Neonatal Research

One recent publication initially looked very interesting from the title, Vesoulis ZA, et al. Empirical estimation of the normative blood pressure in infants <28 weeks gestation using a massive data approach. J Perinatol. 2015. Unfortunately the authors interpretation of ‘massive data’ is to collect huge numbers of samples of blood pressure numbers from a very small number of babies. They initially included 62 infants in the study, but then excluded 17 owing to inotrope use, 6 due to high-grade intraventricular hemorrhage, and 4 because they died. Leaving 35 babies.

The authors seem inordinately proud of the fact that they had 11.9 million data points, but those data points are so numerous because they collected data every 2 seconds.

Just think if they had collected at 2 kHz instead they would have had 40 billion data points!! Maybe they would only have needed 10 babies, then they would still have had a billion data points.

Obviously collecting BP data from a very small number of babies is likely to mean that you won’t have the power to see any effects on BP of gestational age; eliminating all the babies who were treated with inotropes is likely to worsen this effect, as the babies with the lower blood pressures will be eliminated, so you are likely to be left among the most immature babies only those who had higher than average BP. Therefore it is not surprising that the authors state that GA and birth weight were not associated with BP.

Let’s get this straight, because a massive data approach, that is, analyzing BP data collected electronically from large numbers of babies, could actually be helpful. But it is the number of babies that is important, not how often you read the BP from the monitor.

A paper from Mark Mercurio and colleagues has been making some waves. In it they address the question of unilateral DNAR orders (previously called Do Not Resuscitate DNR orders, but now often referred to, more accurately as Do Not Attempt Resuscitation DNAR orders; as most extensive cardiac resuscitation attempts (CPR) fail, the ‘attempt’ is an important addition.)

The point made in the article is that there is no moral obligation to offer treatments that we know will not work. Therefore when we know something is truly futile we can unilaterally decide not to do it.

(There is another part of the arguments that I shall come back to).

In the neonatal period, once you are admitted to an NICU, the only babies for whom there is a reasonable chance of success of cardiac massage and advanced resuscitation are infants with arrhythmias. In general, neonatal CPR (after the delivery room) is indeed “physiologically futile”, it just doesn’t work. At least if by “success” we mean survival to discharge. But that is not the only definition of “success” that might be of value to a family. Sometimes we can get the circulation going temporarily again in order to allow time for an out-of-town family to arrive, sometimes we can give a family who aren’t yet ready to say goodbye a few more minutes. I think those can sometimes be reasonable indications for doing something that we don’t expect to lead to long-term survival, if we can assure that the infant isn’t suffering as a result.

Nonetheless CPR has also become somewhat of a ritual, and is seen by some families as showing that their child is valued, even though the chances of success are very poor, or even zero: the fact that it was tried show that we cared about their infant. Explaining the reality of the situation takes more time and effort than writing a unilateral DNAR, accompanying parents as their child dies is far more emotionally draining, and time consuming, than just writing DNAR and leaving the room.

I think also very important are the consequences of a unilateral DNAR, consequences other than not getting DNAR, once a DNAR order is written there is a tendency to not use other measures of intensive care, even if the intention is just to avoid cardiac massage, children with a DNAR order are less likely to be ventilated, less likely to receive other interventions which do have a chance of success, they are less likely to be closely monitored, and so on. So you can’t consider DNAR orders in a vacuum, something which is not really addressed in this article, but it should be made clear, just because cardiac massage is extremely unlikely to work for a patient doesn’t mean they shouldn’t get oxygen (for example). There is actually empirical evidence that this occurs, as well as personal experience.

I think that a DNAR order is often seen as short hand for, “we are giving up on this baby”, which is why there is this trickle down effect on other interventions.

Writing a DNAR order unilaterally is more of an indication of a lack of respect for the parents input, and the parents role and values.

I have written very few DNAR orders in the last few years, and then only after discussions with parents, more commonly, when an infant is deteriorating, it is important to take time to sit with the parents, explain what things might make a difference, explain those things that will not help, including sometimes, explicitly, cardiac massage. If a baby has a persistent pH less than 7 and there is no real prospect of improvement you can say to the parents, I’m so sorry but X (use their name!) is dying, would you like to hold him for a while? Depending on how you say that, you may not have to discuss cardiac massage at all, and accompanying parents while that all happens can often avoid any demands for further inappropriate therapy.

On the other hand I think that what Marc Mercurio is saying is mostly correct, that when we ‘know’ (as much as we ever know anything) that CPR will not work, there is no obligation to perform it. In other words, if I am certain that a baby who is deteriorating as a result of having profoundly underdeveloped lungs will not have any reasonable chance of successful return of circulation if the heart should stop and I initiate CPR, then I am not under a moral obligation to perform CPR. I do however, think I am under a moral obligation to explain that situation to the parents, if they ask for CPR.

What to do if at that point the parents ask “please doctor, at least give it a try, I still hope for a miracle”? Bill Meadow and John Lantos have advocated what they erroneously call a “slow-code”, what they advocate is complying with the parents wishes, but as there is no universal standard for content or duration of a code in the NICU, early termination of the CPR when there is no response to the first dose of epinephrine, would be medically and ethically appropriate. I agree with this, and indeed I have done it once or twice (in 30 years of practice), when parents can’t agree to forgo cardiac massage, then a real code (not a slow code) but a brief real code can respect the wishes of the parent without harming the child or the health care team.

You could also say that we don’t actually need a DNAR order, any more than we need a Do Not Attempt ECMO, or Do Not Attempt Hemo-Dialysis, I think though that Cardiac Massage is different, it has become part of the consciousness of the public. Partly as a result of movies and TV shows, it is expected that when the cardiac monitor alarm goes off, the code team will run into the room and start the resuscitation; it is that expectation that needs to be addressed.

There is one point in the article by Mercurio and others that gives me some concern, that is the meaning of the phrase “with the possible exception of the most extreme cases, (DNAR) should not be written based on quality of life prognosis”. “Extreme” is a term that will not be interpreted equally by everyone. I think that should be addressed somehow, a child who is irreversibly comatose, for example, could be so extreme that, even if they had an acute arrhythmia with a chance of successful immediate resuscitation, the option of not attempting resuscitation could be considered ethically valid; but to do so against the wishes of the parents? I would say that only if there is no opportunity to discuss it with the parents should that be considered, and usually in such a situation there hasn’t been enough time for reflection among the care team either.

The authors introduce a term that I wasn’t aware of, ‘dysthanasia’ the “exaggerated prolongation of agony, suffering, and death of the patient”, clearly something to be avoided, but can we make that definition before the patient actually dies? If we can avoid ‘agony’, and I think we almost always can these days, then we can avoid dysthanasia; and if the term only applies to those who die, then you can’t really use the term until afterwards, unless you are certain the baby is dying.

The reason that I said some waves were made by this article is that Mark has also recently been a co-author with the other co-author of this article, of a questionnaire study published last month. In that article the authors had asked neonatologists whether a unilateral DNR order was acceptable for ‘patients with no hope of survival’, or in another case where there was ‘serious concern about very profound intellectual disability’. Most respondents felt a unilateral DNAR order was acceptable in the first case, and very few in the second case. In the discussion they state this proviso:

However, there may be extreme examples of neurological disability, not covered by these vignettes, for which a unilateral DNAR order would be considered acceptable to many neonatologists and others. Current debate regarding resuscitation for patients with Trisomy 13 or 18 may, at least in part, be tied to this question.

I think the combination of these 2 articles has led to some people thinking that unilateral DNAR orders might be considered acceptable for babies with trisomy 13 or 18.

Certainly infants with T13-T8 should not be considered under the term, ‘dysthanasia’, the research of Annie Janvier, Barb Farlow, and Ben Wilfond has shown that parents think that their children with T13/T18 do have some more pain than others, but they are not in constant pain, and their quality of life is good to excellent, according to the parents. The babies also show some developmental progress, smiling, responding to their parents, letting their needs be known, see this table for example from the article by Janvier, Farlow and Wilfond, which shows the proportion of children with trisomy 13 and 18 at various ages who demonstrated the behaviour.

So to get back to the point of this long and rambling post, unilateral DNAR orders can usually be avoided, almost always should be avoided, and should certainly not be applied to babies with trisomies 13 or 18, or other babies with intellectual disability. I think writing a DNAR for a stable baby with a ‘quality of life’ issue against the parents wishes is really problematic, fortunately I have never had parents of a brain-dead child, or a child in a persistent vegetative state ask for CPR.

Neonatal research has now passed a total of 400,000 page views since it started, thanks to many people for their encouragement

My researchgate profile now shows over 5,000 citations of articles I have authored, or co-authored. Sometimes when you publish research you don’t know if anyone is going to read it, or take any notice of what you have worked on; It is  gratifying that almost everything I have published has at least one or two, and most over 20 citations, which might mean that people found them helpful, or at least they referenced them in order to criticize them! The most highly cited articles are joint endeavours; both position statements from AAP and CPS, and multi-center trials, which is as it should be.

My talk at the PAS meeting was live-tweeted! A first for me I think, thanks @TexasKidDoc

I recently wrote about the work from Newcastle in the UK about supporting parents who lose one of a pair of twins during the perinatal period. Nick Embleton wrote a comment about that post noting that they now have put some of their resources on-line.

Apart from stealing the title of their website from this blog, (they call it neonatalresearch.net, which is such an obscure name for a website about research in neonatology that I am sure they stole it from me) as I say, apart from that, there is a page about their project on the loss of one infant from a multiple birth which includes the guidelines they are developing. They also have a teaching pack available if you fill in a short survey.

Sehgal A, et al. Systemic arterial stiffness in infants with bronchopulmonary dysplasia: potential cause of systemic hypertension. J Perinatol. 2016.

Elevated systemic pressures are common in infants with moderate or severe BPD; why? Dr Sehgal and his colleagues performed vascular ultrasound in 20 preterm infants with BPD, 7 preterm infants without and 20 term controls. The differences in findings between preterms without BPD and term controls were minor; BP was higher in the babies with BPD, and in addition the aorta intima-media thickness was greater, the stiffness index was greater, and the calculated vascular resistance was higher.

Rao SC, et al. Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis. Pediatrics. 2016;137(3):1-16. Updated systematic review of the effects of probiotic supplementation, this time concentrating on systemic, late-onset sepsis. Probiotics were associated with a 14% reduction in sepsis. The very real previous concerns of the risks of feeding immuno-incompetent preterm babies with live organisms have not been confirmed quite the opposite.

The latest systematic literature search that they performed found now 37 RCTs enrolling over 9,400 babies. I wasn’t aware of 3 of the trials, and there are also 3 or 4 abstracts that I hadn’t seen.  The 3 fully published RCTs that were new to me are :

Tewari VV, et al. Bacillus clausii for Prevention of Late-onset Sepsis in Preterm Infants: A Randomized Controlled Trial. Journal of Tropical Pediatrics. 2015;61(5):377-85.
Van Niekerk E, et al. Probiotics Reduce Necrotizing Enterocolitis Severity in HIV-exposed Premature Infants. Journal of Tropical Pediatrics. 2015;61(3):155-64.

Totsu S, et al. Bifidobacterium and enteral feeding in preterm infants: Cluster-randomized trial. Pediatrics International. 2014;56(5):714-9.

The two from the Journal of Tropical Pediatrics are from India and South Africa respectively, and show positive results, the report from South Africa enrolled babies under 1250 g birthweight, and more than 50% of their mothers were HIV positive. 4/93 placebo babies developed definite NEC compared to 0/91 probiotic babies. There was an apparent reduction in severity of NEC in the HIV exposed babies. From the hospital in New Delhi 244 babies under 34 weeks were enrolled, the incidence of sepsis was relatively low, and slightly, but not significantly lower in the probiotic group (they had very few NEC, 2 in each group).

The Totsu trial was a cluster randomized trial in 19 tertiary NICUs in Japan who enrolled 283 VLBW infants. They had no NEC in either group(!) and significantly less late-onset sepsis with probiotics.

Mychaliska G, et al. Safety and efficacy of perflubron-induced lung growth in neonates with congenital diaphragmatic hernia: Results of a prospective randomized trial. Journal of Pediatric Surgery. 2015;50(7):1083-7. In a previous position I performed a couple of studies of partial liquid ventilation, which I found fascinating, and I hoped it might lead to a new approach to therapy in certain lung diseases, I though that meconium aspiration might be a good candidate disease, but that has become, in my practice at least, much less of  a problem, I think because of room air resuscitation, and more gentle neonatal care. After many years hiatus there is now some new work suggesting that in some babies, that is, babies with diaphragmatic hernia on ECMO, maybe there will be a role. You can make even normal lungs grow by introducing a distending pressure, and the weight of perfluorocarbons is such that they can stimulate lung growth.  A very attractive idea in babies with CDH. Sixteen babies were randomized to either receive partial liquid ventilation with a CPAP of 8 cmH2O while on ECMO, or to have PEEP at 8 cmH2O while on conventional ventilation. The protocol changed a couple of times during the study which makes the results, although interesting, difficult to really interpret. They measured the lung area of the hypoplastic lung on chest x-ray each day, and indeed the lungs did grow. Quite a lot. But the pulmonary hypertension was not any better. Which is disappointing to say the least. I don’t think this is the end of the liquid ventilation story, but it will be hard to think what to do next, how to make the lungs grow and at the same time to remodel their vasculature.

Osman M, et al. Assessment of pain during application of nasal-continuous positive airway pressure and heated, humidified high-flow nasal cannulae in preterm infants. J Perinatol. 2015;35(4):263-7.This was an observational study of PIPP (premature infant pain profile) scores during the initial application of respiratory support with either high flow cannulae (using a 2.4 mm binasal cannula) or CPAP using the INCA prongs. Pain scores were lower when applying the HFNC, and some of the scores in the CPAP group were quite high, 13% had scores over 12. Salivary cortisols also were higher in the CPAP babies.
Carnaghan H, et al. Effect of gestational age at birth on neonatal outcomes in gastroschisis. J Pediatr Surg. 2016.

Early birth of fetuses with gastroschisis was associated with delay in reaching full enteral feeds, prolonged hospitalization, and a higher incidence of sepsis.

No more to say about that.

van Vliet EO, et al. Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. Lancet. 2016.

Atosiban attacks the mechanism of uterine contraction, so it should be better than drugs which block all muscular activity. Or at least have fewer side effects in the mothers; taking lots of nifedipine is not very pleasant. Mothers in this study with threatened preterm labour were randomized; about 250 in each group. This publication is to me a model of a clinical RCT report. In addition to all the CONSORT guidelines there is a text box which includes information from a systematic review of the data before the study, describes the study and why they chose their primary outcome, reports their results and then updates the systematic review with their new data. After all that effort, there was no difference between groups in the composite neonatal morbidity outcome. Nor in delay of delivery of at least 48 hours, nor in the gestational age at eventual delivery, nor in serious adverse effects.

There was an incidence of 5% perinatal mortality in the nifedipine group and 2% in the atosiban group, which may have been due to chance, (RR 2·20 (95% CI 0·91–5·33)) but is enough of a difference that it should mandate further trials. Also, as mentioned above, nifedipine causes headaches, flushing and palpitations (in the mother of course), which may not be life-threatening, but can be quite unpleasant; atosiban, as far as I can see doesn’t usually do any of that; and that is enough for me to say that given our current state of knowledge atosiban should be pursued as a tocolytic agent. If you can get the same clinical outcomes with fewer very uncomfortable side effects, then it seems to me that the balance is on the side of atosiban.

The authors also note the following :

…worldwide nifedipine is not registered for use in pregnancy. This fact is of concern, especially since nifedipine is recommended as a first-line tocolytical drug in international guidelines.