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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Nurses matter!

Posted on 4 February 2013 by Keith Barrington

There are a lot of qualitative studies that make huge generalizations from the very tiniest of samples; on the other hand, some studies of values and wishes of parents and patients can be valuable, and can be well studied only with qualitative techniques.  One example of the latter is a new study from 3 centers in France. (Guillaume S, Michelin N, Amrani E, Benier B, Durrmeyer X, Lescure S, Bony C, Danan C, Baud O, Jarreau P-H et al: Parents’ expectations of staff in the early bonding process with their premature babies in the intensive care setting: A qualitative multicenter study with 60 parents. BMC Pediatrics 2013, 13(1):18.) They interviewed 30 mothers and 30 fathers with very preterm babies in NICU. It is worth a read (freely available on BMC Pediatrics) and I will quote in its entirety the conclusion section of the abstract:

‘At birth and during the first weeks in the NICU, the creation of a bond between mothers and fathers and their premature baby is rooted in their relationship with the caregivers. Nurses’ caring attitude and regular communication adapted to specific needs are perceived by parents as necessary preconditions for parents’ interaction and development of a bond with their baby. These results might allow NICU staff to provide better support to parents and facilitate the emergence of a feeling of parenthood.’

Another study points out the importance of nurses attitudes to what happens in the NICU and to parental experiences. A US study, from an urban center, questioned nurses and mothers about things like whether parents should participate in care of the baby and whether they should be encouraged to be present and to do kangaroo care. (Hendricks-Munoz KD, Li Y, Kim YS, Prendergast CC, Mayers R, Louie M: Maternal and neonatal nurse perceived value of kangaroo mother care and maternal care partnership in the neonatal intensive care unit. American journal of perinatology 2013(EFirst).) I was very surprised by the results. Only 21% of nurses strongly agreed that parents should be encouraged to be present in the NICU, and only 67% of mothers! Knowledge and attitudes towards Kangaroo Care were also poor, and differed greatly between nurses and mothers. The authors identified many barriers to creation of maternal care partnerships that need to be overcome.

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Preventing Stillbirth

Posted on 4 February 2013 by Keith Barrington

A new observational study looking at the causes of Stillbirth in the UK (Gardosi J, Madurasinghe V, Williams M, Malik A, Francis A: Maternal and fetal risk factors for stillbirth: Population based study. BMJ 2013, 346:f108.) identifies potentially modifiable factors that were associated with stillbirth after 24 weeks; they were maternal obesity, smoking, and most importantly intra-uterine growth restriction. ‘195 of the 389 stillbirths in this cohort had fetal growth restriction, but in 160 (82%) it had not been detected antenatally.’

One of the reasons for the increase in prematurity in the developed world is an increase in medical indicated preterm deliveries, many of which are for concerns about fetal status. It looks like there is still much to do, to accurately screen and diagnose fetal growth restriction and develop strategies to avoid stillbirth, and do this without further increasing prematurity rates.

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Iron therapy for anemia of the preterm; now I’m confused!

Posted on 29 January 2013 by Keith Barrington

I thought I knew, sort of, what to do about iron supplementation in the preterm. Preterm babies outgrew their iron supply, there isn’t very much in breast milk, and you need to supplement to minimize the appearance of anemia of prematurity.

There was previously a trial which compared transfusions and iron status among 204 preterm infants (<1300g birth weight) who were randomized to start iron as soon as they were tolerating 100 mL/kg/d of milk, or to wait until they reached 61 days. The babies received 2 mg/kg/d at first and it was increased to 4 if the hematocrit was below 30. That trial showed fewer transfusions and less iron deficiency with early supplementation. They also published long term follow up, although not powered for that outcome, the 164 babies who were studied (most, 85%, of the survivors) tended to have better outcome in the early group.

There is also a Cochrane review showing improved hematocrits with routine enteral iron prophylaxis in the preterm.

Now a new trial has been published which compared giving 2 mg/kg/day of iron, started when the babies were tolerating 120 mL/kg/d of milk, to a multivitamin preparation without iron. The babies were 150 VLBW (<1500g) infants and the primary outcome was hematocrit at 36 weeks, transfusions were also noted. They note that the control group were receiving around 2 mg/kg/d already in the breast milk fortifier that they were adding to the breast milk. There were no differences in the results between the groups. The authors note that they have a ‘liberal’ transfusion policy, which they say is based on the previous evidence regarding ‘long-term benefits of maintaining higher hemoglobin levels in extremely low birth weight (<1000 g birth weight) infants’. What they don’t tell us is how many transfusions the infants received prior to entering the study. That info would have been helpful: a blood transfusion or two would have given substantial amounts of iron to the babies, and could be a reason for not finding a difference between the groups. that would make it less easy to extrapolate the findings to other NICUs, such as ours, where we have not liberalized our transfusion guidelines.

And just how good is that data about long term benefits of liberal transfusion? Although the authors reference the PINT trial and the Cochrane review, neither of those sources show an improved long term outcome! The PINT study showed slightly better 18 month Bayley scores, differences consistent with chance, p value about 0.09, and only when they looked at the proportion of babies less than 85 (not 70 which was pre-specified as the outcome of interest) did they show a difference that looked more convincing. The other trial that has reported some long term outcomes was the trial by Ed Bell and others, who followed only 56 of their 100 patients to early school age, and some measures of cognitive function were better in the liberal transfusion compared to the conservative group.

In summary I do think it seems possible that some outcomes are better with a higher transfusion threshold, but it certainly isn’t definite, and before using a lot more blood transfusions we should get better data. There are other trials in the works.

In the meantime, with a more restrictive transfusion policy, I think continuing to give iron supplementation early, in addition to what we have in the breast milk fortifier still makes sense.

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Not only Neonatology

Posted on 26 January 2013 by Keith Barrington

I really appreciate the writings of Atul Gawande, his articles and his books: ‘Complications’ ‘Better’ and ‘The checklist manifesto’.

I just saw a TED talk he gave in March last year, 19 minutes on how to fix medicine. Link here. I think a lot of his ideas can be used in the NICU, and the very complex care that we sometimes give there.

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Helping Babies Breathe is a Really Good Idea

Posted on 24 January 2013 by Keith Barrington

Two new articles showing that ‘Helping Babies Breathe‘ training really works.

Msemo G, Massawe A, Mmbando D, Rusibamayila N, Manji K, Kidanto HL, Mwizamuholya D, Ringia P, Ersdal HL, Perlman J: Newborn mortality and fresh stillbirth rates in tanzania after helping babies breathe training. Pediatrics 2013.

Goudar SS, Somannavar MS, Clark R, Lockyer JM, Revankar AP, Fidler HM, Sloan NL, Niermeyer S, Keenan WJ, Singhal N: Stillbirth and newborn mortality in india after helping babies breathe training. Pediatrics 2013.

Both used a before and after design, and both showed that stillbirth rates were lower after the HBB training. That may seem strange at first, how could stillbirths be reduced? Of course the answer is that after training, the health workers realize that some babies that were classified as stillbirths previously (either there wasn’t an attempt to resuscitate them or after a failed resuscitation they were called a stillbirth) are now being successfully resuscitated.

Wally Carlo has already shown that the infants who are resuscitated do well in the long run, in a study using a very similar resuscitation program, those babies who received assisted ventilation at birth had long term outcomes the same as the comparison group who had not resuscitation.

 

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