Indeed the review article that the editorial references does refer to the data regarding having a feeding protocol and using more breast milk. It also neglects to mention the most effective intervention that we have for prevention of NEC: Probiotics.

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