Ventilating babies during resuscitation

Three recent-(ish) articles examining how we should ventilate babies and monitor what we are doing.

Milner A, Murthy V, Bhat P, Fox G, Campbell ME, Milner AD, et al. Evaluation of respiratory function monitoring at the resuscitation of prematurely born infants. Eur J Pediatr. 2014:1-4.

In this study, respiratory function monitoring with tidal volume, airway pressure and exhaled CO2 was routinely introduced in 2 London hospitals. The authors then asked trainees whether they found it useful, and what they thought the right tidal volume should be. As you might imagine the answers were quite variable, and integrating more than one sign, such as a lack of exhaled CO2 despite measured tidal volumes, was quite variable.

van Vonderen JJ, Hooper SB, Hummler HD, Lopriore E, Te Pas AB. Effects of a Sustained Inflation in Preterm Infants at Birth. The Journal of pediatrics. 2014.

Tony Milner was one of the authors of that previous article; many years ago he demonstrated that standard ventilation techniques led to an apparent ‘opening pressure’, where a substantial positive pressure was required to get air into the lungs, and that the end-expiratory volume of the lungs in the first few breaths remained very low. In contrast a long slow inflation (3 to 5 seconds) eliminated the opening pressure, in intubated babies, and led to establishment of an FRC. This new article used a pressure of 25 cmH2O and  duration of 10 seconds, delivered by face mask, but was unable to show the establishment of an FRC, unless the babies were breathing.

Murthy V, Creagh N, Peacock J, Fox G, Campbell M, Milner A, et al. Inflation times during resuscitation of preterm infants. Eur J Pediatr. 2012;171(5):843-6. This observational study during resuscitation, using the same respiratory function set up as in the first article, could not show that the variation in inflation times which occurred by chance during resuscitation (from 0.3 to 3 seconds) did not affect inspiratory flow duration.

Neil Finer reviews the current state of the art of prolonged inflations, his conclusion: ‘not ready for prime time’.

Schilleman K, Witlox RS, van Vonderen JJ, Roegholt E, Walther FJ, te Pas AB. Auditing documentation on delivery room management using video and physiological recordings. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. If you video record resuscitations, and then compare the tapes to what is actually written in the patients chart, this is what you get:

The clinical condition of the infant at birth was documented in 76% and 1 min Apgar scores in 98%. Respiratory support was correctly documented in 83%, heart rate in 37% and oxygen saturation in 13%. In 57% use of supplemental oxygen and its indication were correctly reported. Seven infants were intubated and this was correctly documented in 57%. Apgar scores were compared between the recordings and the medical records. At 1 min, 5 min and 10 min after birth the Apgar score, given by the researcher using the recordings, was similar to the scores in the medical records in 33%, 44% and 53%, respectively.

Hmmm.. maybe we need cameras everywhere and make the recordings part of the patients chart… or maybe not!

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Now Cross-Posting to 99NICU.org

Stefan Johansson, who runs the NICU website/community 99NICU.org asked if I would be interested in cross-posting my Neonatal Research posts in the blog section of their website.

I will post most of my musings over at their website as well, probably keeping the ‘not neonatology’ stuff here, and maybe some things when I am more critical.

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Appropriate outcomes for neonatal research

Neil Marlow has published a thoughtful, and thought provoking, article to address the issue outlined in the title. What are the appropriate outcomes when designing neonatal research studies?

It has become almost a rule, that a multi-center trial of an intervention in neonatology, especially if it is planning to enroll very preterm infants, has to have ‘survival without neurological or developmental disability’ as the primary outcome, with the ‘disability’ part measured at about 2 years.

There is some value to this outcome, very preterm infants have high mortality and high morbidity in those domains, infants who die cannot be developmentally delayed, so they are competing outcomes that need to be taken into account if we are trying to construct a dichotomous end-point. Like most things in trial design we have to make compromises, later follow up might be nice, but it will increase costs and increase drop-out rate; follow up to 2 years allows good retention rates, if you work hard at getting parents to return, but means you need to use developmental screening tools which are developed for very young infants.

There are however, numerous problems with this approach, which are discussed in this piece. (Marlow N. Is survival and neurodevelopmental impairment at 2 years of age the gold standard outcome for neonatal studies? Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014).

I also think we do need to rethink this approach for some of the following reasons (which overlap with the reasoning of Neil Marlow)

1 Developmental delay is not a dichotomous outcome. It is convenient for research planning to think of children either having impairment or not, but of course, developmental delay is a continuum, arbitrarily deciding that a Bayley score of 69 is delayed, but a score of 71 is not, misses all sorts of nuances in outcomes.

2. Developmental delay is not stable over time: many children labelled as delayed at 2 years have intellectual abilities in the long term that are close to, or above, average (in fact according to the work of Maureen Hack, 2/3 of them do). The improvement in developmental scores is correlated more closely with social advantages than to anything which occurs in the neonatal period.

3. Developmental delay has little or no influence of quality of life. Children with developmental delay can, and usually do, have an excellent QoL. If the purpose of your research project is to decided which therapies we should use in the future, then whether or not the therapy affects quality of life should be our main consideration, but as far as I know, no therapy has been shown to affect quality of life, apart from effects on quantity of life. In other words, surfactant for RDS increases quality of life, because more children are alive to have a life of good quality!

4. Very few neonatal preterm studies have ever shown an effect on neurological impairment or developmental delay. Of all the studies in the very preterm baby, which have actually been confirmed to reduce developmental delay? Maybe someone should do a systematic review to answer that question, of the top of my head there is Caffeine (at least when defined by developmental screening at 2 years, but not when examined at 5 years), and then there is… well that’s about it. So many of our decisions about which treatments are proven to be beneficial are really based on their impacts on survival, or on other morbidities, such as lung injury (another non-dichotomous outcome that we ‘dichotomize’ for facilitating compound outcomes).

5. Another important consideration is that the effect of an intervention on survival and on neurological or developmental outcomes may be in different directions. Which means that a trial might be ‘negative’ but still have important results that should change practice. I don’t know if this has happened for the outcome of survival and 2 year developmental screening test scores, but it is analogous to what SUPPORT showed. SUPPORT was a negative trial. The composite primary outcome (survival without severe retinopathy) was not affected by different saturation target ranges, because the impacts on the two components of the outcome were in opposite directions.

Neil Marlow includes a discussion of the TIPP trial, which showed a reduction in severe brain injury, a reduction in serious pulmonary hemorrhage, and a reduction in need for PDA ligation. But, the study did not show an overall improvement in  developmental outcomes with indomethacin prophylaxis compared to control. I think it was an excellent trial with reliable results, but because of the lack of improvement in the primary outcome it has discouraged the use of prophylactic indomethacin. However, there was a reduction in severe hemorrhage from 13 to 9%: if the only effect of indomethacin on the brain or on development was the reduction in IVH, and if the patients who had a severe IVH had an increase in neurodevelopmental ‘impairment'; then any benefit would only have been on those 4% who escaped IVH, and the impact on the scores of the groups as a whole would have been very small. This study was therefore grossly underpowered, in the sense that it would not be able to show that a reduction in severe IVH of that magnitude had an overall effect on the developmental scores of the entire group.

In their answer to an article which questioned why prophylactic indomethacin was not more widely used, De Mauro et al stated

” TIPP failed to demonstrate any long-term benefit of indomethacin prophylaxis, but the study also failed to prove the absence of long-term harm”

Which is true, but I would say it is not the whole story, because you could equally well say, ”TIPP failed to prove the absence of long term benefit, but the study also failed to demonstrate any long-term harm ”

A study with no statistically significant overall effect on developmental outcome always means that there is some possibility that developmental outcomes are actually improved, or actually harmed, depending on the range of the confidence intervals of the result. TIPP gives some confidence that developmental outcomes are not dramatically harmed by indomethacin, but there will also be a possibility that in reality there is some impact on development: the confidence intervals of the study result gives us a range within which we can say, with 95% confidence, the true difference in the means of the Bayley scores lie. Uncertainty has been reduced by doing the trial, it means it is likely that the true impact on the Odds of an infant (similar to those eligible for the trial) having a Bayley score below 70 are between an Odds ratio of 0.8 and 1.4 if they receive prophylactic indomethacin rather than not. Or, to put it in terms that I find easier to conceptualize, the risk of having a Bayley score below 70 is probably (with 95% confidence) between a 17% reduction and 29% increase in risk, if you get prophylactic indomethacin.

If most survivors of NICU do well (as they do) and almost all have a good quality of life (which they do) and the history of neonatal intensive care research has shown it is extremely difficult to demonstrate improved developmental outcomes at 2 years (as I discuss above); and developmental outcomes at later ages than that (when testing is more relevant for functional ability) have never been affected by a neonatal intervention, then maybe we should reconsider our outcomes. I think that trials should be designed and powered to examine effects on improving survival and other serious short term complications, such as severe cerebral hemorrhage, necrotizing enterocolitis and so forth, and that surveillance for other medium and long term outcomes, including developmental screening test scores, should be considered important for ensuring safety.

I also think we should be asking parents about these things. Is a reduction in severe brain hemorrhage an outcome that they think is important, even if we can’t prove an advantage in terms of Bayley scores?

Which is all very similar to what Neil Marlow says in his article. So he must be right.

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Upcoming Webinar

If you are on their mailing list you will have received the following notice:

Keith Barrington Oct. 22

Register today for our 2014-2015 Children’s Mercy Bioethics Center webinar series.

The focus this year is “Ethical Issues in Pediatric Clinical Research.” Our first webinar is Wednesday, Oct. 22 with Keith Barrington, MD. Dr. Barrington will discuss,

“More or Less: the Ethical Responsibilities of Clinical Researchers. ” 

Visit https://cmhbioethics.webex.com/ for registration information. 

I believe you can register for this wherever you are (I guess that’s a webinar!) and that it is without cost and without other obligations, you just need to register to get access.

I hope to be able to be stimulating and perhaps challenging.

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Probiotics prevent NEC in rats too!

Mark Underwood has been very active in the investigations of probiotics and their effects on the neonatal bowel. His new publication is a fascinating exploration of what happens in a rat model of NEC when they receive bifidobacterium infantis, also known as bifidobacterium longum subspecies infantis. (I don’t pretend to understand how bacteriologists decide if 2 strains are the same species or subspecies, it all seems somewhat arcane to me; I sort of get Gram stains but after that…).

One of the first good things about this study is the opening line of the abstract ‘

Probiotics decrease the risk of necrotising enterocolitis

No ifs, ands, or buts; I like it.

The introduction is a brief  resumé of the lines of evidence in animal models regarding the efficacy of probiotics for prevention of NEC.

The most promising preventative approaches to date include provision of human milk and probiotics (4,5). The observations that many Enterobacteriaceae out-compete commensal organisms in the inflamed intestine by utilizing an alternative respiratory pathway (6), together with the recent descriptions of a bloom of Enterobacteriaceae associated with NEC (7) shed new light on a possible central role of the intestinal microbiota in this disease.

The neonatal rat model of NEC is an invaluable experimental tool for examining the pathogenesis of NEC and potential mechanisms of protection (8,9,10). The strength of this model is its inclusion of stressors and enteral feeding, both of which are factors associated with human NEC. In the rat model, the stressors include separation from the dam, tube feeding, hypoxia, hypothermia, and enteral nourishment with bovine-based rat milk substitute (11).

Previous studies with this model have demonstrated a protective effect of probiotic Bifidobacterium bifidum with decreased NEC, decreased apoptosis, and decreased inflammation (8,9,10). Mouse and piglet studies have demonstrated alterations of the intestinal microbiota in NEC (12,13)

The references are all listed at the end of this post for those interested.

These investigators studied 3 groups of neonatal rats. They either got donor breast milk (that is they were fed by surrogate rat mummies) or they received artificial formula, or they received artificial formula and probiotics. The animals in the 3 groups were exposed to asphyxia and cold stress, 1 minute of breathing 100% nitrogen and 10 minutes of being put in the fridge (at 4 degrees). None of the breast-milk fed baby ratlings developed NEC, but 80% of the formula fed ones did. Giving B. infantis decreased this to about 36%. There was a decreased expression of a number of pro-inflammatory mediators in their intestines and less histologic injury also. Interestingly they weren’t able to find a lot of bifidobacteria in the caecum of the animals, or to note any consistent difference in the microbiomes between those which got bifidos and those which did not.

Apart from the demonstration of gut protection and NEC prevention and reduced inflammation with probiotics, this study also illustrates what we don’t yet understand about probiotics. In our work, which we haven’t yet finished analyzing to publish, in preterm babies who all received probiotics, only a tiny proportion of fecal organisms were the probiotics. Nevertheless they have clinical effects. Work like this new study will help us to understand, and eventually to select the most promising organisms for future clinical trials.

4. Underwood MA. Human milk for the premature infant. Pediatr Clin North Am2013;60:189207.

5. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010;125:92130.

6. Winter SE, Winter MG, Xavier MN, et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 2013;339:70811.

7. Mai V, Young CM, Ukhanova M, et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 2011;6:e20647.

8. Khailova L, Dvorak K, Arganbright KM, et al. Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol2009;297:G9409.

9. Khailova L, Mount Patrick SK, Arganbright KM, Halpern MD, Kinouchi T, Dvorak BBifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2010;299:G111827.

10. Underwood MA, Kananurak A, Coursodon CF, et al. Bifidobacterium bifidum in a rat model of necrotizing enterocolitis: antimicrobial peptide and protein responses. Pediatr Res2012;71:54651.

11. Dvorak K, Coursodon-Boyiddle CF, Snarrenberg CL, Kananurak A, Underwood MA, Dvorak B. Helicobacter hepaticus increases intestinal injury in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2013;305:G58592.

12. Carlisle EM, Poroyko V, Caplan MS, Alverdy JA, Liu D. Gram negative bacteria are associated with the early stages of necrotizing enterocolitis. PLoS One 2011;6:e18084.

13. Azcarate-Peril MA, Foster DM, Cadenas MB, et al. Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteria. Gut Microbes 2011;2:23443.

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The voice of Parents, now in print.

Katharina Staub and other parents have written and published an article in Acta Paediatrica. ‘ Our child is not just a gestational age‘.

In the NICU babies are often referred to by how many weeks they spent in the uterus, so X is a 24 weeker, Y is a 23 weeker, etc. Worse, decisions are made about whether or not to institute or continue life sustaining interventions based on estimates of completed weeks of gestational age, when other factors are just as important, and babies may not even be offered active intervention as a result of a sometimes very limited analysis; which gives an overwhelming influence to the estimated (or often, guesstimated) gestational age.

I have already discussed this article in a post, as it was already available on-line, but as it has now appeared in the print edition I thought I would give another mention to this article, one of too few which have really given a voice to parents.

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Can Paracetamol (acetaminophen) close the ductus arteriosus?

A new publication by Afif El-Khuffash and his colleagues (El-Khuffash A et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res. 2014;76(3):238-44) describes a retrospective review of paracetamol use in newborn infants, and an in vitro study using mouse ductal tissue. The clinical part of the paper shows that with a short course of oral paracetamol there was no response, with a longer course of oral paracetamol there were some responses, and with intravenous paracetamol for between 2 and 6 days there were many PDA closures, and others that tended to constrict. The numbers are very small but suggestive.

Afif also reports the effects of paracetamol and indomethacin on preterm and term mouse ductal tissue. Paracetamol had no effect on the preterm, and lesser effect on the term, compared to indomethacin. With high enough concentrations of paracetamol there were indeed constrictive responses to paracetamol.

This all suggests that it is indeed possible that paracetamol might be effective. But I won’t be expecting miraculous results.

This is also the suggestion of an article from Israel (Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol. 2014;34(10):748-9), 7 extremely preterm infants with large PDA were treated, they either had failed ibuprofen or had a contra-indication. Most closed without surgery. Again suggestive but no more than that.

Presumably there are placebo controlled trials coming, I hope so.

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